When Prevention Fails: Obesity Treatment Strategies

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THE AMERICAN JOURNAL of MEDICINE

April 2009 Volume 122 Number 4A

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The Obesity Epidemic: Strategies in Reducing Cardiometabolic Risk GUEST EDITORS: Louis J. Aronne, MD Clinical Professor of Medicine Weill Cornell Medical College Director The Comprehensive Weight Control Program New York-Presbyterian Hospital New York, New York Stephen Havas, MD, MPH, MS Former Vice President Science, Quality, and Public Health American Medical Association Chicago, Illinois

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THE AMERICAN JOURNAL of MEDICINE ®

April 2009 Volume 122 Number 4A

The Obesity Epidemic: Strategies in Reducing Cardiometabolic Risk GUEST EDITORS Louis J. Aronne, MD Clinical Professor of Medicine Weill Cornell Medical College Director The Comprehensive Weight Control Program New York-Presbyterian Hospital New York, New York Stephen Havas, MD, MPH, MS Former Vice President Science, Quality, and Public Health American Medical Association Chicago, Illinois This supplement is supported by an educational grant from sanofi-aventis Pharmaceuticals, Inc. Editorial support by IMED Communications, Califon, New Jersey. Statement of Peer Review: All supplement manuscripts submitted to The American Journal of Medicine for publication are reviewed by the Guest Editor(s) of the supplement, by an outside peer reviewer who is independent of the supplement project, and by the Journal’s Supplement Editor (who ensures that questions raised in peer review have been addressed appropriately and that the supplement has an educational focus that is of interest to our readership). Author Disclosure Policy: All authors contributing to supplements in The American Journal of Medicine are required to fully disclose any primary financial relationship with a company that has a direct fiscal or financial interest in the subject matter or products discussed in the submitted manuscripts, or with a company that produces a competing product. These relationships (e.g., ownership of stock or significant honoraria or consulting fees) and any direct support of research by a commercial company must be indicated on the title page of each manuscript. This information will be published in the frontmatter of each supplement. Editor-in-Chief: Joseph S. Alpert, MD Executive Supplements Editor: Brian Jenkins Editor, Supplements: William H. Frishman, MD Senior Production Editor: Mickey Kramer Publishing Director: Pamela Poppalardo

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THE AMERICAN JOURNAL of MEDICINE ®

April 2009 Volume 122 Number 4A

The Obesity Epidemic: Strategies in Reducing Cardiometabolic Risk S1

Introduction Stephen Havas, Louis J. Aronne, and Kristina A. Woodworth

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Obesity: Why Be Concerned? W. Virgil Brown, Ken Fujioka, Peter W. F. Wilson, and Kristina A. Woodworth

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Regulation of Energy Homeostasis and Health Consequences in Obesity Judith Korner, Stephen C. Woods, and Kristina A. Woodworth

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Obesity Prevention: Recommended Strategies and Challenges Anne M. Wolf and Kristina A. Woodworth

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When Prevention Fails: Obesity Treatment Strategies Louis J. Aronne, Thomas Wadden, Kathy Keenan Isoldi, and Kristina A. Woodworth

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An Obesity/Cardiometabolic Risk Reduction Disease Management Program: A Population-Based Approach Victor G. Villagra

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CME Section

The Obesity Epidemic: Strategies in Reducing Cardiometabolic Risk

Guest Editors Louis J. Aronne, MD Clinical Professor of Medicine Weill Cornell Medical College Director The Comprehensive Weight Control Program New York-Presbyterian Hospital New York, New York

Stephen Havas, MD, MPH, MS Former Vice President, Science, Quality, and Public Health American Medical Association Chicago, Illinois

Faculty W. Virgil Brown, MD Charles Howard Candler Professor Emory University School of Medicine Atlanta, Georgia Ken Fujioka, MD Director, Nutrition and Metabolic Research Director, Center for Weight Management Scripps Clinic San Diego, California Kathy Keenan Isoldi, MS, RD, CDE Coordinator, Clinical Nutrition Services The Comprehensive Weight Control Program New York-Presbyterian Hospital New York, New York Judith Korner, MD, PhD Assistant Professor of Clinical Medicine Columbia University Director, Weight Control Center Columbia University Medical Center New York, New York Bruce S. Pyenson, FSA, MAAA Member of the Healthcare Financial Management Association Principal and Consulting Actuary Milliam Consultants and Actuaries New York, New York

Victor G. Villagra, MD Assistant Clinical Professor Department of Medicine University of Connecticut President, Health & Technology Vector, Inc. Farmington, Connecticut Thomas A. Wadden, PhD Professor of Psychology University of Pennsylvania School of Medicine Director, Center for Weight and Eating Disorders University of Pennsylvania Philadelphia, Pennsylvania Peter W. F. Wilson, MD Professor of Medicine Emory University School of Medicine Atlanta, Georgia Anne M. Wolf, RD, MS Instructor of Research University of Virginia School of Medicine Charlottesville, Virginia Stephen C. Woods, PhD Professor of Psychiatry Director, Obesity Research Center University of Cincinnati Cincinnati, Ohio

Discussants Earl S. Ford, MD, MPH Medical Officer Centers for Disease Control and Prevention Atlanta, Georgia William Griffith Director of Marketing National Minority Health Month Foundation Washington, DC Van S. Hubbard, MD, PhD Rear Admiral, US Public Health Service Director, NIH Division of Nutritional Research Coordination National Institutes of Health Senior Advisor to the Secretary on Obesity Department of Health and Human Services Bethesda, Maryland

Medical Writer Kristina A. Woodworth SciMantis Communications, Inc. Pen Argyl, Pennsylvania

Mark S. Johnson, MD, MPH New Jersey Chapter of the American Academy of Family Physicians Chairman and Professor of Family Medicine UMDNJ-New Jersey Medical School Newark, New Jersey

Wahida Karmally, DrPH, RD, CDE American Dietetic Association Associate Research Scientist and Director of Nutrition Irving Center for Clinical Research Columbia University New York, New York

Faculty Disclosures Faculty are expected to disclose to the program audience any real or apparent conflict(s) of interest related to the content of their presentation(s). The information presented represents the views and opinions of the individual authors and does not constitute the opinion or endorsement of, or promotion by, the American Medical Association, IMED Communications, or sanofiaventis Pharmaceuticals, Inc. Reasonable efforts have been made to present educational subject matter in a balanced, unbiased fashion and in compliance with regulatory requirements. The participant must always use his or her own personal and professional judgment when considering further application of this information, particularly as it may relate to patient diagnostic or treatment decisions including, without limitation, US Food and Drug Administration–approved uses and any off-label uses.

Louis J. Aronne, MD, has received financial support for research from Amylin Pharmaceuticals, Inc, GlaxoSmithKline, Medtronic, Inc, Merck & Co, Inc, Obecure Ltd, Orexigen Therapeutics, Inc, Pfizer Inc, sanofi-aventis Pharmaceuticals, Inc, and Transneuronix, Inc; is a consultant for Manhattan Pharmaceuticals, Inc, Metabolic Therapeutics, Inc, and sanofi-aventis Pharmaceuticals, Inc; is a member of a Speakers’ Bureau for Pfizer Inc and sanofi-aventis Pharmaceuticals, Inc; and has received grant support or consulted for Arena Pharmaceuticals, Inc, GI Dynamics, Johnson & Johnson, Novo Nordisk, TransTech Pharma, Inc, and Vivus Inc. W. Virgil Brown, MD, is a consultant for Abbott Laboratories, AstraZeneca, AtherGenics, Inc, Bayer, Bristol-Myers Squibb Company, Merck & Co, Inc, Pfizer Inc, Reliant Pharmaceuticals, Inc, Daiichi Sankyo Co, Ltd, and Schering-Plough Corporation; is a speaker and advisory committee member for Abbott Laboratories, AstraZeneca, Merck & Co, Inc, Pfizer Inc, and Schering-Plough Corporation; and has received grant research support from Abbott Laboratories, AstraZeneca, Eli Lilly and Company, Kos Pharmaceuticals, Inc, Merck & Co, Inc, Pfizer Inc, Schering-Plough Corporation, and Takeda Pharmaceuticals North America, Inc. Earl S. Ford, MD, MPH, has no relevant financial relationships with a commercial entity producing healthcare-related products and/or services. Ken Fujioka, MD, has disclosed that the commercial entities with which he has relationships do not produce healthcarerelated products or services relevant to the content he is planning, developing, or presenting for this activity. William Griffith has no relevant financial relationships with a commercial entity producing healthcare-related products and/or services. Stephen Havas, MD, MPH, MS, has no relevant financial relationships with a commercial entity producing healthcarerelated products and/or services. Van S. Hubbard, MD, PhD, has no relevant financial relationships with a commercial entity producing healthcare-related products and/or services. Kathy Keenan Isoldi, MS, RD, CDE, has no relevant financial relationships with a commercial entity producing healthcarerelated products and/or services. Mark S. Johnson, MD, MPH, has no relevant financial relationships with a commercial entity producing healthcare-related products and/or services. Wahida Karmally, DrPH, RD, CDE, has no relevant financial relationships with a commercial entity producing healthcarerelated products and/or services. Judith Korner, MD, PhD, is a consultant for GlaxoSmithKline and a paid speaker for Merck & Co, Inc, and sanofi-aventis Pharmaceuticals, Inc.

Bruce S. Pyenson, FSA, MAAA, is a consultant for Amylin Pharmaceuticals, Inc, APS Healthcare, Inc, GlaxoSmithKline, Matria Healthcare, Novartis, Pfizer Inc, and numerous insurers, employers, and health maintenance organizations. Victor G. Villagra, MD, is a member of the Board of Directors of Genomas Inc, a consultant for Healthways, Inc, and sanofi-aventis Pharmaceuticals, Inc, and an independent contractor for the Disease Management Association of America. Thomas A. Wadden, PhD, is a consultant for Abbott Laboratories. Peter W. F. Wilson, MD, has received grant support from GlaxoSmithKline, sanofi-aventis Pharmaceuticals, Inc, and Wyeth. Anne M. Wolf, RD, MS, has disclosed that the commercial entities with which she has relationships do not produce healthcare-related products or services relevant to the content she is planning, developing, or presenting for this activity. Stephen C. Woods, PhD, is a consultant and paid speaker for sanofi-aventis Pharmaceuticals, Inc. Kristina A. Woodworth has no relevant financial relationships with a commercial entity producing healthcare-related products and/or services.

CME INFORMATION The Obesity Epidemic: Strategies in Reducing Cardiometabolic Risk Target Audience Primary care physicians

Educational Objectives Upon completion of this activity, the participant should be able to: ● Describe the impact of obesity on public health, resource utilization, healthcare expenditures and mortality risk, and quality of life. ● Recognize the role of adipose tissue as an endocrine organ and the effect that alterations in energy homeostasis may have on fat storage and function. ● Discuss the endogenous endocannabinoid system and its effect on energy balance, fat storage, and the adipose endocrine system. ● Identify effective strategies at the disposal of primary care clinicians for recognizing patients at risk of cardiovascular and metabolic disease. ● Specify current and future options, including behavioral and pharmacologic strategies, to reduce risk factors for cardiovascular and metabolic disease in the community setting.

Accreditation Statement The American Medical Association is accredited by the Accreditation Council for Continuing Medical Education to provide continuing medical education for physicians.

Designation Statement The American Medical Association designates this educational activity for a maximum of 4.0 AMA PRA Category 1 Credits™. Physicians should only claim credit commensurate with the extent of their participation in the activity. To receive AMA PRA Category 1 Credits™ for your participation in this educational activity, you must read the supplement and complete both the posttest and the evaluation form.

Release Date: April 2009 Expiration Date: No credit will be given after April 30, 2010

Supplement issue

Introduction The problem of obesity in the United States has become increasingly prominent and is now recognized as a critical target for public health intervention. Obesity rates have increased from 13.4% of the American population in 1960 to 30.9% in 2000.1 Although the actual number of overweight or obese individuals in the United States has been debated, one analysis estimates that 66% of Americans are overweight or obese (body mass index [BMI] ⱖ25).2 Public health advocates are now beginning to signal a call to action. For example, the Robert Wood Johnson Foundation is devoting $500 million in funds to combat childhood obesity and its potential for lasting impact in adults of the next generation, with a goal of reversing the obesity epidemic in American children by 2015.3 A multidisciplinary panel of experts with experience in cardiometabolic risk convened recently to review the evolving literature; discuss current clinical practice issues as they relate to diagnosis, treatment, and prevention; and evaluate new options for treatment of obesity. Select faculty elected to develop articles based on these discussions with the intent of providing clinicians with valuable information to make informed decisions within their practice. These contributions form the basis for the articles in this supplement to The American Journal of Medicine. In the first article, Dr. W. Virgil Brown and colleagues highlight the seriousness of the obesity epidemic by examining the wide array of health risks that can accompany overweight and obesity, potentially leading to mortality and morbidity. Obesity can have detrimental health effects on almost every major organ system, the most prominent impact being the increased risk for cardiovascular disease and type 2 diabetes mellitus related to hypertension, dyslipidemia, and insulin resistance.4 Moreover, obesity has been linked to an increased risk for certain cancers in both men and women.5,6 The increased morbidity and early mortality from these health risks can have a far-reaching impact on the healthcare system in terms of resources and costs. The potential for early mortality from obesity was made strik-

Statement of author disclosure: Please see the Author Disclosures section at the end of this article. Requests for reprints should be addressed to Louis J. Aronne, MD, Weill Cornell Medical College, Comprehensive Weight Control Program, New York-Presbyterian Hospital, 1165 York Avenue, New York, New York 10028. E-mail address: [email protected]

0002-9343/$ -see front matter © 2009 Published by Elsevier Inc. doi:10.1016/j.amjmed.2009.01.001

ingly clear in an analysis concluding that the gains in life expectancy achieved in the US population during the 20th century could level off or decline if current obesity rates are not reversed.7 Concern exists that the correlations between BMI, an indirect measure of overweight and obesity, and certain health outcomes, particularly mortality, have been inconsistent. However, the inconsistencies may reflect, in part, inadequate control of confounding variables or improved treatment of comorbid conditions in overweight and obese individuals. In addition, risk of adverse health outcomes associated with both BMI and waist circumference, including mortality, varies with age, sex, race/ ethnicity, and socioeconomic status, and may reflect population-specific differences in body composition, fat distribution, causes of overweight, and genetic susceptibility. Although BMI remains a useful screening tool to assess a patient’s overall disease risk in association with weight, clinicians should recognize that additional assessment tools, including waist circumference and waistto-hip ratio, are available to help develop a better picture of global health risk in patients evaluated for overweight and obesity. It is critical to understand that the available obesity assessment tools are indirect measures of body fatness, as reflected by the continuing controversy in identifying the best instrument to predict different health risks related to excess weight. Ultimately, clinicians should take into account an individual’s global health and lifestyle, including the presence of other diseases, other disease risk factors, and family history, when considering a person’s overall disease risk. As discussed in the second article, by Dr. Judith Korner and colleagues, the importance of obesity as a medical issue, and not just a matter of cosmetics or lifestyle choice, has resulted in a research impetus to identify the underlying mechanisms of energy homeostasis and obesity. These investigations have uncovered important neuroendocrine pathways that regulate food intake at each meal, energy expenditure, and fat storage. An important finding in these investigations has been the endocrine function of adipose tissue in releasing hormones that regulate energy homeostasis.8-10 Moreover, detrimental inflammatory endocrine effects of adipose tissue are accentuated in obesity, which is likely a contributing factor to the cardiometabolic risk demonstrated with excess body weight.11-15

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The American Journal of Medicine, Vol 122, No 4A, April 2009

Large-scale prevention strategies have been proposed in light of the current obesity epidemic. Systematic reviews performed by an independent Task Force on Community Preventive Services that are summarized in the Centers for Disease Control and Prevention’s (CDC) Guide to Community Preventive Services stress that available literature supports the value of school-based and workplace interventions to combat obesity, such as providing nutritional counseling and opportunities for exercise.16,17 Nevertheless, current obesity prevention efforts are often undermined by a toxic food environment of convenience food portions that have been increasing in size, a higher percentage of meals eaten outside of the home, a high consumption of sugar-based drinks, and higher levels of dietary sodium in the diet that increase thirst and the consumption of these high-calorie drinks.18-21 Dietitian Anne M. Wolf and Kristina A. Woodworth present a review of strategies for obesity prevention, including the need for more effective community-wide intervention programs. Effective prevention and treatment strategies are clearly needed to stem the tide of potential health complications related to the obesity epidemic. Although lifestyle interventions, behavioral therapy, and pharmacotherapy have all demonstrated the ability to achieve the modest weight loss that can mitigate many of the health risks of obesity,22,23 long-term weight maintenance is still elusive for many individuals. New pharmacotherapeutic strategies are being assessed for their ability to contribute to lasting weight loss in obesity. As discussed in the fourth article, by Dr. Louis J. Aronne and coworkers, a combination approach that incorporates all of these interventions may be the most successful available approach to long-term weight loss in obesity.24,25 Current efforts to highlight the health risks of obesity should emphasize the importance of making these treatment strategies more accessible to a greater number of individuals affected by obesity. In the final article, Dr. Victor G. Villagra explains how designing comprehensive obesity and cardiometabolic risk reduction disease management programs using a chronic care model can overcome individual and healthcare system barriers, resulting in a wider adoption of evidence-based treatments. Because clinicians encounter higher rates of overweight and obesity in daily practice, the increased risks of excessive body weight and the beneficial health effects of even modest decreases in weight mitigating these risks must be brought to the forefront of medical care. Obesity must be recognized as a critical health issue. It is hoped that the topics addressed in this supplement will assist clinicians and other health professionals by highlighting some of the most important current issues in obesity and lifelong healthy weight management. Stephen Havas, MD, MPH, MS Formerly with the Division of Science, Quality, and Public Health American Medical Association Chicago, Illinois, USA

Louis J. Aronne, MD Department of Medicine Weill Cornell Medical College The Comprehensive Weight Control Program New York-Presbyterian Hospital New York, New York, USA

Kristina A. Woodworth SciMantis Communications, Inc Pen Argyl, Pennsylvania, USA

AUTHOR DISCLOSURES The authors who contributed to this article have disclosed the following industry relationships: Stephen Havas, MD, MPH, MS, has no relevant financial relationships with a commercial entity producing healthcare-related products and/or services. Louis J. Aronne, MD, has received financial support for research from Amylin Pharmaceuticals, Inc, GlaxoSmithKline, Medtronic, Inc, Merck & Co, Inc, Obecure Ltd, Orexigen Therapeutics, Inc, Pfizer Inc, sanofi-aventis Pharmaceuticals, Inc, and Transneuronix, Inc; is a consultant for Manhattan Pharmaceuticals, Inc, Metabolic Therapeutics, Inc, and sanofi-aventis Pharmaceuticals, Inc; is a member of a Speakers’ Bureau for Pfizer Inc and sanofiaventis Pharmaceuticals Inc; and has received grant support or consulted for Arena Pharmaceuticals, Inc, GI Dynamics, Johnson & Johnson, Novo Nordisk, TransTech Pharma, Inc, and Vivus Inc. Kristina A. Woodworth has no relevant financial relationships with a commercial entity producing healthcarerelated products and/or services.

References 1. Flegal KM, Carroll MD, Ogden CL, Johnson CL. Prevalence and trends in obesity among US adults, 1999-2000. JAMA. 2002;288:1723-1727. 2. Ogden CL, Carroll MD, Curtin LR, McDowell MA, Tabak CJ, Flegal KM. Prevalence of overweight and obesity in the United States, 19992004. JAMA. 2006;295:1549-1555. 3. Robert Wood Johnson Foundation Announces $500-Million Commitment to Reverse Childhood Obesity in US [press release]. Princeton, NJ: Robert Wood Johnson Foundation, April 4, 2007. Available at: http://www.rwjf.org/newsroom/product.jsp?id⫽21938. Accessed December 14, 2008. 4. National Heart, Lung, and Blood Institute (NHLBI). The Practical Guide: Identification, Evaluation, and Treatment of Overweight and Obesity in Adults. Bethesda, MD: National Heart, Lung, and Blood Institute, National Institutes of Health, Dept of Health and Human Services, October 2000. NIH Publication No. 00-4084. 5. Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of US adults. N Engl J Med. 2003;348:1625-1638. 6. Lukanova A, Bjor O, Kaaks R, et al. Body mass index and cancer: results from the Northern Sweden Health and Disease Cohort. Int J Cancer. 2006;118:458-466. 7. Olshansky SJ, Passaro DJ, Hershow RC, et al. A potential decline in life expectancy in the United States in the 21st century. N Engl J Med. 2005;352:1138-1145. 8. Schwartz MW, Woods SC, Porte D Jr, Seeley RJ, Baskin DG. Central nervous system control of food intake. Nature. 2000;404:661-671.

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9. Marx J. Cellular warriors at the battle of the bulge. Science. 2003;299: 846-849. 10. Korner J, Aronne LJ. The emerging science of body weight regulation and its impact on obesity treatment. J Clin Invest. 2003;111:565-570. 11. Marette A. Mediators of cytokine-induced insulin resistance in obesity and other inflammatory settings. Curr Opin Clin Nutr Metab Care. 2002;5:377-383. 12. Lyon CJ, Law RE, Hsueh WA. Minireview: adiposity, inflammation, and atherogenesis. Endocrinology. 2003;144:2195-2200. 13. Trayhurn P, Wood IS. Adipokines: inflammation and the pleiotropic role of white adipose tissue. Br J Nutr. 2004;92:347-355. 14. Steinberg HO, Baron AD. Vascular function, insulin resistance and fatty acids. Diabetologia. 2002;45:623-634. 15. Caballero AE. Endothelial dysfunction in obesity and insulin resistance: a road to diabetes and heart disease. Obes Res. 2003;11:1278-1289. 16. Centers for Disease Control and Prevention (CDC). Guide to Community Preventive Services (Community Guide). [CDC Website.] Available at: http://www.thecommunityguide.org/obese/default.htm. Accessed April 10, 2007. 17. Katz DL, O’Connell M, Yeh MC, et al, for the Task Force on Community Preventive Services. Public health strategies for preventing and controlling overweight and obesity in school and worksite settings. MMWR Recomm Rep. 2005;54:1-12. Available at: http://www.cdc.gov/ mmwr/preview/mmwrhtml/rr5410a1.htm. Accessed April 20, 2007.

S3 18. Rolls BJ, Morris EL, Roe LS. Portion size of food affects energy intake in normal-weight and overweight men and women. Am J Clin Nutr. 2002;76:1207-1213. 19. Rolls BJ, Kim S, Fedoroff IC. Effects of drinks sweetened with sucrose or aspartame on hunger, thirst and food intake in men. Physiol Behav. 1990;48:19-26. 20. McCrory MA, Fuss PJ, Hays NP, Vinken AG, Greenberg AS, Roberts SB. Overeating in America: association between restaurant food consumption and body fatness in healthy adult men and women ages 19 to 80. Obes Res. 1999;7:564-571. 21. Karppanen H, Mervaala E. Sodium intake and hypertension. Prog Cardiovasc Dis. 2006;49:59-75. 22. Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346:393-403. 23. Tuomilehto J, Lindstrom J, Eriksson JG, et al, for the Finnish Diabetes Prevention Study Group. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med. 2001;344:1343-1350. 24. Wadden TA, Berkowitz RI, Womble LG, et al. Randomized trial of lifestyle modification and pharmacotherapy for obesity. N Engl J Med. 2005;353:2111-2120. 25. Wadden TA, Berkowitz RI, Sarwer DB, Prus-Wisniewski R, Steinberg C. Benefits of lifestyle modification in the pharmacologic treatment of obesity: a randomized trial. Arch Intern Med. 2001;161:218-227.

Supplement issue

Obesity: Why Be Concerned? W. Virgil Brown, MD,a Ken Fujioka, MD,b Peter W. F. Wilson, MD,a Kristina A. Woodworthc a Department of Internal Medicine, Emory University School of Medicine, Atlanta, Georgia, USA; bCenter for Weight Management, Scripps Clinic, San Diego, California, USA; cSciMantis Communications, Inc, Pen Argyl, Pennsylvania, USA

ABSTRACT The obesity epidemic in the United States represents a critical public health issue that has the potential to incur major healthcare costs because of the substantial risks associated with excess body fat. Whereas many recognize the significant risk of cardiovascular disease and diabetes mellitus associated with excess body fat, a myriad of other health problems can accompany overweight and obesity, potentially leading to early morbidity and mortality. Public recognition of obesity as an important health crisis, and not simply a matter of cosmetics or lifestyle choice, is clearly needed. A greater awareness of the health risks associated with excess weight will facilitate more frequent obesity screenings and discussions about healthy weight management that have the potential to result in a greater commitment of healthcare resources to effective obesity prevention and management strategies. © 2009 Published by Elsevier Inc. • The American Journal of Medicine (2009) 122, S4 –S11 KEYWORDS: Cardiovascular disease; Health care costs; Lipoproteins; Metabolic syndrome; Obesity; Risk factor

Obesity is a problem that has reached epidemic proportions in the United States. Data from the National Health Examination Survey (NHES) and the National Health and Nutrition Examination Survey (NHANES) demonstrated a steady increase in obesity rates over the second half of the 20th century. It is now estimated that ⬎66% of the US adult population is overweight or obese (body mass index [BMI] ⱖ25).1 An analysis reported by Olshansky and associates2 projected a reversal of 20th-century gains in American life expectancy owing to the health consequences of the obesity epidemic; these findings highlight the critical importance of addressing overweight and obesity, including the associated health risks, from the perspectives of public education and policy. In an effort to prompt a greater level of commitment to healthy weight management, this review discusses the substantial health concerns that present with excess body fat.

DEFINING OBESITY BMI is commonly accepted as a general measure of overweight and obesity. It is calculated by dividing the patient’s Statement of author disclosure: Please see the Author Disclosures section at the end of this article. Requests for reprints should be addressed to W. Virgil Brown, MD, Emory University School of Medicine, Atlanta VAMC 111, 1670 Clairmont Road, Atlanta, Georgia 30033. E-mail address: [email protected].

0002-9343/$ -see front matter © 2009 Published by Elsevier Inc. doi:10.1016/j.amjmed.2009.01.002

weight in kilograms by the square of the individual’s height in meters. Adults with a BMI in the range of 25 to 29.9 are classified as overweight, and those with a BMI of ⱖ30 are classified as obese.3 The location of excess body fat is also a factor in the detrimental effects of obesity. Intra-abdominal fat is more closely associated with diabetes mellitus and vascular disease. Therefore, measurements of waist size have been used to predict the extent of excess risk with body fat.

THE METABOLIC SYNDROME AND OBESITY In defining the metabolic syndrome, the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) recognized elevated waist circumference, or abdominal obesity, as an independent component of the syndrome along with elevated triglyceride concentrations, low high-density lipoprotein (HDL) cholesterol levels, elevated blood pressure, and high fasting glucose concentrations (Table 1).4 Individuals with ⱖ3 of these factors are classified as having the metabolic syndrome.4 A joint statement by the American Heart Association (AHA) and the National Heart, Lung, and Blood Institute (NHLBI) concurs with this definition but lowers the threshold for elevated fasting glucose concentrations from 110 mg/dL to 100 mg/dL (1 mg/dL ⫽ 0.05551 mmol/L), because of the importance of this marker in assessing diabetic risk.5 With the 2001 update in recommendations, NCEP ATP III emphasized the impor-

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Table 1 Clinical Components of the Metabolic Syndrome as Defined by the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) Risk Factor Abdominal obesity (waist circumference) Men Women Triglycerides* HDL cholesterol† Men Women Blood pressure Fasting glucose

Defining Level ⬎102 cm (⬎40 in) ⬎88 cm (⬎35 in) ⱖ150 mg/dL ⬍40 mg/dL ⬍50 mg/dL ⱖ130/ⱖ85 mm Hg ⱖ110 mg/dL‡

HDL ⫽ high-density lipoprotein. *1 mg/dL ⫽ 0.01129 mmol/L. † 1 mg/dL ⫽ 0.02586 mmol/L. ‡ The American Heart Association/National Heart, Lung, and Blood Institute (AHA/NHLBI) lowered this threshold to ⱖ100 mg/dL (1 mg/dL ⫽ 0.05551 mmol/L). Adapted with permission from JAMA.4

tance of focusing on multiple risk factors in mitigating the substantial health consequences associated with the metabolic syndrome and suggested that clinicians consider the metabolic syndrome as a secondary target for risk-reduction therapy after the management of low-density lipoprotein (LDL) cholesterol, because of the substantial disease burden associated with the syndrome.4 Furthermore, the NCEP ATP III recommended weight reduction and increased physical activity as a strategy to treat all of the factors that define the metabolic syndrome.4 The cluster of cardiometabolic factors referred to as the metabolic syndrome substantially increases the risk of important health consequences, including heart attack, stroke, and type 2 diabetes, all of which can result in morbidity and early mortality. Data from NHANES III (1988 to 1994) revealed that in Americans ⱖ50 years of age, the ageadjusted prevalence of coronary heart disease (CHD) was 19.2% in those with the metabolic syndrome and diabetes compared with 8.7% in those without the metabolic syndrome or diabetes.6 Diabetes substantially increased the rate of CHD in individuals with the metabolic syndrome. An analysis from the San Antonio Heart Study reported that the metabolic syndrome, as defined by the NCEP ATP III, predicted both all-cause mortality and cardiovascular mortality.7 Likewise, in a large population-based study of familial type 2 diabetes conducted in Finland and Sweden, the metabolic syndrome was associated with a significant risk for CHD, myocardial infarction, and stroke, as well as a significant risk for both all-cause mortality and cardiovascular mortality (P ⬍0.001).8 In light of the substantial risks presented by the metabolic syndrome, it is critical that clinicians develop routine strategies to control these factors in daily practice. Furthermore, the links between obesity, particularly abdominal obesity, and the metabolic syndrome suggest that many of

S5 the factors comprising the NCEP ATP III definition are present in patients with excess body weight. Clinicians therefore should recognize the importance of weight control in mitigating risk and the benefits of screening overweight and obese patients for underlying conditions, including hypertension, dyslipidemia, and type 2 diabetes.

OBESITY AND CARDIOVASCULAR DISEASE The recognition of the association between increased cardiovascular disease incidence and overweight and obesity suggests that weight loss represents an important opportunity for primary cardiovascular disease prevention. An analysis from the Framingham Heart Study resulted in the findings that both overweight and obesity increased the risk of the development of cardiovascular risk factors, including hypertension, hypercholesterolemia, and diabetes, as well as overt cardiovascular disease.9 It is critical to control underlying cardiovascular risk factors and encourage weight loss in individuals presenting with overweight and obesity to avoid substantial long-term cardiovascular disease.

Mechanisms of Cardiovascular Risk Excess weight, especially excess adipose tissue, exacerbates a number of cardiovascular and metabolic risk factors. It is now recognized that this increased risk is characterized by a series of metabolic changes that alter lipid profiles and increase the potential for atherosclerosis due to inflammation. Adipose tissue, especially intra-abdominal visceral fat associated with abdominal obesity, has an independent endocrine function that results in the release of inflammatory adipokines, including tumor necrosis factor–␣, interleukin-6, and plasminogen-activator inhibitor–1 (PAI-1).10-12 These hormones increase risk for atherosclerosis, thrombosis, and diabetes. Adipokines also may affect the progression of endothelial dysfunction, which further increases inflammation and the risk for atherosclerosis.13 Inflammatory adipokines increase atherogenic potential by altering the normal function of arterial smooth muscle cells and white blood cells, including lymphocytes and monocytes. The adipokine PAI-1 has a prothrombotic effect that increases the risk for thromboembolic events. Inflammatory adipokines may also increase insulin resistance and diabetes in obesity.10-12 Free fatty acids are also produced more readily in the visceral fat associated with abdominal obesity and may decrease insulin sensitivity, impair vascular reactivity, and increase endothelial dysfunction.13,14 Meanwhile, higher blood concentrations of adiponectin are associated with less evidence of inflammation and improved insulin sensitivity; however, adiponectin levels have been shown to decrease with increasing levels of obesity and adiponectin is counterregulated by the inflammatory adipokines.12,13,15 Abnormal lipid metabolism, particularly the cluster of lipid abnormalities that characterize atherogenic dyslipidemia, is common in individuals with obesity and type 2

S6 diabetes and increases the risk for cardiovascular events. Individuals with obesity and the metabolic syndrome present with increased concentrations of very-low-density lipoprotein (VLDL) particles, increased triglycerides, and small-particle LDL, increased LDL particle number, and decreased HDL particle size. This has been confirmed by measuring particle numbers through nuclear magnetic resonance spectral analysis.16-18 These lipoproteins can also undergo a process of oxidation that results in the formation of foam cells and enhanced monocyte binding that results in the early stages of atherosclerotic plaque.19 Meanwhile, small-particle LDL has a greater atherogenic potential and is more common in individuals with diabetes.20 However, it should be stressed that the total number of lipoprotein particles may be a more important factor in predicting the potential for cardiovascular disease.21 Elevated triglyceride concentrations are associated with greater circulating numbers of triglyceride-rich VLDL particles and higher levels of VLDL cholesterol, an environment that alters the metabolism of LDL and HDL cholesterol and contributes to atherogenic potential.22 Elevated triglyceride concentration is an important independent risk factor for atherosclerotic potential and may partly explain the inability of statin therapies that address hypercholesterolemia in fully protecting against cardiovascular events.23 Weight loss is associated with increases in adiponectin levels, a reversal of inflammatory adipokine release, and improved endothelial function.13 These findings strongly support the importance of obesity as a risk factor for cardiovascular disease, including atherosclerosis and thromboembolic events, and highlight the value of weight loss as a therapeutic modality.

Evidence of Cardiovascular Risk with Excess Weight The increased cardiovascular risk associated with overweight, obesity, and the metabolic syndrome is routinely demonstrated in clinical practice. One population-based study found that the presence of the metabolic syndrome as defined by the NCEP and the World Health Organization (WHO) in a cohort of middle-aged men was an accurate predictor of cardiovascular mortality and all-cause mortality.24 This increased mortality risk was independent of other confounding traits such as smoking, alcohol consumption, and LDL cholesterol levels. In a population of postmenopausal women, subjects with NCEP-defined metabolic syndrome or a combination of enlarged waist and elevated triglyceride concentrations were at a significantly increased risk for cardiovascular and all-cause mortality (P ⬍0.05).25 The authors of this study noted that the combination of enlarged waist and elevated triglyceride concentrations was a stronger predictor of atherogenesis than was the metabolic syndrome and concluded that the use of enlarged waist circumference and elevated triglyceride concentrations could be a valuable,

The American Journal of Medicine, Vol 122, No 4A, April 2009 cost-savings tool to identify individuals at risk in clinical practice. The Framingham Heart Study, which followed ⬎5,000 individuals for a period of up to 44 years, likewise reported substantial cardiovascular risk linked to overweight and obesity. In one analysis, overweight and obesity were independently associated with an increased risk for developing cardiovascular disease as well as established cardiovascular risk factors, including hypertension, hypercholesterolemia, and type 2 diabetes.9 It is important to note that cardiovascular risk not only was increased in obese persons but also was elevated in overweight individuals.9 Additionally, it is notable that another Framingham analysis found that the Framingham Risk Score was significantly superior to metabolic syndrome in predicting cardiovascular risk.26 These findings highlight the importance of healthy weight maintenance and the clinical value of assessing patients exhibiting overweight and obesity for underlying cardiovascular disease.

OBESITY AND ENDOCRINE DISEASE Obesity clearly increases the risk of developing type 2 diabetes. Large population studies have confirmed the links between excess weight and the development of insulin resistance and diabetes, suggesting that patients with excessive weight are at substantial risk for developing diabetes. In the Nurses’ Health Study, which followed close to 85,000 female nurses, a BMI of ⱖ25 (overweight) was the single most important risk factor for the development of type 2 diabetes over a 16-year period.27 The authors noted that modifiable changes in lifestyle and health, including maintenance of a BMI ⱕ25; consumption of a diet high in fiber and low in fat and glycemic load; regular exercise; avoidance of smoking; and moderate alcohol consumption reduced the incidence of type 2 diabetes by approximately 90% compared with subjects who did not demonstrate these factors or make these changes. BMI, as a measure of excess weight, can be an important predictor of developing diabetes. In fact, BMI has been shown to correlate linearly with the risk for both CHD and diabetes. One analysis found that BMI values ⬎30 correlated directly with the risk for developing type 2 diabetes, as well as hypertension, CHD, and gallbladder disease.28 Furthermore, men with a BMI of 26 had a 4-fold higher risk for developing type 2 diabetes than did men whose BMI was ⬍21; women with a BMI of 26 had an 8-fold higher risk for developing type 2 diabetes than did women whose BMI was ⬍21. Abdominal obesity, classified as an elevated BMI plus elevated waist circumference (⬎102 cm [⬎40 in] in men and ⬎88 cm [⬎35 in] in women),4 may be a more accurate predictor of diabetic risk. The Nurses’ Health Study reported that, in female subjects, measures of abdominal obesity, including waist circumference and waist-to-hip ratio, were more predictive of diabetes risk than was BMI alone.29 A study of men aged 22 to 70 examined abdominal obesity

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by analyzing abdominal adipose tissue through magnetic resonance imaging.30 Researchers reported that body weight was inversely proportional to insulin sensitivity but weight alone could not fully explain the risk of developing insulin resistance. Meanwhile, the accumulation of body fat in the abdominal region was found to be an important contributor to insulin resistance, as measured by both global insulin sensitivity and hepatic insulin sensitivity.30 Clinicians should recognize the importance of screening for diabetes as an important component to global risk assessment in patients presenting with chronic excess weight, especially those demonstrating abdominal obesity.

S7 developing type 2 diabetes compared with a placebo group and a 39% reduced risk compared with a group receiving metformin therapy to reduce diabetic risk.33 Over a mean follow-up of 3.2 years, another study that tracked the effects of weight-loss lifestyle interventions on the incidence of type 2 diabetes in individuals with impaired glucose tolerance likewise reported a 58% reduction in type 2 diabetes incidence with weight loss.34 Although large-scale campaigns to achieve weight loss through lifestyle interventions may be associated with substantial costs, these costs may be attenuated by the resulting decrease in disease risk.

OTHER HEALTH EFFECTS OF OBESITY OBESITY AND HEALTHCARE COSTS The increased cardiometabolic risks associated with obesity, including cardiovascular disease and type 2 diabetes, have important treatment implications in terms of healthcare utilization and resulting healthcare costs. Costs attributable to obesity in 1995 US dollars were estimated to total $99.2 billion per year, $51.64 billion of which were associated with direct medical costs.31 Furthermore, an analysis of healthcare costs and wages found that in populations receiving workplace healthcare benefits, the increased healthcare costs associated with obesity are passed on to obese workers through lower wages.32 In individuals who are overweight or obese, effective treatment strategies are needed to either achieve weight loss or attenuate the underlying cardiometabolic risk factors that are present with excess body weight. Researchers have found that efforts to prevent obesity may be less costly than are the substantial costs associated with the treatment of obesity and comorbid cardiometabolic risk. In one analysis, the pharmaceutical treatment of obesity, achieving weight loss of 8.2% to 10.6% of initial body weight, was associated with substantial pharmaceutical cost savings due to a reduced need for medications to treat diabetes, hyperlipidemia, and hypertension.31 Weight loss was maintained at 1 year with the pharmaceutical intervention. Also, the achieved weight loss demonstrated the ability to improve risk factors for cardiovascular disease, including total cholesterol, systolic blood pressure, LDL cholesterol, and HDL cholesterol. The pharmaceutical costs associated with weight loss medications were more than offset by the reduced need for medications to treat cardiometabolic risk factors. Lifestyle interventions that reduce weight may also reduce the risk of developing type 2 diabetes and the substantial pharmaceutical costs associated with treatment. In a trial conducted by the Diabetes Prevention Program (DPP) Research Group, a population of individuals with elevated fasting glucose concentrations were treated with a lifestyle modification program with the goals of a ⱖ7% reduction in weight and physical activity totaling ⱖ150 minutes per week, to determine the effects of resulting weight loss on diabetic risk.33 Over a mean follow-up period of 2.8 years, researchers reported that individuals receiving lifestyle interventions to achieve weight loss had a 58% reduced risk of

The projected decrease in overall life expectancy if the current obesity epidemic is not reversed2 highlights the importance of excess weight as a public health issue. As noted earlier, the presence of obesity and the metabolic syndrome increases the mortality risk associated with cardiovascular disease.7,8,24,25 In one analysis, obese, 40-yearold individuals demonstrated life expectancies that were reduced by 7.1 years in women and 5.8 years in men compared with those of normal weight,35 demonstrating the far-reaching, lifelong implications of excess body weight.

Cancer Risk Obesity is associated with the development of certain cancers in both men and women. A prospective analysis of a population of ⬎900,000 US adults who were cancer free at baseline found that individuals with extreme obesity (BMI ⱖ40) had a substantially higher risk of death due to cancer (52% and 62% in men and women, respectively) than did those of normal weight during the 16 years of follow-up. The authors of the study concluded that of all cancer deaths in the United States, 14% of cases in men and 20% of cases in women ⱖ50 years of age may be attributable to overweight and obesity. Overall, they predicted that 90,000 cancer deaths could be avoided if all Americans could maintain a BMI ⬍25 throughout life.36 Researchers have cited several potential mechanisms that increase the risk of cancer with obesity, including the higher levels of insulin and sex hormones observed in overweight and obese individuals.36 Other physiologic factors have been cited in the link between specific cancers and excess weight. For instance, a higher incidence of gastroesophageal reflux has been cited as a possible causative factor in the increased risk of esophageal cancer in overweight and obesity. A higher rate of gallstones with overweight and obesity has also been cited as a possible causative factor in an increased risk of gallbladder cancer with excess weight, particularly in women.36 In men, significant positive correlations were found between BMI and rates of death due to all cancers, as well as esophageal cancer, stomach cancer, colorectal cancer, liver cancer, gallbladder cancer, pancreatic cancer, prostate cancer, kidney cancer, non-Hodgkin’s lymphoma, multiple myeloma, and leukemia (P ⱕ0.03).36 In women, BMI corre-

S8 lated significantly with deaths due to all cancers, as well as colorectal cancer, liver cancer, gallbladder cancer, pancreatic cancer, lung cancer, breast cancer, uterine cancer, cervical cancer, ovarian cancer, kidney cancer, non-Hodgkin’s lymphoma, and multiple myeloma (P ⱕ0.001). Uterine cancer was most strongly associated with excess body weight. Women may be particularly vulnerable to cancer mortality associated with excess body weight.36 The strong association between BMI and cancer risk in women was reported in a Swedish population study. Investigators concluded that up to 7% of cancers in the women studied were attributable to overweight and obesity. Moreover, up to 30% of endometrial cancers, 20% of colon cancers, and 22% of ovarian cancers were estimated to be attributable to overweight and obesity.37 Based on the findings of epidemiologic studies, the International Agency for Research on Cancer (IARC) has concluded that sufficient evidence exists to demonstrate that the avoidance of weight gain over time can be an effective preventive strategy for colorectal cancer, postmenopausal breast cancer, endometrial cancer, kidney cancer, and esophageal cancer.38 Successful obesity prevention and management strategies may prevent the substantial morbidity and early mortality associated with common cancers.

Pulmonary Disease Obesity increases respiratory demand and has an important effect on pulmonary function that can predispose an individual to a range of pulmonary problems, including obstructive sleep apnea and obesity hypoventilation syndrome. The reduced pulmonary function common in obesity results in dyspnea and decreased exercise capacity, which can contribute substantially to poor quality of life.39 Obesity has been found to be a primary risk factor for the development of sleep apnea. One observational study found that subjects with obstructive sleep apnea exhibited substantially greater BMI, waist circumference, percentage of body fat, and fat mass than did controls.40 Obstructive sleep apnea not only was associated with excess weight but also was linked to features of the metabolic syndrome, including increased blood pressure, increased fasting insulin levels, increased triglyceride concentrations, decreased HDL cholesterol levels, and an increased total cholesterol–to–HDL cholesterol ratio.40 Moreover, obesity has been identified as an important risk factor for mortality in persons with sleep apnea.41

The American Journal of Medicine, Vol 122, No 4A, April 2009 improved with weight reductions of ⬎5.1% over a 20-week period.43 Plantar heel pain, or plantar fasciitis, is also common in obesity because of chronic excessive weight load on the heel. Whereas obesity may provide a protective benefit against hip and wrist fractures in the elderly, obese children are more vulnerable to wrist fractures. Overall, the musculoskeletal problems associated with obesity carry a 4-fold higher risk of pain that restricts work.42 Weight loss is often the most important therapy for musculoskeletal problems associated with obesity. Along with the observed impact of obesity on pulmonary function, the long-term morbidity associated with osteoarthritis, plantar fasciitis, and other musculoskeletal conditions may be important factors that limit exercise and hamper achievement of weight loss recommendations in obesity.

Gastrointestinal and Hepatic Disorders Obesity predisposes individuals to gastrointestinal and hepatic complications that contribute to morbidity and possible mortality. Nonalcoholic fatty liver disease, or hepatic steatosis, is the most common chronic liver disease in the United States44; it can be hypothesized that increasing rates are linked to the obesity epidemic, because the most important risk factors for hepatic steatosis are obesity, insulin resistance, and hyperlipidemia.44,45 An analysis of data from NHANES found that factors associated with elevated alanine aminotransferase (ALT) levels, which may signal the presence of liver dysfunction, included higher BMI, waist-to-hip circumference ratio, and fasting serum leptin, triglyceride, insulin, and glucose concentrations.46 Investigators concluded that 65% of elevated ALT activity was related to overweight and obesity (BMI ⱖ25). Although hepatic steatosis does not progress to substantial complications in most patients, up to 3% of patients develop cirrhosis. Moreover, obesity is a major risk factor for the development of hepatic fibrosis, which can lead to cirrhosis, hepatocellular carcinoma, and early mortality.44 Gallbladder disease is another common complication of obesity, and abdominal obesity may further increase the risk of developing this condition. In the Health Professionals Follow-Up Study (HPFS), abdominal obesity, as measured by waist circumference and waist-to-hip ratio, was associated with a significant increase in the risk of developing symptomatic gallbladder disease (P ⬍0.001).47 This effect persisted even when findings were adjusted for BMI.

Reproductive Disorders Musculoskeletal Disorders Musculoskeletal problems are also common in obesity because of the added strain on bones and joints due to excessive body weight. Obesity carries a greater risk of osteoarthritis of weight-bearing joints, especially the knees, because of the chronic loading of the musculoskeletal system with walking and other daily tasks.42 In a meta-analysis of randomized controlled trials, researchers noted that disability associated with knee osteoarthritis was significantly

Reproductive problems are commonly associated with obesity in both women and men. In women, obesity substantially increases risk for polycystic ovary syndrome (PCOS). One study reported a 28.3% rate of PCOS in premenopausal overweight and obese subjects, compared with a 5-fold lower rate of 5.5% in matched lean women.48 Furthermore, individuals with PCOS were more likely to exhibit insulin resistance than were matched controls with similar BMI and obesity severity.

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Obesity and Health Concerns

Potential Health Concerns Associated with Obesity

Organ System/ Disease State Cancers

Cardiovascular Dermatologic

Endocrine Gastrointestinal Musculoskeletal

Pulmonary Reproductive

Health Effects Men: esophageal cancer, stomach cancer, colorectal cancer, liver cancer, gallbladder cancer, pancreatic cancer, prostate cancer, kidney cancer, non-Hodgkin’s lymphoma, multiple myeloma, leukemia Women: uterine cancer, cervical cancer, ovarian cancer, breast cancer, colorectal cancer, liver cancer, gallbladder cancer, kidney cancer, non-Hodgkin’s lymphoma, multiple myeloma Atherosclerosis, myocardial infarction, stroke Acanthosis nigricans, skin tags, acne, boils, hirsutism, pathologies of augmented folds, plantar hyperkeratosis, cellulite, stretch marks, varicose veins Insulin resistance, type 2 diabetes mellitus Nonalcoholic fatty liver disease, gallbladder disease Osteoarthritis and degenerative joint disease, changes in foot anatomy due to excess load Obstructive sleep apnea Men: premature testosterone decline, erectile dysfunction Women: polycystic ovary syndrome

Obesity can also lead to substantial reproductive problems in men, including premature testosterone decline and erectile dysfunction. Data from 2 lipid treatment trials that collected baseline total serum testosterone levels were pooled to examine the effects of BMI and the metabolic syndrome on testosterone levels.49 The authors reported a significant correlation between low testosterone levels in aging men (mean age, 52 years) and the presence of the metabolic syndrome (P ⬍0.0001). The components of the metabolic syndrome linked to this effect included obesity, diabetes, and hypertriglyceridemia. Another study found that abdominal obesity significantly increased risk for erectile dysfunction in men 61 to 81 years of age who did not have other important comorbidities, including diabetes and hypertension (P ⱕ0.04).50 In a study of men who had undergone bariatric surgery to address severe obesity, researchers reported significant weight loss 1 year after bariatric surgery (P ⬍0.001) and found that testosterone levels were inversely proportional to BMI and fat mass.51 The correction of severe obesity with bariatric surgery normalized testosterone levels in all subjects and improved sexual performance in 80%.

Dermatologic Disease Many dermatologic complications are also associated with obesity and the metabolic syndrome. Insulin resistance and

S9 obesity can result in important cellular changes that can lead to acanthosis nigricans, a disorder characterized by dark plaques, and skin tags. Up to 74% of obese individuals exhibited acanthosis nigricans and skin tags in one analysis.52 Importantly, acanthosis nigricans and skin tags are markers of insulin resistance in obesity based on the fact that hyperinsulinemia causes the cellular changes that result in these conditions.53 The hyperandrogenism in obesity also results in important skin manifestations, including acne, boils, and hirsutism.53 Plantar hyperkeratosis is another common condition in obesity characterized by chronic calluses that develop in response to changes in the anatomy of the foot due to excessive weight load.53,54 Stretch marks, varicose veins, intertrigo (friction-related injury associated with fat folds), and cellulite may also be produced or exacerbated by obesity.53 A summary of the potential health concerns associated with excess weight is presented in Table 2. The increased risk of developing this wide range of health problems underscores the importance of obesity prevention and management in clinical practice.

SUMMARY The obesity epidemic requires new strategies to mitigate the substantial health effects linked to excess body weight. The health risks associated with overweight and obesity are considerable. They require an increased level of intensive patient management to address healthy weight maintenance, and suggested strategies to achieve and maintain weight loss. A greater public awareness of obesity and health risks is required to move past the potential stigma associated with discussing weight so that clinicians and patients can work together to achieve long-term health goals.

AUTHOR DISCLOSURES The authors who contributed to this article have disclosed the following industry relationships: W. Virgil Brown, MD, is a consultant for Abbott Laboratories, AstraZeneca, AtherGenics, Inc, Bayer, Bristol-Myers Squibb Company, Merck & Co, Inc, Pfizer Inc, Reliant Pharmaceuticals, Inc, Daiichi Sankyo Co, Ltd, and Schering-Plough Corporation; is a speaker and advisory committee member for Abbott Laboratories, AstraZeneca, Merck & Co, Inc, Pfizer Inc, and Schering-Plough Corporation; and has received grant research support from Abbott Laboratories, AstraZeneca, Eli Lilly and Company, Kos Pharmaceuticals, Inc, Merck & Co, Inc, Pfizer Inc, Schering-Plough Corporation, and Takeda Pharmaceuticals North America, Inc. Ken Fujioka, MD, has disclosed that the commercial entities with which he has relationships do not produce healthcare-related products or services relevant to the content he is planning, developing, or presenting for this activity.

S10 Peter W. F. Wilson, MD, has received grant support from GlaxoSmithKline, sanofi-aventis Pharmaceuticals, Inc, and Wyeth. Kristina A. Woodworth has no relevant financial relationships with a commercial entity producing healthcarerelated products and/or services.

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metabolic syndrome: analysis of the Treating to New Targets study. Lancet. 2006;368:919-928. Libby P. Vascular biology of atherosclerosis: overview and state of the art. Am J Cardiol. 2003;91:3A-6A. Haffner SM. Management of dyslipidemia in adults with diabetes. Diabetes Care. 2003;26(suppl 1):S83-S86. Cromwell WC, Otvos JD. Low-density lipoprotein particle number and risk for cardiovascular disease. Curr Atheroscler Rep. 2004;6:381-387. Brown WV. High-density lipoprotein and transport of cholesterol and triglyceride in blood. J Clin Lipidol. 2007;1:7-19. Libby P. The forgotten majority: unfinished business in cardiovascular risk reduction. J Am Coll Cardiol. 2005;46:1225-1228. Lakka HM, Laaksonen DE, Lakka TA, et al. The metabolic syndrome and total and cardiovascular disease mortality in middle-aged men. JAMA. 2002;288:2709-2716. Tankó LB, Bagger YZ, Qin G, Alexandersen P, Larsen PJ, Christiansen C. Enlarged waist combined with elevated triglycerides is a strong predictor of accelerated atherogenesis and related cardiovascular mortality in postmenopausal women. Circulation. 2005;111:1883-1890. Wannamethee SG, Shaper AG, Lennon L, Morris RW. Metabolic syndrome vs Framingham Risk Score for prediction of coronary heart disease, stroke, and type 2 diabetes mellitus. Arch Intern Med. 2005; 165:2644-2650. Hu FB, Manson JE, Stampfer MJ, et al. Diet, lifestyle, and the risk of type 2 diabetes mellitus in women. N Engl J Med. 2001;345:790-797. Willett WC, Dietz WH, Colditz GA. Guidelines for healthy weight. N Engl J Med. 1999;341:427-434. Carey VJ, Walters EE, Colditz GA, et al. Body fat distribution and risk of non-insulin-dependent diabetes mellitus in women: the Nurses’ Health Study. Am J Epidemiol. 1997;145:614-619. Abate N, Garg A, Peshock RM, Stray-Gundersen J, Grundy SM. Relationships of generalized and regional adiposity to insulin sensitivity in men. J Clin Invest. 1995;96:88-98. Greenway FL, Ryan DH, Bray GA, Rood JC, Tucker EW, Smith SR. Pharmaceutical cost savings of treating obesity with weight loss medications. Obes Res. 1999;7:523-531. Bhattacharya J, Bundorf MK. The incidence of the healthcare costs of obesity. National Bureau of Economic Research Working Paper Series. Cambridge, MA: National Bureau of Economic Research, May 2005. Available at: http://www.nber.org/papers/w11303. Accessed June 5, 2007. Knowler WC, Barrett-Connor E, Fowler SE, et al. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346:393-403. Tuomilehto J, Lindstrom J, Eriksson JG, et al. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med. 2001;344:1343-1350. Peeters A, Barendregt JJ, Willekens F, Mackenbach JP, Al Mamun A, Bonneux L. Obesity in adulthood and its consequences for life expectancy: a life-table analysis. Ann Intern Med. 2003;138:24-32. Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of US adults. N Engl J Med. 2003;348:1625-1638. Lukanova A, Bjor O, Kaaks R, et al. Body mass index and cancer: results from the Northern Sweden Health and Disease Cohort. Int J Cancer. 2006;118:458-466. Calle EE, Thun MJ. Obesity and cancer. Oncogene. 2004;23:63656378. Parameswaran K, Todd DC, Soth M. Altered respiratory physiology in obesity. Can Respir J. 2006;13:203-210. Coughlin SR, Mawdsley L, Mugarza JA, Calverley PM, Wilding JP. Obstructive sleep apnoea is independently associated with an increased prevalence of metabolic syndrome. Eur Heart J. 2004;25:735-741. Lavie P, Herer P, Lavie L. Mortality risk factors in sleep apnoea: a matched case-control study. J Sleep Res. 2007;16:128-134. Wearing SC, Hennig EM, Byrne NM, Steele JR, Hills AP. Musculoskeletal disorders associated with obesity: a biomechanical perspective. Obes Rev. 2006;7:239-250.

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43. Christensen R, Bartels EM, Astrup A, Bliddal H. Effect of weight reduction in obese patients diagnosed with knee osteoarthritis: a systematic review and meta-analysis. Ann Rheum Dis. 2007;66: 433-439. 44. McCullough AJ. The clinical features, diagnosis and natural history of nonalcoholic fatty liver disease. Clin Liver Dis. 2004;8:521-533. 45. Browning JD, Szczepaniak LS, Dobbins R, et al. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology. 2004;40:1387-1395. 46. Ruhl CE, Everhart JE. Determinants of the association of overweight with elevated serum alanine aminotransferase activity in the United States. Gastroenterology. 2003;124:71-79. 47. Tsai CJ, Leitzmann MF, Willett WC, Giovannucci EL. Prospective study of abdominal adiposity and gallstone disease in US men. Am J Clin Nutr. 2004;80:38-44. 48. Alvarez-Blasco F, Botella-Carretero JI, San Millan JL, Escobar-Morreale HF. Prevalence and characteristics of the polycystic ovary syndrome in overweight and obese women. Arch Intern Med. 2006;166: 2081-2086.

S11 49. Kaplan SA, Meehan AG, Shah A. The age related decrease in testosterone is significantly exacerbated in obese men with the metabolic syndrome: what are the implications for the relatively high incidence of erectile dysfunction observed in these men? J Urol. 2006;176(pt 1):1524-1527; discussion 1527-1528. 50. Riedner CE, Rhoden EL, Ribeiro EP, Fuchs SC. Central obesity is an independent predictor of erectile dysfunction in older men. J Urol. 2006;176(pt 1):1519-1523. 51. Alagna S, Cossu ML, Gallo P, et al. Biliopancreatic diversion: longterm effects on gonadal function in severely obese men. Surg Obes Relat Dis. 2006;2:82-86. 52. Hud JA Jr, Cohen JB, Wagner JM, Cruz PD Jr. Prevalence and significance of acanthosis nigricans in an adult obese population. Arch Dermatol. 1992;128:941-944. 53. Garcia Hidalgo L. Dermatological complications of obesity. Am J Clin Dermatol. 2002;3:497-506. 54. Garcia-Hidalgo L, Orozco-Topete R, Gonzalez-Barranco J, Villa AR, Dalman JJ, Ortiz-Pedroza G. Dermatoses in 156 obese adults. Obes Res. 1999;7:299-302.

Supplement issue

Regulation of Energy Homeostasis and Health Consequences in Obesity Judith Korner, MD, PhD,a Stephen C. Woods, PhD,b Kristina A. Woodworthc a Department of Medicine, Columbia University College of Physicians and Surgeons, and Weight Control Center, Columbia University Medical Center, New York, New York, USA; bObesity Research Center and Department of Psychiatry, University of Cincinnati, Cincinnati, Ohio, USA; and cSciMantis Communications, Inc, Pen Argyl, Pennsylvania, USA.

ABSTRACT The growing awareness of the obesity epidemic as a critical matter of health concern has prompted research into the mechanisms underlying energy homeostasis and the pathophysiology of obesity. Food intake, energy expenditure, and fat storage all are regulated by a complex neuroendocrine system. It is now recognized that in addition to central neurohumoral pathways, adipose tissue has an independent endocrine function that contributes to energy homeostasis. Moreover, adipose tissue exerts inflammatory effects that are linked to the most important health problems associated with obesity, including cardiovascular disease and type 2 diabetes mellitus, each of which has the potential to confer long-term morbidity and increased mortality risks. This inflammatory effect of adipose tissue is more pronounced in abdominal obesity, which is reflected by the heightened cardiometabolic risk observed in persons with excess abdominal adiposity. The endocrine impact of adipose tissue on energy homeostasis and inflammation highlights the critical health implications of obesity, particularly abdominal obesity, and the importance of effective prevention and management strategies in clinical practice. © 2009 Elsevier Inc. All rights reserved. • The American Journal of Medicine (2009) 122, S12–S18 KEYWORDS: Endocannabinoids; Metabolic syndrome; Gut hormones; Visceral adiposity; Melanocortin system

A complex neuroendocrine system that regulates energy intake and energy expenditure, and ultimately affects the amount of energy stored as fat, has been uncovered.1 It is now recognized that adipose tissue plays an independent endocrine role that may result in an inflammatory response that increases the risk of cardiovascular disease and type 2 diabetes mellitus,2-4 syndromes that can result in substantial morbidity and early mortality. This review provides an overview of the underlying mechanisms of energy homeostasis, important regulatory systems that affect energy homeostasis and fat storage, and the endocrine effects of visceral abdominal fat.

from the gastrointestinal system, central nervous system, and adipose tissue, among other sources, to regulate both short-term and long-term balances between energy intake and energy expenditure (Figure 1).1,5-7 Meal initiation in humans is likely to be influenced by a variety of environmental factors, such as food availability and palatability, emotions, and time of day; by contrast, meal size and meal cessation are more likely to be regulated by a variety of changes in body fuel stores and resulting adiposity signals, in addition to neurohormonal signals emanating from the gastrointestinal tract.1

MECHANISMS OF ENERGY HOMEOSTASIS

The Hypothalamus and Energy Regulation

It is now recognized that energy homeostasis involves a complex network of neuroendocrine signals originating

Neurotransmitters and hormones in the brain contribute to the control of energy intake (eating) and energy expenditure (metabolism). The arcuate nucleus in the hypothalamus of the brain is the home of a regulatory process that controls these functions.5 Agouti-related peptide/neuropeptide Y (AgRP/NPY) neurons in the arcuate nucleus stimulate appetite and reduce metabolism. Other types of neurons found in the arcuate nucleus, known as proopiomelanocortin/

Statement of author disclosure: Please see the Author Disclosures section at the end of this article. Requests for reprints should be addressed to Judith Korner, MD, PhD, Weight Control Center, Columbia University Medical Center, 650 West 168th Street, New York, New York 10032. E-mail address: [email protected]

0002-9343/$ -see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.amjmed.2009.01.003

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Figure 1 Gut hormone regulation of energy homeostasis. AgRP ⫽ Agoutirelated peptide; ARC ⫽ arcuate nucleus; GLP-1 ⫽ glucagon-like peptide; NPY ⫽ neuropeptide Y; OXM ⫽ oxyntomodulin; POMC ⫽ proopiomelanocortin; PVN ⫽ paraventricular nucleus; PP ⫽ pancreatic peptide; PYY3-36 ⫽ peptide YY3-36. (Adapted with permission from Nature.7)

cocaine- and amphetamine-regulated transcript (POMC/ CART) neurons, release ␣-melanocyte–stimulating hormone, a neurotransmitter that inhibits food intake.1,5,6 Satiety- and hunger-inducing hormones and other signals affect this regulatory system to control energy homeostasis. For instance, peptide YY3-36 (PYY), a hormone secreted by the gut in direct proportion to the caloric content of a meal, decreases AgRP/NPY activity and reduces food intake in both animals and humans.6 Meanwhile, many other hormones also have potent neuroendocrine functions that control food intake and energy expenditure.

Insulin and Leptin Insulin and leptin serve as peripheral adiposity signals to the arcuate nucleus in the hypothalamus to control food intake and metabolism. Both AgRP/NPY and POMC/CART neurons in the arcuate express both insulin and leptin receptors, and the direct administration of either hormone into the brain reduces food intake.1 Insulin is secreted by the pancreas in response to meals and circulating nutrients, and leptin is secreted by adipocytes, or fat cells, in proportion to their fat content.1 Whereas both insulin and leptin levels

increase proportionately with body fat, leptin levels decrease more rapidly with food deprivation than with reductions in body fat content, which may occur to allow compensatory mechanisms to be activated before energy stores decrease substantially.1 Leptin may, in fact, have an especially important role in protecting against starvation as opposed to preventing weight gain.8 Decreased leptin secretion associated with decreased fat stores results in a compensatory increase in appetite and decrease in metabolism. However, beyond a certain level of elevated fat stores and resulting increased leptin production, few changes in appetite or metabolism have been observed.5 These findings are consistent with the fact that leptin levels are substantially increased in obese individuals and suggest that obesity is associated with a certain level of leptin resistance.9

Cholecystokinin Cholecystokinin (CCK) is a short-term satiety signal that controls meal size but is unlikely to play an important role in long-term weight regulation.10,11 Released by neuroendocrine cells in the intestinal wall in response to nutrient

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Figure 2 The role of endocannabinoids in energy homeostasis. Black wavy lines indicate sites at which cannabinoid CB1 receptors are expressed. ARC ⫽ arcuate nucleus; CCK ⫽ cholecystokinin; GI ⫽ gastrointestinal; LHA ⫽ lateral hypothalamic area; NPY ⫽ neuropeptide Y; NTS ⫽ nucleus tractus solitarii; PFA ⫽ perifornical area; POMC ⫽ proopiomelanocortin; PVN ⫽ paraventricular nucleus; SNS ⫽ sympathetic nervous system. (Reprinted with permission from Nature.1)

stimulation during a meal, CCK initiates neural signals to the brain to cause meal termination.1 CCK also slows gastric emptying and stimulates gallbladder contractions in response to dietary fat intake to enhance nutrient absorption.6 The effect of CCK to reduce meal size appears to be independent of the counterregulatory processes controlling body fat content that occurs in the arcuate nucleus and occurs in regions of the brain outside of the hypothalamus.1

Ghrelin Ghrelin, a hormone secreted by the stomach, is a potent appetite stimulator that induces subjective hunger and food intake by stimulating AgRP/NPY function.5,6 Unlike leptin and insulin, which have predominantly long-term implications in terms of food intake, metabolism, and body weight, ghrelin and CCK both have significant short-term effects on food intake. Circulating ghrelin concentrations increase preprandially and decrease postprandially, suggesting a role for ghrelin in meal initiation and/or termination. Ghrelin concentrations are decreased in obese individuals, indicating that it is unlikely that ghrelin plays a major etiologic role in their obesity. However, diet-induced weight loss is associated with an increase in plasma ghrelin levels, a factor that may contribute to increased hunger and difficulty in the maintenance of reduced body weight.12 It is important to note that other endogenous signaling systems, including the endocannabinoid system, also have been identified recently as having a major role in regulating energy balance.

REGULATION OF ENERGY HOMEOSTASIS: THE ROLE OF THE ENDOCANNABINOID SYSTEM As previously discussed, leptin functions as a strong mediator of energy homeostasis by downregulating the neurons that control food intake, including PYY. For example, leptin inhibits the action of arcuate AgRP/NPY neurons, and it also inhibits endocannabinoid activity in the hypothalamus.13 Like insulin and leptin levels, endocannabinoid levels have been found to be increased in obesity, and it has been suggested that endocannabinoids regulate food intake and energy expenditure.13 Endocannabinoids play a prominent role in obesity, and these hormones are active in numerous tissues, including the brain, the liver, muscle, the gastrointestinal tract, and adipose tissue (Figure 2).1,13 In the presence of palatable food or other pleasant situations, endocannabinoids are released in the brain and act on the endocannabinoid receptor cannabinoid-1 (CB1), which is located on presynaptic neuronal membranes to attenuate satiety signals. This results in continued eating despite opposing hormonal signals that a sufficient amount of food has been consumed, i.e., endocannabinoids in some brain areas result in largerthan-normal meals being consumed. The CB1 receptor has been identified as an important factor in obesity and cardiometabolic risk. Ravinet Trillou and colleagues14 reported that genetically engineered knockout mice that lacked the CB1 receptor gene were lean

Korner et al Table 1

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Cardiometabolic effects of key adipokines

Adipokine

Levels in Intra-Abdominal Obesity

Adiponectin

Levels 2

IL-6

Levels 1

TNF-␣

Levels 1

PAI-1

Levels 1

Hormonal Effects

Cardiometabolic Impact

● Inhibits foam cell formation and vascular remodeling (important steps in the formation of atherosclerotic plaque) ● Improves insulin sensitivity, opposes the development of hyperglycemia ● Systemic inflammatory hormone ● Exerts adverse, proatherogenic effects in the vasculature ● Exacerbates insulin resistance ● Reduces insulin sensitivity ● Increases free fatty acid production, resulting in hypertriglyceridemia ● Increases risk for thromboembolic events

● Antiatherogenic ● Antidiabetic ● Proatherogenic ● Prodiabetic ● Proatherogenic ● Prodiabetic ● Prothrombotic

IL ⫽ interleukin; PAI ⫽ plasminogen activator inhibitor; TNF ⫽ tumor necrosis factor; 1 ⫽ increase; 2 ⫽ decrease.

and resistant to obesity caused by excess food consumption; the researchers concluded that CB1 likely regulates both food intake and body weight. Another study of these CB1 knockout mice reported similar findings of decreased body weight, reduced fat mass, and reduced food intake.15 A critical role of endocannabinoids in energy homeostasis can be inferred from these reports because of the observed lack of compensation from other hormones that induce feeding and reduce energy metabolism. Other animal studies, some that measured endocannabinoid levels after different feeding patterns and others that assessed the effect of endocannabinoid injections directly into the hypothalamus, support an important role of the CB1 receptor and endocannabinoids in appetite and body weight regulation.16,17 Interestingly, endocannabinoids secreted by the upper gastrointestinal tract have also been implicated in increasing ghrelin secretion, because ghrelin secretion was attenuated following administration of an investigational CB1 receptor antagonist in an animal model.18 The CB1 receptor has also been investigated as a target of pharmacologic intervention in human obesity. In the randomized, double-blind, placebo-controlled Rimonabant in Obesity (RIO)–North America and RIO-Europe trials, researchers found that the selective CB1 receptor antagonist rimonabant effectively reduced body weight and waist circumference in obese individuals.19,20 Cardiometabolic risk factors were also improved with rimonabant administration. Similarly, in a randomized placebo-controlled trial of overweight individuals with untreated dyslipidemia, rimonabant 20 mg/day reduced weight and waist circumference, and improved cardiometabolic risk factors to a significantly greater degree than placebo.21 However, although rimonabant has resulted in promising rates of weight loss in clinical studies, the frequency of psychiatric adverse events has limited its potential as a marketable weight loss agent.

THE ENDOCRINE FUNCTION OF ADIPOSE TISSUE Adipose tissue, once considered an inert storage depot for fat, is now recognized as an endocrine organ that affects

energy homeostasis and cardiovascular health through release of adipokines that regulate food intake, energy expenditure, insulin sensitivity, and inflammation. The key properties of adipokines related to the risk of cardiovascular disease and diabetes, or cardiometabolic risk clustering, are listed in Table 1.2-4,22 The inflammatory properties of some adipokines result in an increased potential for atherogenesis, thrombosis, and diabetes. Interleukin-6 (IL-6), for instance, stimulates hepatic production of C-reactive protein (CRP), which is known to increase atherogenic risk.3 CRP may add predictive value to total cholesterol and high-density lipoprotein (HDL) cholesterol in evaluating the risk for myocardial infarction in otherwise healthy men.23 There also is increasing evidence that insulin resistance in liver, muscle, and adipose tissue is associated with, and may be the result of, increased proinflammatory cytokines.22 In contrast, the adipocyte hormone adiponectin exerts beneficial anti-inflammatory and anti-diabetic properties. Adiponectin enhances insulin sensitivity and inhibits a number of steps in the inflammatory process. The expression and release of adiponectin is decreased in obese individuals3,22; this is thought to be owing to increased CB1 receptor activity.24 Thus, the accumulation of excess fat may, in part, increase the risk for cardiovascular disease and diabetes through a relative overabundance of proinflammatory cytokines and a deficiency in adiponectin.

ABDOMINAL OBESITY AND CARDIOMETABOLIC RISK Anatomic fat location is highly determinant of the metabolic and endocrine effects of the adipocytes associated with this tissue. As discussed previously, adipocytes have important proinflammatory endocrine effects that increase cardiometabolic risk,22 and these risks may be particularly increased in individuals with abdominal obesity. In a detailed analysis of obese men, visceral adipose tissue was predictive of fasting insulin levels and insulin– glucose response to oral glucose load independent of the extent of obesity, the amount of

S16 subcutaneous adipose tissue, and the proportion of abdominal fat as measured by the ratio of abdominal to femoral fat deposition.25 An analysis of men of Asian Indian ethnicity found that these individuals had a high level of body fat relative to body mass index (BMI) and muscle mass, as well as a high proportion of visceral abdominal fat; fasting serum triglyceride and HDL cholesterol levels were directly correlated with insulin resistance and visceral fat but not subcutaneous adipose tissue.26 It is hypothesized that a predominance of visceral fat in abdominal obesity increases the rate of free fatty acid deposition in the liver and that this mechanism may explain the increased risks for insulin resistance and type 2 diabetes in ethnic populations that have a greater genetic propensity to store visceral fat as opposed to subcutaneous fat.22,26 Likewise, it has been proposed that the inability of the liver to metabolize excessive free fatty acids from visceral fat in abdominal obesity leads to intracellular fat accumulation. This hypothesis, along with the proposed endocrine consequences of abdominal obesity in terms of metabolism and insulin sensitivity, provide a new framework for considering the links between abdominal adiposity and diabetes risk.27 The association between abdominal adiposity and the risk of developing type 2 diabetes is well established. Hanley and colleagues28 reported that in a population of ⬎1,000 individuals, both BMI and waist circumference correlated directly with fasting insulin levels and were metabolic predictors of developing type 2 diabetes over a mean follow-up period of 5.2 years. Data from the Nurses’ Health Study likewise reported that BMI, waist circumference, and waist-to-hip ratio were all independent predictors of type 2 diabetes risk in women.29 Waist circumference ⬎100 cm (⬎39 in) in men and women has been linked to altered lipoprotein metabolism, as well as impaired insulin metabolism.30

Clinical Relevance of the Metabolic Syndrome The metabolic syndrome has been identified as a constellation of risk factors that increase cardiometabolic risk. The National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) identifies the metabolic syndrome in individuals exhibiting ⱖ3 critical traits, including waist circumference ⬎102 cm (⬎40 in) in men and ⬎88 cm (⬎35 in) in women, fasting triglycerides ⱖ150 mg/dL (1 mg/dL ⫽ 0.01129 mmol/L), HDL cholesterol ⬍40 mg/dL in men and ⬍50 mg/dL in women (1 mg/dL ⫽ 0.02586 mmol/L), blood pressure ⱖ130/ⱖ85 mm Hg or use of a blood pressure medication, and impaired fasting glucose ⱖ110 mg/dL (1 mg/dL ⫽ 0.05551 mmol/L).31,32 A joint statement by the American Heart Association (AHA) and the National Heart, Lung, and Blood Institute (NHLBI) proposed a similar definition but lowered the impaired fasting glucose threshold to ⱖ100 mg/dL (Table 2).33,34 The medical community continues to debate the importance of the metabolic syndrome in clinical practice. Some researchers contend that the label of metabolic syndrome in individuals with height-

The American Journal of Medicine, Vol 122, No 4A, April 2009 Table 2

Criteria defining the metabolic syndrome*

Risk Factor

Defining Level †

‡

Abdominal obesity (waist circumference) Men Women Triglycerides§ HDL cholesterol储 Men Women Blood pressure Fasting glucose¶

⬎102 cm (⬎40 in) ⬎88 cm (⬎35 in) ⱖ150 mg/dL ⬍40 mg/dL ⬍50 mg/dL ⱖ130/ⱖ85 mm Hg ⱖ100 mg/dL

HDL ⫽ high-density lipoprotein. *As defined by the National Cholesterol Education Program Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults III (NCEP ATP III) and a joint statement by the American Heart Association (AHA) and the National Heart, Lung, and Blood Institute (NHLBI). † Thresholds decrease to 90 cm and 80 cm in Asian men and women, respectively. ‡ Some male patients can develop multiple metabolic risk factors when the waist circumference is only marginally increased (e.g., 94-102 cm [37-40 in]). § 1 mg/dL ⫽ 0.01129 mmol/L. 储 1 mg/dL ⫽ 0.02586 mmol/L. ¶ 1 mg/dL ⫽ 0.05551 mmol/L. Adapted with permission from Circulation33 and JAMA.34

ened cardiometabolic risk does not offer any additional prognostic information.32,35 Another analysis concluded that the metabolic syndrome, as defined by NCEP ATP III, is less predictive of cardiometabolic risk than are the Diabetes Risk Score and the Framingham Risk Score, because both of these measures were tailored to specifically identify cardiovascular and diabetes disease risk.36 However, others still emphasize the importance of the metabolic syndrome as an independent cardiovascular risk factor.37 Regardless of the identification of the metabolic syndrome in individuals, the constellation of risk factors that define this syndrome has been shown to independently increase the risk for coronary heart disease.38 Abdominal adiposity substantially increases the risk of developing the metabolic syndrome, as defined by NCEP ATP III, and may be an important independent predictor of developing the associated cardiometabolic risk factors over time. In an observational analysis that tracked subjects over a period of 8 years, individuals with waist circumference levels above the cutoff levels for abdominal obesity identified by NCEP ATP III for white, black and Hispanic individuals (ⱖ102 cm [ⱖ40 in] in men and ⱖ88 cm [ⱖ35 in] in women) were 3 to 8 times more likely to develop the metabolic syndrome than were those with waist circumference levels ⬍94 cm (⬍37 in) in men and ⬍80 cm (⬍31 in) in women.39 The metabolic syndrome was defined as exhibiting ⱖ3 of the metabolic disorders identified in the NCEP ATP III definition, including dyslipidemia, hypertension, or type 2 diabetes.39 Regardless of the clinical significance of the metabolic syndrome as an independent disease

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entity, it is clear that abdominal obesity increases the risk for developing the cardiometabolic risk factors that define the syndrome.

SUMMARY Energy homeostasis is regulated by a neuroendocrine system that involves hormones secreted by the gut, central nervous system, and other sources, including adipose tissue. The endocrine effects of adipose tissue include a proinflammatory effect that contributes to the insulin resistance and atherosclerosis associated with overweight and obesity. In particular, evidence now suggests that excessive visceral fat is an important source of inflammation, and persons who exhibit abdominal obesity may be at higher risk for cardiometabolic disease that results in excess morbidity and mortality risk. Abdominal adiposity is a critical diagnostic tool to determine overall cardiometabolic risk in overweight and obesity, and patients should be assessed for BMI, as well as waist circumference, to determine global health risk profiles in clinical practice.

Author Disclosures The authors who contributed to this article have disclosed the following industry relationships: Judith Korner, MD, PhD, is a consultant for GlaxoSmithKline and a paid speaker for Merck & Co, Inc, and sanofi-aventis Pharmaceuticals, Inc. Stephen C. Woods, PhD, is a consultant and paid speaker for sanofi-aventis Pharmaceuticals, Inc. Kristina A. Woodworth has no relevant financial relationships with a commercial entity producing healthcarerelated products and/or services.

References 1. Schwartz MW, Woods SC, Porte D Jr, Seeley RJ, Baskin DG. Central nervous system control of food intake. Nature. 2000;404:661-671. 2. Lyon CJ, Law RE, Hsueh WA. Minireview: adiposity, inflammation, and atherogenesis. Endocrinology. 2003;144:2195-2200. 3. Trayhurn P, Wood IS. Adipokines: inflammation and the pleiotropic role of white adipose tissue. Br J Nutr. 2004;92:347-355. 4. Marette A. Mediators of cytokine-induced insulin resistance in obesity and other inflammatory settings. Curr Opin Clin Nutr Metab Care. 2002;5:377-383. 5. Marx J. Cellular warriors at the battle of the bulge. Science. 2003;299: 846-849. 6. Korner J, Aronne LJ. The emerging science of body weight regulation and its impact on obesity treatment. J Clin Invest. 2003;111:565-570. 7. Murphy KG, Bloom SR. Gut hormones and the regulation of energy homeostasis. Nature. 2006;444:854-859. 8. Leibel RL. The role of leptin in the control of body weight. Nutr Rev. 2002;60(pt 2):S15-S19. 9. Considine RV, Sinha MK, Heiman ML, et al. Serum immunoreactiveleptin concentrations in normal-weight and obese humans. N Engl J Med. 1996;334:292-295. 10. Beglinger C, Degen L, Matzinger D, D’Amato M, Drewe J. Loxiglumide, a CCK-A receptor antagonist, stimulates calorie intake and hunger feelings in humans. Am J Physiol Regul Integr Comp Physiol. 2001;280:R1149-R1154.

S17 11. West DB, Fey D, Woods SC. Cholecystokinin persistently suppresses meal size but not food intake in free-feeding rats. Am J Physiol. 1984;246(pt 2):R776-R787. 12. Korner J, Aronne LJ. Pharmacological approaches to weight reduction: therapeutic targets. J Clin Endocrinol Metab. 2004;89:2616-2621. 13. Di Marzo V, Goparaju SK, Wang L, et al. Leptin-regulated endocannabinoids are involved in maintaining food intake. Nature. 2001;410: 822-825. 14. Ravinet Trillou C, Delgorge C, Menet C, Arnone M, Soubrie P. CB1 cannabinoid receptor knockout in mice leads to leanness, resistance to diet-induced obesity and enhanced leptin sensitivity. Int J Obes Relat Metab Disord. 2004;28:640-648. 15. Cota D, Marsicano G, Tschop M, et al. The endogenous cannabinoid system affects energy balance via central orexigenic drive and peripheral lipogenesis. J Clin Invest. 2003;112:423-431. 16. Kirkham TC, Williams CM, Fezza F, Di Marzo V. Endocannabinoid levels in rat limbic forebrain and hypothalamus in relation to fasting, feeding and satiation: stimulation of eating by 2-arachidonoyl glycerol. Br J Pharmacol. 2002;136:550-557. 17. Jamshidi N, Taylor DA. Anandamide administration into the ventromedial hypothalamus stimulates appetite in rats. Br J Pharmacol. 2001;134:1151-1154. 18. Cani PD, Montoya ML, Neyrinck AM, Delzenne NM, Lambert DM. Potential modulation of plasma ghrelin and glucagon-like peptide–1 by anorexigenic cannabinoid compounds, SR141716A (rimonabant) and oleoylethanolamide. Br J Nutr. 2004;92:757-761. 19. Pi-Sunyer FX, Aronne LJ, Devin J, Rosenstock J. Effect of rimonabant, a cannabinoid-1 receptor blocker, on weight and cardiometabolic risk factors in overweight or obese patients, Rio-North America: a randomized controlled trial. JAMA. 2006;295:761-775. 20. Van Gaal LF, Rissanen AM, Scheen AJ, Ziegler O, Rossner S. Effects of the cannabinoid-1 receptor blocker rimonabant on weight reduction and cardiovascular risk factors in overweight patients: 1-year experience from the RIO-Europe study. Lancet. 2005;365:1389-1397. 21. Després JP, Golay A, Sjostrom L. Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia. N Engl J Med. 2005;353:2121-2134. 22. Eckel RH, Grundy SM, Zimmet PZ. The metabolic syndrome. Lancet. 2005;365:1415-1428. 23. Ridker PM, Glynn RJ, Hennekens CH. C-reactive protein adds to the predictive value of total and HDL cholesterol in determining risk of first myocardial infarction. Circulation. 1998;97:2007-2011. 24. Matias I, Gonthier MP, Orlando P, et al. Regulation, function, and dysregulation of endocannabinoids in models of adipose and betapancreatic cells and in obesity and hyperglycemia. J Clin Endocrinol Metab. 2006;91:3171-3180. 25. Pouliot MC, Després JP, Nadeau A, et al. Visceral obesity in men: associations with glucose tolerance, plasma insulin, and lipoprotein levels. Diabetes. 1992;41:826-834. 26. Banerji MA, Faridi N, Atluri R, Chaiken RL, Lebovitz HE. Body composition, visceral fat, leptin, and insulin resistance in Asian Indian men. J Clin Endocrinol Metab. 1999;84:137-144. 27. Heilbronn L, Smith SR, Ravussin E. Failure of fat cell proliferation, mitochondrial function and fat oxidation results in ectopic fat storage, insulin resistance and type II diabetes mellitus. Int J Obes Relat Metab Disord. 2004;28(suppl 4):S12-S21. 28. Hanley AJ, Festa A, D’Agostino RB Jr, et al. Metabolic and inflammation variable clusters and prediction of type 2 diabetes: factor analysis using directly measured insulin sensitivity. Diabetes. 2004; 53:1773-1781. 29. Carey VJ, Walters EE, Colditz GA, et al. Body fat distribution and risk of non-insulin-dependent diabetes mellitus in women: the Nurses’ Health Study. Am J Epidemiol. 1997;145:614-619. 30. Pouliot MC, Després JP, Lemieux S, et al. Waist circumference and abdominal sagittal diameter: best simple anthropometric indexes of abdominal visceral adipose tissue accumulation and related cardiovascular risk in men and women. Am J Cardiol. 1994;73:460468.

S18 31. Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation. 2002;106:3143-3421. 32. Iribarren C, Go AS, Husson G, et al. Metabolic syndrome and earlyonset coronary artery disease: is the whole greater than its parts? J Am Coll Cardiol. 2006;48:1800-1807. 33. Grundy SM, Cleeman JI, Daniels SR, et al. Diagnosis and management of the metabolic syndrome: an American Heart Association/National Heart, Lung, and Blood Institute Scientific Statement. Circulation. 2005;112:2735-2752. 34. Executive Summary of The Third Report of The National Cholesterol Education Program (NCEP). JAMA. 2001;285:2486-2497 35. Kahn R, Buse J, Ferrannini E, Stern M. The metabolic syndrome: time for a critical appraisal. Joint statement from the American Diabetes

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36.

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Association and the European Association for the Study of Diabetes. Diabetes Care. 2005;28:2289-2304. Stern MP, Williams K, Gonzalez-Villalpando C, Hunt KJ, Haffner SM. Does the metabolic syndrome improve identification of individuals at risk of type 2 diabetes and/or cardiovascular disease? Diabetes Care. 2004;27:2676-2681. Grundy SM. Metabolic syndrome: a multiplex cardiovascular risk factor. J Clin Endocrinol Metab. 2007;92:399-404. Alexander CM, Landsman PB, Teutsch SM, Haffner SM. NCEPdefined metabolic syndrome, diabetes, and prevalence of coronary heart disease among NHANES III participants age 50 years and older. Diabetes. 2003;52:1210-1214. Han TS, Williams K, Sattar N, Hunt KJ, Lean ME, Haffner SM. Analysis of obesity and hyperinsulinemia in the development of metabolic syndrome: San Antonio Heart Study. Obes Res. 2002;10:923-931.

Supplement issue

Obesity Prevention: Recommended Strategies and Challenges Anne M. Wolf, RD, MS,a Kristina A. Woodworthb a Department of Public Health Sciences, University of Virginia School of Medicine, Charlottesville, Virginia, USA; and bSciMantis Communications, Inc, Pen Argyl, Pennsylvania, USA.

ABSTRACT Lifelong healthy weight maintenance is an important goal for all Americans to avoid the health problems associated with excessive body weight. In those who are overweight, even modest weight loss can reduce the risk of developing diseases associated with obesity. Federal health agencies, including the Centers for Disease Control and Prevention and the US Department of Agriculture, have recognized the critical nature of the obesity epidemic and the importance of lifelong weight management. As a result, these agencies have published evidence-based dietary and exercise recommendations, as well as analyses of population-based efforts to achieve weight loss that specifically address strategies to maintain a healthy weight. Despite the availability of recommendations and increased public education efforts, however, obesity rates continue to climb. The rising prevalence of obesity in the United States suggests that current efforts to control weight have been inadequate. Large-scale prevention programs that involve interventions targeting individuals as well as the larger community, including initiatives spearheaded through workplaces and schools, are needed to control weight and reduce the risk of long-term health consequences. © 2009 Elsevier Inc. All rights reserved. • The American Journal of Medicine (2009) 122, S19 –S23 KEYWORDS: Prevention; Obesity; Diet; Physical activity

INTRODUCTION Weight maintenance is an important lifelong health goal to reduce the risk of cardiometabolic complications and other substantial health problems that can arise with overweight and obesity. Lifestyle interventions that achieve even modest weight loss may reduce the risk of developing type 2 diabetes mellitus in overweight individuals with insulin resistance.1-3 Likewise, modest reductions in abdominal fat may reduce overall cardiometabolic risk.4 The substantial health benefits of healthy weight management are now recognized and have resulted in a call for large-scale prevention efforts. The likely benefits of obesity prevention have been recognized by organizations devoted to public health, including the Robert Wood Johnson Foundation. The foundation has vowed to devote $500 million in funds to combat childhood obesity, with a goal of reversing the obesity Statement of author disclosure: Please see the Author Disclosures section at the end of this article. Requests for reprints should be addressed to Anne M. Wolf, RD, MS, Department of Public Health Sciences, University of Virginia School of Medicine, 5030 Rutherford Rd, Charlottesville, VA 22901. E-mail address: [email protected]

0002-9343/$ -see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.amjmed.2009.01.004

epidemic trend in American children by 2015.5 This review discusses current dietary and exercise guidelines for healthy weight maintenance, the call to action for large-scale obesity prevention strategies, the role that the community can play in helping individuals achieve long-term weight management goals, and the barriers to implementing effective obesity prevention programs.

CENTERS FOR DISEASE CONTROL AND PREVENTION OBESITY CONTROL EFFORTS The Centers for Disease Control and Prevention (CDC) has examined the importance of population-based efforts to control obesity and increase physical activity. Results from these analyses are available in the CDC Guide to Community Preventive Services as a resource for local officials to develop communityspecific and site-specific plans to improve health.6

Population-Based Interventions The CDC Guide to Community Preventive Services provides a systematic review of the effectiveness of population-based interventions in preventing obesity, including school-based interventions, worksite interventions, healthcare system inter-

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Table 1

Centers for Disease Control and Prevention (CDC) Evidence-Based Recommendations for Promoting Physical Activity Intervention

Informational approaches Community-wide campaigns “Point-of-decision” prompts Behavioral and social approaches Individually adapted health behavior change programs School-based physical education Nonfamily social support Environmental and policy approaches Creation of and/or enhanced access to places for physical activity combined with informational outreach activities

Description Large-scale, highly visible, community-wide campaigns through television, radio, newspapers, movie theaters, billboards, and mailings Signs posted at elevators and escalators encouraging individuals to use stairs Teach behavioral skills to help incorporate physical activity into daily routines Longer classes, encouraging students to be more active during class Social networks of exercise groups Groups working to change the environment to promote physical activity with the creation of, or improved access to, for example, walking trails and exercise facilities.

Adapted from Physical activity, 2007 in The Community Guide.8

ventions, and community-wide interventions.6 Analyses have been completed for school-based interventions and interventions in the workplace. Worksite interventions are supported by the available literature and were therefore recommended by the CDC to combat obesity. The CDC suggests multicomponent interventions that target diet, physical activity, and behavioral changes, because these strategies have been found to be effective when delivered through the workplace.6 Singlecomponent programs that targeted only nutrition, physical activity, or behavioral intervention lacked sufficient evidence for support based on systematic reviews.7 The CDC report noted that worksite interventions to prevent and control overweight and obesity are cost-effective, with an estimated cost of less than $1 per employee per year to reach 1% of the population at risk, which may be an important selling point in encouraging employers to support these onsite programs.7 A full summary of the systematic reviews that resulted in the CDC recommendations for obesity prevention in schools and the workplace was published in 2005.7 Although insufficient evidence is available to fully recommend systematic school-based interventions, the CDC guide noted that several program elements should be considered when designing future policies aimed at combating childhood obesity. Modest positive changes were found with interventions that integrated nutritional education with physical activity; allotted additional time for physical activity during the school day; included noncompetitive sports, such as dance, in the physical education curriculum; and emphasized the limitations of sedentary activities, especially television viewing. Internet use and video games were also cited as possible sources of additional sedentary time that were worthy of future investigation.7

Physical Activity Recommendations The CDC Guide to Community Preventive Services likewise offers a systematic review of efforts designed to increase phys-

ical activity, including informational approaches, behavioral and social approaches, and environmental and policy approaches.7 The CDC review of the literature has identified multiple strategies for increasing physical activity that are strongly supported by the literature. These strategies are summarized in Table 1, and additional details are available in the published document.8 Additional strategies to promote physical activity are currently under review, including transportation policy and infrastructure changes to promote nonmotorized transit and new urban planning approaches that change zoning and land use.8

US DEPARTMENT OF AGRICULTURE DIETARY GUIDELINES AND WEIGHT CONTROL The US Department of Agriculture (USDA) Dietary Guidelines for Americans are updated every 5 years and were last published in 2005.9 Individuals should be encouraged to follow these established dietary guidelines regularly for long-term weight maintenance. The guidelines stress the importance of a diet rich in fruits and vegetables, suggesting that individuals with a 2,000-calorie daily target should consume 2 cups of fruits and 2.5 cups of vegetables each day (1 c ⫽ 0.24 L), which translates to ⱖ9 daily servings of fruits and vegetables. Furthermore, the guidelines emphasize that individuals should choose a variety of fruits and vegetables from all 5 vegetable subgroups (dark green, orange, legumes, starchy vegetables, and other vegetables) several times each week.9 In support of these recommendations, the CDC offers publications to support a large-scale campaign to increase fruit and vegetable consumption.10 The USDA also recommends that individuals consume ⱖ3 ounce-equivalent (1 oz ⫽ 30 mL) servings of whole grain products daily and emphasizes that ⱖ50% of grain products consumed should come from whole grains.9 This level of whole grains in the diet, along with suggested amounts of fruits and vegetables, contributes to the daily

Wolf and Woodworth Table 2

Strategies and Challenges in Obesity Prevention

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Key Recommendations of the US Department of Agriculture (USDA) Dietary Guidelines for Americans, 2005 Category

Food group Fruits and vegetables Grains Macronutrients Fiber Total fat Saturated fat Physical activity To prevent chronic disease To help manage body weight and avoid weight gain To help maintain weight loss

Recommendations at the 2,000-Calorie Level Choose a diet rich in fruits and vegetables, consuming 2 cups of fruits and 2.5 cups* of vegetables each day, which translates to ⱖ9 daily servings Consume ⱖ3 or more ounce-equivalent† servings of whole-grain products daily; ⱖ50% of grain products consumed should come from whole grains 28 g/day 20%-35% of calories consumed should come from fat ⬍10% of calories consumed should come from saturated fat ⱖ30 min of moderate-intensity physical activity on most days of the week ⱖ60 min of moderate- to vigorous-intensity physical activity on most days of the week 60-90 min of moderate-intensity physical activity daily

Adapted from Dietary Guidelines for Americans.9 *1 c ⫽ 0.24 L. † 1 oz ⫽ 30 mL.

fiber intake of 25 to 30 g/day recommended by the USDA and the American Heart Association (AHA).11 Of note, Howarth and colleagues12 found that high-fiber diets of 25 to 30 g/day increase satiety, reduce hunger, and improve weight loss. The authors concluded that the prevalence of obesity could be reduced if individuals increased target daily fiber levels from 15 g to 25 to 30 g, with the goal achieved by replacing refined grain products with whole grains and increasing fruit and vegetable consumption. According to the USDA guidelines, individuals should limit total fat intake to 20% to 35% of daily calories, with most fats coming from polyunsaturated or monounsaturated sources.9 Meta-analyses of low-fat diets that consist of only 25% to 30% of total calories from fat confirm that these recommendations likely contribute to weight loss. One meta-analysis of 16 studies of low-fat diets with 19 intervention groups concluded that this dietary strategy results in weight loss of 3.2 kg greater than that in control groups.13 Another meta-analysis of 37 studies likewise found a positive correlation between fat intake and weight loss.14 The 2005 update of the USDA dietary guidelines represents the first time that physical activity recommendations were offered, with the goals of promoting health, psychological well-being, and weight maintenance.9 The guidelines recommend that adults should engage in ⱖ30 minutes of moderate-intensity physical activity on most days of the week to prevent chronic disease. To help manage body weight and avoid weight gain, the guidelines suggest that individuals should engage in ⱖ60 minutes of moderateto vigorous-intensity activity on most days of the week; to help maintain weight loss, moderate-intensity exercise of 60 to 90 minutes daily is recommended. A summary of the USDA dietary and exercise guidelines is presented in Table 2.9

A TOXIC ENVIRONMENT: INCREASED AVAILABILITY AND CONSUMPTION OF UNHEALTHY FOODS Portion Control, Sugar-Sweetened Drinks, and Sodium Intake Portion control at each meal is critical to maintain weight and prevent weight gain over time, and has been cited as an important contributor to the current obesity epidemic. Rolls and associates15 demonstrated a significant relation between the amount of a particular food (macaroni and cheese) offered at each meal and the amount of that food consumed (P ⬍0.0001). The authors noted that in contrast to observations from previous studies, larger portion sizes led to greater amounts of energy consumed: overall, 30% more energy was consumed with the largest portion size compared with energy consumed with the smallest portion size. These findings stress the importance of portion control and highlight the likely health ramifications of convenience foods that are offered in ever-increasing portion sizes. The habitual consumption of high-calorie, sugar-based drinks is another appropriate target to control daily energy intake and prevent weight gain. In another study by Rolls and associates,16 sugar-based drinks consumed with meals increased the overall energy intake during the meal because individuals demonstrated a lack of compensation by consuming fewer food calories during the meal. Drinks sweetened with the artificial sweetener aspartame, meanwhile, did not increase the amount of food consumed during the meal and therefore did not increase energy intake. Sugar-based drinks also had a lower ability to quench thirst than did aspartame-sweetened drinks and water, suggesting that a higher amount of sugar-based drink, and consequently a greater energy intake, may be consumed during a meal if this type of drink is chosen as a meal accompaniment.16 In

S22 school-aged children, the incidence of childhood obesity was found to be 1.6 times greater with each serving of sugar-sweetened drinks consumed per day. Likewise, baseline consumption of sugar-based drinks and changes in consumption over the course of the study independently predicted changes in body mass index (BMI).17 Interventions that stress reductions in the amount of sugar-based drinks consumed may have an important impact on obesity prevention. Increases in sodium intake by the American population in recent decades may be another important underlying factor in the current obesity epidemic. According to the Salt Institute, a North American trade organization, total purchases of salt intended for human consumption in the United States increased by 86%, and per capita sales increased by 55%, between 1983 and 1998.18 Meanwhile, energy consumption from sugar-sweetened beverages increased by 135% from 1977 to 2001, and milk consumption declined by 38% during the same period. A higher level of dietary sodium results in a greater degree of thirst, which may contribute to obesity in an environment of high levels of energy consumed from sugar-sweetened drinks, especially carbonated soft drinks. Overall, it is estimated that Americans now consume an additional 278 calories each day because of changes in patterns of drink consumption.18

Food Consumption Outside of the Home An increase in the number of meals consumed outside of the home and a simultaneous decrease in the number of meals prepared at home have also been cited as contributing to the problem of obesity. In a study of 73 adults who completed questionnaires on the frequency of food intake from various restaurant settings, McCrory and coworkers19 reported that the frequency of eating foods from restaurants serving fried chicken, burgers, pizza, Chinese food, Mexican food, fried fish, and other convenience foods was directly associated with body fatness. A greater frequency of consuming these restaurant foods was also associated with higher levels of total fat and saturated fat intake and lower levels of fiber intake. Although healthy meals prepared at home may be ideal, public education efforts should at least emphasize healthy food choices and closer attention to restaurant and convenience foods consumed on a regular basis. Current patterns of food consumption in the United States highlight the importance of public education efforts designed to improve eating habits and public health. Whereas education may be 1 component in a larger strategy to reduce the obesity trend, society-wide changes will ultimately be necessary to bring about lasting change.

THE ROLE OF THE COMMUNITY IN OBESITY PREVENTION Society can play a critical role in supporting obesity prevention efforts. As suggested by the CDC recommendations for physical activity,8 obesity prevention strategies should recognize the limitations of individual lifestyle changes

The American Journal of Medicine, Vol 122, No 4A, April 2009 when the surrounding environment and community do not support these efforts. Prevention efforts should be designed to exert influence at the level of the individual, the overall community environment, and governmental policy. Social networks, including churches, community groups, schools, and other organizations, are important targets for intervention to achieve large-scale obesity prevention at the population level.20

Obesity Prevention: A Global Call to Action The obesity crisis has been highlighted by the fact that the World Health Organization (WHO) has recognized obesity as a critical concern that needs to be addressed through global health policy. The Global Alliance for the Prevention of Obesity and Related Chronic Disease is a worldwide initiative to combat obesity and comprises 5 organizations linked to the WHO, including the International Association for the Study of Obesity (IASO), the World Heart Federation (WHF), the International Diabetes Federation (IDF), the International Pediatric Association (IPA), and the International Union of Nutritional Sciences (IUNS). In response to a call to action from the WHO to prevent chronic disease linked to unhealthy diet, sedentary lifestyles, and tobacco use, the Alliance is now in the process of developing guidelines that focus on preventing childhood obesity through improvements in diet and physical activity, as well as developing local, best-practice prevention models.21

CHALLENGES IN ACHIEVING WEIGHT LOSS AND MAINTAINING WEIGHT Despite increasing levels of concern and the introduction of large-scale public health initiatives, obesity prevention efforts to date have been essentially ineffective in reversing obesity trends in the United States. The Trust for America’s Health, a nonpartisan health advocacy organization, has reported that US obesity prevention efforts are failing.22 The organization cites several critical barriers to effective obesity prevention: funds and political prioritization are lacking to support sustained obesity prevention efforts; obesity research is not being translated effectively into clinical practice; the public perceives obesity as an individual concern; and current measurements of success and behavior change, including BMI and weight loss, are limited. Public education programs that highlight the health risks of overweight and obesity may be required to motivate individuals to lose weight. Moreover, substantial policy changes are necessary to promote obesity prevention efforts.

SUMMARY The high prevalence of obesity represents a public health crisis that requires effective prevention efforts to stem the rising costs of managing cardiometabolic risk and other substantial health problems that arise with excessive body weight. Although the problem of obesity is now being recognized with large-scale prevention efforts, it is clear that treatment strategies are needed to address the health

Wolf and Woodworth

Strategies and Challenges in Obesity Prevention

risks and resulting medical costs in the large population of individuals who already suffer from obesity. Lifestyle modification that emphasizes a healthy diet and regular exercise is the ideal route to combat overweight and obesity, but many individuals may realize lasting weight loss only with advanced treatment interventions. Current obesity prevention efforts should be driven by interventions through schools and worksites that promote healthy diets and regular exercise, and these interventions should be complemented by larger environmental and policy initiatives that expand opportunities for physical activity.

8.

9.

10.

AUTHOR DISCLOSURES The authors who contributed to this article have disclosed the following industry relationships: Anne M. Wolf, RD, MS, has disclosed that the commercial entities with which she has relationships do not produce healthcare-related products or services relevant to the content she is planning, developing, or presenting for this activity. Kristina A. Woodworth has no relevant financial relationships with a commercial entity producing healthcarerelated products and/or services.

11.

12. 13.

14.

References 1. Knowler WC, Barrett-Connor E, Fowler SE, et al, for the Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346:393-403. 2. Orchard TJ, Temprosa M, Goldberg R, et al, for the Diabetes Prevention Program Research Group. The effect of metformin and intensive lifestyle intervention on the metabolic syndrome: the Diabetes Prevention Program randomized trial. Ann Intern Med. 2005;142:611-619. 3. Tuomilehto J, Lindström J, Eriksson JG, et al, for the Finnish Diabetes Prevention Study Group. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med. 2001;344:1343-1350. 4. Després JP. Dyslipidaemia and obesity. Baillières Clin Endocrinol Metab. 1994;8:629-660. 5. Robert Wood Johnson Foundation Announces $500-Million Commitment to Reverse Childhood Obesity in US [press release]. Princeton, NJ: Robert Wood Johnson Foundation, April 4, 2007. Available at: http://www.rwjf.org/newsroom/product.jsp?id⫽21938. Accessed December 14, 2008. 6. Centers for Disease Control and Prevention (CDC). Guide to Community Preventive Services (The Community Guide). [CDC Website.] Updated June 14, 2005. Available at: http://www.thecommunityguide. org/obese/default.htm. Accessed March 24, 2008. 7. Katz DL, O’Connell M, Yeh M-C, et al. Public health strategies for preventing and controlling overweight and obesity in school and worksite settings: a report on recommendations from the Task Force on

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Community Preventive Services. MMWR Recomm Rep. 2005;54:1-12. Available at: http://www.cdc.gov/mmwr/preview/mmwrhtml/rr5410a1. htm. Accessed March 24, 2008. Centers for Disease Control and Prevention (CDC). Physical activity. In: Guide to Community Preventive Services (The Community Guide). [CDC Website.] Updated December 7, 2004. Available at: http:// www.thecommunityguide.org/pa/. Accessed March 24, 2008. US Department of Health and Human Services (HHS), US Department of Agriculture (USDA). Dietary Guidelines for Americans. [HHS Website.] Updated October 16, 2006. Washington, DC: Office of Disease Prevention and Health Promotion, US Dept of Health and Human Services, 2005. Available at: http://health.gov/dietaryguidelines/. Accessed March 24, 2008. Centers for Disease Control and Prevention (CDC). Eat a variety of fruits & vegetables every day [campaign]. Publications. [CDC Website.] Available at: http://www.fruitsandveggiesmatter.gov/publications/index.html. Accessed December 30, 2008. Krauss RM, Deckelbaum RJ, Ernst N, et al. Dietary guidelines for healthy American adults: a statement for health professionals from the Nutrition Committee, American Heart Association. Circulation. 1996; 94:1795-1800. Howarth NC, Saltzman E, Roberts SB. Dietary fiber and weight regulation. Nutr Rev. 2001;59:129-139. Astrup A, Grunwald GK, Melanson EL, Saris WH, Hill JO. The role of low-fat diets in body weight control: a meta-analysis of ad libitum dietary intervention studies. Int J Obes Relat Metab Disord. 2000;24: 1545-1552. Yu-Poth S, Zhao G, Etherton T, Naglak M, Jonnalagadda S, KrisEtherton PM. Effects of the National Cholesterol Education Program’s Step I and Step II dietary intervention programs on cardiovascular disease risk factors: a meta-analysis. Am J Clin Nutr. 1999;69:632646. Rolls BJ, Morris EL, Roe LS. Portion size of food affects energy intake in normal-weight and overweight men and women. Am J Clin Nutr. 2002;76:1207-1213. Rolls BJ, Kim S, Fedoroff IC. Effects of drinks sweetened with sucrose or aspartame on hunger, thirst and food intake in men. Physiol Behav. 1990;48:19-26. Ludwig DS, Peterson KE, Gortmaker SL. Relation between consumption of sugar-sweetened drinks and childhood obesity: a prospective, observational analysis. Lancet. 2001;357:505-508. Karppanen H, Mervaala E. Sodium intake and hypertension. Prog Cardiovasc Dis. 2006;49:59-75. McCrory MA, Fuss PJ, Hays NP, Vinken AG, Greenberg AS, Roberts SB. Overeating in America: association between restaurant food consumption and body fatness in healthy adult men and women ages 19 to 80. Obes Res. 1999;7:564-571. Stokols D. Translating social ecological theory into guidelines for community health promotion. Am J Health Promot. 1996;10:282-298. Global Alliance for the Prevention of Obesity and Related Chronic Disease [Website]. Available at: http://www.preventionalliance.net/. Accessed March 24, 2008. Trust for America’s Health. F as in Fat: How Obesity Policies Are Failing in America, 2006 [report]. [TFAH Website.] August 2006. Available at: http://healthyamericans.org/reports/obesity2006/. Accessed March 24, 2008.

Supplement issue

When Prevention Fails: Obesity Treatment Strategies Louis J. Aronne, MD,a Thomas Wadden, PhD,b Kathy Keenan Isoldi, MS, RD, CDE,c Kristina A. Woodworthd a Department of Medicine, Weill Cornell Medical College, and Comprehensive Weight Control Program, New York-Presbyterian Hospital, New York, New York, USA; bDepartment of Psychology, University of Pennsylvania School of Medicine, and Center for Weight and Eating Disorders, University of Pennsylvania, Philadelphia, Pennsylvania, USA; cClinical Nutrition Services, Comprehensive Weight Control Program, New York-Presbyterian Hospital, New York, New York, USA; and dSciMantis Communications, Inc, Pen Argyl, Pennsylvania, USA

ABSTRACT The obesity epidemic has resulted in increasingly urgent calls for large-scale prevention strategies. Meanwhile, effective treatment approaches that result in sustainable weight loss are needed to attenuate the cardiometabolic risks that may lead to comorbid illnesses and early mortality. Public education efforts geared toward those afflicted with obesity should emphasize that a relatively modest reduction in body weight dramatically reduces disease risk, thereby improving overall long-term health. Setting realistic weight loss goals with patients should reduce the overwhelming frustration often associated with the belief that large amounts of weight loss are needed for improved health. This misconception often impedes overweight and obese individuals from seeking treatment. Effective strategies are available to help overweight and obese individuals achieve reasonable weight loss goals. Important challenges exist in preventing weight regain following weight loss intervention. Studies are underway to identify new therapeutic strategies to effectively reduce weight, as well as to provide long-term data on successful weight loss maintenance strategies. © 2009 Published by Elsevier Inc. • The American Journal of Medicine (2009) 122, S24 –S32 KEYWORDS: Exercise; Diet and lifestyle intervention; Obesity treatment; Pharmacotherapy; Weight loss

Obesity rates in the United States have more than doubled from 1960 to 2000,1 suggesting that current efforts to prevent excess weight gain in this country have been unsuccessful. Obesity confers an increased risk of developing debilitating and life-threatening illnesses, including cardiovascular disease and type 2 diabetes mellitus, that often leads to substantial comorbid disease burden and early mortality.2 Substantial health benefits can be realized with relatively modest weight loss.3,4 However, research reports indicate that many obese individuals unrealistically desire to lose ⬎25% of their body weight.5 Public education efforts should stress the benefits of modest, obtainable weight loss to encourage overweight and obese individuals to engage in weight loss interventions. Effective strategies, including lifestyle interventions that emphasize calorie restrictions Statement of author disclosure: Please see the Author Disclosures section at the end of this article. Requests for reprints should be addressed to Louis J. Aronne, MD, Weill Cornell Medical College, Comprehensive Weight Control Program, New York-Presbyterian Hospital, 1165 York Avenue, New York, New York 10028. E-mail address: [email protected]

0002-9343/$ -see front matter © 2009 Published by Elsevier Inc. doi:10.1016/j.amjmed.2009.01.005

and increased physical activity, as well as appropriate pharmacologic treatments, have been shown to promote modest weight loss.6,7 However, many individuals continue to encounter multiple obstacles that prevent maintenance of lost weight over long periods. Strategies that reduce weight and maintain weight loss over time should be made available to all overweight and obese individuals; however, individuals who are most vulnerable to substantial, long-term health risks should be targeted for intensive risk factor reduction. Treatment strategies, including novel pharmacologic options, are being investigated for their role in reducing weight and supporting long-term weight loss in obese individuals. This review highlights important issues in obesity treatment and the role of multifaceted management strategies in achieving longterm weight loss success.

INITIAL PATIENT PRESENTATION AND EVALUATION Obese and overweight patients who are at risk for health complications should receive a complete physical examination

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Table 1 Overweight and obesity classifications by body mass index (BMI)

Table 2 Waist circumference thresholds for abdominal obesity by race/ethnicity

Classification

BMI

Race/Ethnicity

Men

Underweight Normal weight Overweight Obesity (class 1) Obesity (class 2) Extreme obesity (class 3)

⬍18.5 18.5-24.9 25-29.9 30-34.9 35-39.9 ⱖ40

White/black/Hispanic* White† South Asian Chinese Japanese

⬎102 ⱖ94 ⱖ90 ⱖ90 ⱖ85

Adapted from JAMA.2

and review of blood chemistries to investigate whether excess weight gain is owing to a physiologic cause, such as thyroid dysfunction. Clinicians should review current medication use with their patients to screen for likely weight gain culprits, because many medications can induce weight gain.8,9 Medications that may promote weight gain include, but are not limited to, common diabetes treatments (sulfonylureas, thiazolidinediones, insulin), antiepileptics (gabapentin, sodium valproate), antipsychotics (clozapine, risperidone, olanzapine), steroid hormones (corticosteroids), tricyclic antidepressants, and certain other antidepressants.8,10 Initial patient evaluations should include assessments of body mass index (BMI), waist circumference, and overall medical risk.2 The clinician should aim to evaluate the patient’s personal motivations for wishing to lose weight. It is important to also discuss the patient’s understanding of the possible risks of weight loss interventions, the benefits of effective weight loss, the patient’s history of methods and outcomes of previous weight loss attempts, anticipated support from family and friends, personal attitudes toward physical activity, time availability, and possible barriers to weight loss, including financial limitations.2 Although the content of this important discussion appears lengthy, the information can be obtained rather quickly, will set the foundation for continued follow-up care, and ultimately will lead to improvement in overall weight loss outcome.

Body Mass Index BMI is an important screening tool to assess patients with excess body weight and stratify treatments according to the likelihood of underlying disease risk. BMI is calculated by dividing an individual’s weight in kilograms by the squared product of the individual’s height in meters.2 The determination of BMI may provide a better determination of global disease risk than does assessing the patient’s weight alone. However, BMI is a limited diagnostic tool in very muscular individuals and those with little muscle mass, such as elderly patients.2 Clinical judgment, as well as the use of varied tools to assess risk, should aid in appropriately diagnosing overweight or obesity. Overweight and obesity classifications by BMI are presented in Table 1. Persons with a BMI of 25 to 29.9 are classified as overweight, whereas those with a BMI ⱖ30 are considered obese.2

Women cm cm cm cm cm

(⬎40 (ⱖ37 (ⱖ35 (ⱖ35 (ⱖ33

in) in) in) in) in)

⬎88 ⱖ80 ⱖ80 ⱖ80 ⱖ90

cm cm cm cm cm

(⬎35 (ⱖ31 (ⱖ31 (ⱖ31 (ⱖ35

in) in) in) in) in)

*National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) definition. † International Diabetes Federation (IDF) definition. Adapted from Circulation,13 IDF,14 and JAMA.15

Assessment of Abdominal Obesity Whereas BMI is an important screening tool, waist circumference provides important additional prognostic information, especially when BMI is not substantially increased but an unhealthy level of excessive adiposity is still suspected.11 Waist circumference correlates with abdominal obesity, the presence of which confers a higher absolute disease risk.11 To accurately measure waist circumference, the clinician should stand to the right of the patient and locate the patient’s right iliac crest by palpating the upper hipbone. A horizontal mark should be drawn at the uppermost lateral border of the right iliac crest, and the mark should be crossed with a vertical mark. A tape measure should be used to measure the waist circumference at this point, taking care to keep the plane of the tape parallel to the floor and avoid compression of the skin with the tape. The measurement is made at the end of a normal expiration.11 Waist circumference is an important surrogate measure of abdominal obesity and disease risk. A higher risk for diabetes, dyslipidemia, hypertension, and cardiovascular disease has been associated with a waist circumference ⬎102 cm (⬎40 in) in men and ⬎88 cm (⬎35 in) in women. One study demonstrated effective utility of waist circumference as a predictor of the metabolic syndrome, type 2 diabetes, and other cardiometabolic risk factors.12 However, waist measurements do not add any value in estimating disease risk in individuals with a BMI ⱖ35.2 Moreover, it should be emphasized that waist circumference thresholds for abdominal obesity vary with race/ethnicity (Table 2).13-15 In summary, waist circumference, along with BMI, should be used to assess obesity, cardiovascular disease risk, and the efficacy of weight loss regimens.11

Cardiometabolic Risk Assessment Excess weight increases the risk of developing cardiovascular and metabolic diseases and ensuing complications. Overweight and obese individuals who have a history of established coronary heart disease (CHD), other atherosclerotic diseases, type 2 diabetes, or sleep apnea are at the highest level of absolute risk for morbidity and mortality.2 Overweight and obese patients should be evaluated for these conditions and managed appropriately. A high level of ab-

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The American Journal of Medicine, Vol 122, No 4A, April 2009 1

Patient encounter

2

Hx of ≥ 25 BMI?

Yes 3

BMI measured in past 2 years? 5

• Measure weight, height, 4

and waist circumference • Calculate BMI

BMI ≥25 OR waist circumference > 35 in (88 cm) (F) > 40 in (102 cm) (M)

7

6

Yes

Assess risk factors

BMI ≥ 30 OR {[BMI 25 to 29.9 OR waist circumference > 35 in (F) > 40 in (M)] AND ≥ 2 risk factors }

Yes 8

Clinician and patient devise goals and treatment strategy for weight loss and risk factor control

No

14

Hx ≥ 25 BMI? 15

12

Does patient want to lose weight?

13

No

Brief reinforcement/ educate on weight management

16

No

Yes

Advise to maintain weight/address other risk factors

Periodic weight, BMI, and waist circumference check

Examination

Yes

9

No

Progress being made/goal achieved? Yes

No

Maintenance counseling: • Dietary therapy • Behavior therapy • Physical activity

Assess reasons for failure to lose weight 10

Treatment

11

* This algorithm applies only to the assessment for overweight and obesity and subsequent decisions based on that assessment. It does not reflect any initial overall assessment for other cardiovascular risk factors that are indicated.

Figure 1 Treatment algorithm for the assessment of patients with overweight and obesity. BMI ⫽ body mass index; F ⫽ females; Hx ⫽ history; M ⫽ males. (Adapted with permission from The Practical Guide: Identification, Evaluation, and Treatment of Overweight and Obesity in Adults.2)

solute risk is also associated with individuals who exhibit ⱖ3 of the following characteristics: hypertension, cigarette smoking, high low-density lipoprotein (LDL) cholesterol levels, low high-density lipoprotein (HDL) cholesterol levels, impaired fasting glucose, a family history of early cardiovascular disease, and advanced age (ⱖ45 years in men, ⱖ55 years in women).2 A suggested treatment algorithm to address excess weight and cardiometabolic risk has been developed and published by the National Heart, Lung, and Blood Institute (NHLBI) (Figure 1).2

DECIDING ON TREATMENT The NHLBI Practical Guide has recommended appropriate weight loss therapy in patients with a BMI ⱖ30; likewise, weight loss interventions are recommended in patients with a BMI ⱖ25 or a high waist circumference plus ⱖ2 risk factors.2 Clinicians should discuss available treatment options with the patient to develop an effective weight loss strategy that is appropriate for the level of risk and the individual’s lifestyle. Regardless of the amount of weight a patient wishes to lose, it is important that the patient be assured that significant health benefit can be achieved with even modest weight loss.

Lifestyle Intervention Using Behavioral Modification Lifestyle modification is recommended as the primary treatment intervention for overweight and obese individuals. Behavior modification uses strategies focusing on behavior change targeted at reducing overeating and sedentary activities to achieve and maintain weight loss. This type of intervention has been found to be effective in multiple, short-term clinical trials.16 Dietary Strategies for Weight Loss. Components of the ideal weight loss plan have been elusive, and the benefits of the low-fat versus low-carbohydrate diet for weight loss debate continues. Low-fat and low-carbohydrate diets have been investigated for their ability to achieve and maintain weight loss. In a meta-analysis by Nordmann et al, 5 trials that included 447 individuals were evaluated to compare the efficacy of lowfat interventions compared with low-carbohydrate interventions in reducing weight and cardiometabolic risk factors.17 Whereas those following the low-carbohydrate diets achieved greater weight loss within the first 6 months of the intervention, at the 12-month mark after diet initiation no significant difference in weight loss was shown between the 2 diet types. Weight loss may have been linked to adherence rates; investigators noted a higher rate of adherence to the

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low-carbohydrate diet over the first 6 months of the intervention, but no detectable difference in adherence rates for the 2 dietary strategies was found at 12 months.17 Researchers reported differences in lipid profile response to the low-fat and low-carbohydrate diets. Greater decreases in total cholesterol and LDL cholesterol levels were found in patients following the low-fat diet, and increased levels of HDL cholesterol and reduced triglyceride levels were reported in patients following the low-carbohydrate diet.17 Personal preference, readiness to begin a diet program, and the individual’s ability to incorporate a particular diet into his or her daily routine are important determinants of diet efficacy. Furthermore, individual physiologic response to a particular dietary intervention appears to play an important role. In a recent trial of 73 obese adults aged 18 to 35 years, researchers found that patients with serum insulin levels above the median following a 75-g glucose challenge lost significantly greater amounts of weight and body fat if they were on the low-glycemic-load diet compared with participants who were on the low-fat diet. Researchers postulate that the difference found may be owing to variance in individual hormonal response.18 Very-low-calorie diets (VLCDs) have waned in popularity since the 1980s. A meta-analysis of low-calorie diets (LCDs) and VLCDs, totaling approximately 800 cal/day, was performed to determine the efficacy and safety of VLCDs.19 VLCDs consist of mainly liquid meal replacements along with some conventional foods. Results of the meta-analysis revealed that short-term weight loss was greater in patients treated with VLCDs; however, long-term weight loss results in patients treated with LCDs or VLCDs were comparable. The authors proposed that VLCDs may have the greatest utility if followed by a long-term management plan providing additional therapeutic support, such as pharmacologic therapy, to sustain the initial weight loss of 15% to 25% observed with VLCDs in other studies.19-21 Meal replacements have become popular options for individuals who do not have time to prepare food or who have difficulty controlling portion size. The variety of prepackaged meals, shakes, and snack bars has expanded over the past few years, and the usefulness of these products in aiding weight management has been studied. One study compared 2 diets of identical energy intake, including a standard diet and a diet containing meal replacements eaten twice per day (once as a meal and once as a snack).22 Researchers found that patients receiving the meal replacement diet lost a significantly greater amount of weight (6.9% vs. 5.9% of initial weight; P ⬍0.0001) than did patients restricted to the standard diet. Blood pressure, serum triglyceride, and blood glucose levels decreased with weight loss in both groups during the course of this 27-month study. Investigators concluded that the use of meal replacements in conjunction with a low-fat, calorierestricted diet is an effective strategy for promoting weight loss and lasting change in eating patterns.22 Support for this premise was found in a trial of longer duration. Researchers followed a group of dieters using 1 meal replacement, in-

S27 corporated into the daily diet in conjunction with a calorierestricted, low-fat diet.23 Sustained reductions in energy intake, maintenance of weight loss, and improvements in cardiometabolic risk factors over a span of 4 years were reported. Exercise and Weight Loss. Exercise is a component of any lifestyle modification program aimed at improving health and reducing body fat. Increasing daily physical activity helps overweight and obese individuals achieve and maintain a healthy body weight. The 2005 Healthy Guidelines for Americans, developed by the United States Department of Agriculture (USDA) and the Department of Health and Human Services (DHHS), recommends 60 to 90 minutes of daily physical activity to maintain weight loss.24 Obese individuals who engage in regular exercise, regardless of weight loss outcome, find improved health that appears to attenuate cardiovascular risk. Research supports that there are many health benefits gained in both men and women by being physically fit. In an observational cohort study of 21,925 men 30 to 83 years of age, Lee and colleagues25 reported that moderate-to-high levels of physical fitness reduced mortality risk, regardless of body composition. Lean men in the study exhibited increased longevity only if they also exhibited cardiorespiratory fitness. Unfit, lean men had a 2-fold greater mortality risk than did fit, lean men, and unfit, lean men had a greater mortality risk than did fit, obese men. Obese men who were fit did not have an increased mortality risk. In an analysis of 2,506 women and 2,860 men enrolled in the Lipids Research Clinics Study, researchers reported an independent effect of fitness on all causes of mortality.26 In this cohort of subjects, higher quintiles of BMI conferred a higher mortality risk; however, fitness was more strongly associated than was BMI with mortality outcomes. Research suggests that increasing time spent exercising may not induce weight loss in the short term, but does prevent the loss of muscle mass. Redman and colleagues27 reported that although exercise represents a favorable change in energy balance that may result in weight loss, body composition and fat distribution are similarly affected by exercise or reduced caloric intake. The authors noted, however, that exercise has independent salutary effects on cardiovascular and metabolic outcomes, most likely explaining the data reported by Lee and colleagues25 correlating improved fitness level with decreased mortality, regardless of BMI.

Potential Long-Term Impact of Behavior Modification Successful weight loss with behavioral therapy that focuses on lifestyle modification has the potential to improve health and prevent the progression to type 2 diabetes in vulnerable individuals. The Diabetes Prevention Program (DPP) Research Group reported that in individuals with glucose intolerance, intensive lifestyle interventions—including a reduced-fat and reduced-calorie diet, regular moderate physical activity, and behavior modification techniques de-

S28 signed to achieve a weight loss goal of 7% of initial body weight—reduced the incidence of type 2 diabetes by 58%, compared with a matched control group, after a follow-up period averaging 2.8 years.28 Furthermore, lifestyle interventions were substantially more effective than was metformin therapy in preventing progression to type 2 diabetes. A total of 53% of the 3,234 participants enrolled in the DPP Research Group study had the metabolic syndrome at baseline, according to the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III). The NCEP ATP III defines the metabolic syndrome by the presence of ⱖ3 of the following characteristics: waist circumference ⬎102 cm (⬎40 in) in men and ⬎88 cm (⬎35 in) in women, serum triglyceride levels ⱖ1.7 mmol/L (ⱖ150 mg/dL), HDL cholesterol levels ⬍1.03 mmol/L (⬍40 mg/dL) in men and ⬍1.3 mmol/L (⬍50 mg/dL) in women, blood pressure of ⱖ130/85 mm Hg, and fasting plasma glucose levels of ⱖ6.2 mmol/L (ⱖ110 mg/dL).28 Lifestyle intervention was most effective in preventing the development of the metabolic syndrome in patients not afflicted with the syndrome at baseline. The 3-year cumulative incidences of the metabolic syndrome were 51%, 45%, and 34% in the placebo, metformin, and lifestyle groups, respectively. In life table analyses, the incidence of the metabolic syndrome was reduced by 41% in the lifestyle group and by 17% in the metformin group, compared with placebo.28 Resolution of the metabolic syndrome in patients who met the criteria at baseline was significant between groups, with the greatest reduction reported in the lifestyle group. At 3 years, the metabolic syndrome was resolved in 18%, 23%, and 38% of patients in the placebo, metformin, and lifestyle groups, respectively (P ⬍0.001).28 The Finnish Diabetes Prevention Study Group enrolled individuals with impaired glucose tolerance to receive no intervention or an intervention program with a goal of ⱖ5% weight loss through counseling to reduce fat intake, increase intake of fiber-rich foods, and engage in 30 minutes of physical activity daily.4 In findings similar to those reported by the DPP Research Group, patients receiving lifestyle intervention had a 58% lower risk of developing type 2 diabetes than did those who received no intervention (P ⬍0.001).4

Can Behavioral Therapy and Lifestyle Interventions Achieve Long-Term Success? Behavioral therapy aimed at fostering lifestyle modifications has been reported as effective in aiding overweight and obese individuals in achieving weight loss, as well as in reducing cardiometabolic risk. However, weight regain following weight loss success remains a significant challenge limiting the benefits of intervention. A review of behavioral treatment of obesity notes that individuals receiving behavioral therapy for periods of 20 to 30 weeks regained approximately 30% to 35% of weight initially lost within the year following treatment.29 Although the rate of weight

The American Journal of Medicine, Vol 122, No 4A, April 2009 regain diminished after the first year, ⱖ50% of individuals returned to baseline weight within 5 years of treatment.29 Long-term maintenance of lost weight has been exceedingly difficult for many dieters to achieve. Experts point to overlapping physiologic mechanisms designed to defend body fat as a survival strategy as 1 major obstacle to longterm weight loss success.30 Additionally, exposure to an environment that supports overconsumption of food and inactivity presents multiple daily challenges for overweight and obese individuals.31 Long-term behavioral therapy is most likely required to achieve the lasting benefits of weight loss interventions. Regular follow-up strategies, including contact through onsite meetings, telephone calls, mailings, or Internet communication, have been suggested to improve lasting weight loss outcome.29 The ongoing Look AHEAD (Action for Health in Diabetes) study will better determine the long-term impact of lifestyle interventions on the rate of serious cardiovascular events (cardiovascular death, nonfatal myocardial infarction, and nonfatal stroke) in a population of overweight and obese individuals with type 2 diabetes.32 Lifestyle interventions consist of reduced-calorie diets, increased physical activity, and portion-controlled foods; individuals receiving this intervention strategy will be compared with a control group receiving diabetes support and education alone. Participants will be followed for up to 11.5 years during the course of the study. Lifestyle interventions have generally demonstrated the ability to achieve weight loss of 8% to 10% of initial weight,33 but lifestyle changes may be most effective when coupled with pharmacologic treatment to improve weight loss outcome. A 1-year study of men and women that compared lifestyle intervention alone (30 group counseling sessions), sibutramine therapy alone, the combination of both regimens, and sibutramine plus brief therapy sessions delivered in the primary care setting found that the combination of sibutramine and group counseling achieved the greatest degree of weight loss, averaging 12.1 ⫾ 9.8 kg (0.45 kg ⫽ 1 lb).6 A study in women likewise found that sibutramine plus group lifestyle modification sessions resulted in significantly greater weight loss than did sibutramine alone (P ⬍0.05), and the benefits of this strategy persisted at 1 year.5 A combination strategy that includes lifestyle modifications as well as pharmacotherapy could therefore be a more effective intervention for lasting weight loss.

Pharmacotherapeutic Strategies for Managing Overweight and Obesity The NHLBI Practical Guide suggests that individuals who already exhibit cardiometabolic risk and have a BMI of 27 to 29.9 may receive pharmacotherapy to aid weight loss efforts.2 In those without comorbidities, pharmacologic intervention is reserved for those with a BMI ⱖ30. The Practical Guide emphasizes that pharmacotherapy should

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Obesity Treatment Strategies

S29

Efficacy and safety of weight loss medications

Medication

FDA Approval Year/Intended Use

Action

Weight Loss Pooled Data (placebo-corrected)

Length of Treatment (wk)

Phentermine

1959/Short-term weight loss7

Sympathomimetic amine7

⫺3.6 kg

Orlistat

1999/Long-term weight loss7 1998/Long-term weight loss7

Lipase inhibitor7

⫺2.75 kg7

527

Combined norepinephrine and serotonin reuptake inhibitor7 Weight loss may be due to inhibition of norepinephrine and dopamine uptake30 Weight loss mechanism unknown30 Weight loss mechanism unknown30 Insulin sensitizer; suppresses hepatic glucose production

⫺4.45 kg7

527

⫺2.77 kg7

24-527

Sibutramine

Bupropion

1985/Antidepressant; smoking cessation30

Topiramate

1996/Seizure disorder7

Zonisamide*

2000/Seizure disorder7

Metformin†

1994/Diabetes mellitus

7

7

2-24

Common Side Effects Palpitations, tachycardia, elevated blood pressure, gastrointestinal effects7 Diarrhea, flatulence, bloating7 Increased blood pressure, increased pulse, dry mouth, insomnia, constipation30 Dry mouth, diarrhea, constipation, insomnia7

⫺6.5%7

247

Paresthesia, taste aversion7

⫺5.0%7

167

Fatigue; small, but significant increase in serum creatinine30 Gastrointestinal

⫺2.0 kg3,30

14630

*Data obtained from only one trial. † Data obtained from the Diabetes Prevention Program Trial; individuals with impaired fasting glucose were treated with drug. Adapted from N Engl J Med,3 Ann Intern Med,7 and J Clin Endocrinol Metab.30

be used as only 1 aspect of a comprehensive strategy of behavioral therapy, dietary changes, and increased physical activity to reduce weight and maintain lost weight.2 The American Medical Association (AMA) also discourages the use of pharmacotherapy without supportive lifestyle modification counseling. Additionally, the AMA suggests that pharmacotherapy for weight loss should be limited to agents approved by the US Food and Drug Administration (FDA).34 Available Pharmacologic Agents. Available pharmacotherapy options for overweight and obesity include anorexiants (appetite suppressants) and a lipase inhibitor.2 Anorexiants work to either promote satiety or reduce appetite. Orlistat is a novel gastric and pancreatic lipase inhibitor that prevents the absorption of 33% of the fat consumed in meals.7 The mechanism of action and side-effect profile of approved weight loss agents are listed in Table 3.3,7,30 The choice of agent is often limited by the relative ability of the patient to tolerate anticipated side effects. Although sibutramine, phentermine, and orlistat are all approved by the FDA for weight loss, other agents on the

market approved for other uses, such as antidepressants and drugs used to prevent seizures, have also been shown to promote weight loss in preliminary clinical trials. However, these drugs are not approved for weight loss because of lack of randomized large-scale trials to support their efficacy and safety.7 In a meta-analysis of agents currently used for weight loss management, sibutramine, orlistat, and phentermine, as well as the agents bupropion and topiramate, were shown to promote weight loss for ⱖ6 months, when administered in conjunction with lifestyle modification.7 The meta-analysis found that only modest weight loss occurred with pharmacotherapy, averaging ⬍5 kg at 1 year, but the authors noted that this weight loss amount may be clinically significant. Emerging Therapies. Investigational agents for weight loss are understandably attractive to both clinicians and patients because of the difficulty many individuals encounter in reducing weight and maintaining weight loss. Bupropion and topiramate are approved for other uses and are still being investigated for their utility in weight loss. Bupropion is a norepinephrine and dopamine uptake inhibitor that is

S30 approved for use as an antidepressant and smoking cessation aid.35 Although the drug is not approved for weight loss, randomized trials have been performed that suggest a role in weight management; researchers continue to exhibit interest in determining the relative efficacy and safety of bupropion compared with that of currently approved agents.35 Topiramate, a therapy approved for migraine prevention and the treatment of seizures, has likewise attracted interest for its potential use in weight management. Most recently, topiramate, in conjunction with lifestyle modifications, was found to result in significant weight loss and improved glucose homeostasis (P ⬍0.001 for both vs. placebo) in obese, drug-naive subjects with type 2 diabetes. However, researchers note that the weight loss benefits of topiramate must be balanced against the potential for central nervous system side effects.36 Exenatide. Exenatide is a novel incretin mimetic that has been approved by the FDA for adjunctive therapy to improve glycemic control in patients with type 2 diabetes. Exenatide is an injectable medication taken twice daily before mealtime and has been demonstrated to improve glucose regulation and promote weight loss in patients with type 2 diabetes.37 In 2 randomized, placebo-controlled 30week trials of exenatide in participants with type 2 diabetes, Riddle and coworkers37 reported that adjunctive treatment with exenatide reduced glycosylated hemoglobin (A1C) as well as body weight (–1.4 and –2.1 kg for 5 ␮g and 10 ␮g bid, respectively, at 30 weeks).37 In open-label extensions of these studies in which all patients received exenatide 10 ␮g bid, weight loss was progressive (⫺4.0 kg ) over 82 weeks of treatment. Another analysis of the extension study data at 2 years similarly reported that adjunctive exenatide resulted in progressive reductions in weight and sustained reductions of A1C, as well as improvements in blood pressure and liver enzymes.38 Side effects noted with exenatide therapy were mild-to-moderate nausea and hypoglycemia.37,38 Combination Strategies. Combination pharmacotherapy regimens that address the cardiometabolic risks of overweight and obesity while inducing reasonable weight loss may represent a new strategy for long-term management. Research is also addressing the effects of established treatments for hypertension, dyslipidemia, and type 2 diabetes and their relative ability to support weight loss achieved with concomitant therapy in obesity. Scholze and associates39 reported that in a population of obese, hypertensive patients, a combination antihypertensive regimen consisting of angiotensin-converting enzyme inhibitors and calcium channel blockers was more effective than was a combination ␤-blocker and diuretic regimen in supporting weight loss in patients also receiving sibutramine. The authors concluded that these findings may prompt further research on the specific effects of different therapeutic combinations in obesity and may guide future evidence-based treatment recommendations for overweight and obesity.

The American Journal of Medicine, Vol 122, No 4A, April 2009 Cannabinoid Receptor Antagonist (rimonabant). The endocannabinoid system has been investigated as a novel therapeutic pathway to target to manage weight in overweight and obese individuals.40 Endocannabinoids are ligands that are produced and degraded endogenously and activate the endocannabinoid system through coupling at specific receptor sites. To date, cannabinoid receptor–1 (CB1) and cannabinoid receptor–2 have been identified and cloned. CB1 receptors appear to influence energy and appetite regulation, as well as glucose and lipid metabolism.40 Preliminary animal studies demonstrated that endocannabinoid levels increase with food deprivation,41 and exposure to endocannabinoids increases food intake.42 Furthermore, mice lacking CB1receptors were leaner and consumed less food.43,44 Exposure to increased levels of endocannabinoids increased food intake in rats, and this effect was reversed with the administration of an investigational CB1 receptor blocker (rimonabant), highlighting the role that the CB1receptor plays in feeding signals.45 Subsequent clinical trials have supported the role of CB1receptor antagonism in appetite reduction, weight loss, and the reduction of cardiometabolic risk factors. In a randomized, double-blind, placebo-controlled study reported by Pi-Sunyer and associates,46 the administration of a CB1receptor antagonist (rimonabant) effectively reduced weight (– 6.3 kg with 20 mg rimonabant vs. –1.6 kg with placebo; P ⬍0.001) and waist circumference (– 6.1 cm with 20 mg rimonabant vs. –2.5 cm with placebo; P ⬍0.001) in overweight and obese patients over a period of 2 years. Furthermore, rimonabant administration was associated with beneficial changes in HDL cholesterol (12.6% increase with rimonabant vs. 5.4% increase with placebo; P ⬍0.001) and triglycerides (5.3% reduction with rimonabant vs. 7.9% increase with placebo; P ⬍0.001). The magnitude of cardiometabolic risk factor reduction was much greater than would be expected from weight loss alone. The researchers hypothesized that administration of a CB1 receptor blocker has a direct effect on glucose and lipid metabolism beyond the ability to reduce food intake and achieve weight loss. A similar 1-year trial conducted primarily at European sites reported similar findings in support of rimonabant.47 In another trial targeting a population of high-risk overweight or obese individuals with drug-naive dyslipidemia, rimonabant administration resulted in substantial weight loss, reduced waist circumference, increased HDL cholesterol levels, and reduced triglyceride concentrations.48 Rimonabant was also associated with favorable changes in LDL particle size, adiponectin levels, glucose tolerance, insulin levels, and plasma C-reactive protein concentrations, as well as a decrease in the proportion of individuals meeting the NCEP ATP III criteria for the metabolic syndrome. The safety and efficacy of rimonabant treatment in overweight and obese individuals with type 2 diabetes was investigated in a 1-year, randomized, placebo-controlled trial in adults on monotherapy for diabetes control.49 In addition to significant declines in weight and waist circumference, and favorable changes in lipid profile, participants

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receiving rimonabant experienced a significant 0.7%, placebo-corrected reduction in A1C levels, when compared with the placebo group. Rimonabant therapy has been associated with mood disorders, including anxiety and depression. The Rimonabant in Obesity (RIO)–North America trial reported higher rates of depression and anxiety in patients treated with rimonabant at doses of 5 mg/day or 20 mg/day than in placebotreated patients, but anxiety and depression scores were similar between the groups over 2 years of treatment.46 In the RIO-Europe study, discontinuation rates due to anxiety were higher in patients receiving rimonabant 20 mg/day than in those receiving rimonabant 5 mg/day or placebo.47 Another randomized, placebo-controlled trial of 1-year therapy with rimonabant 5 mg/day, rimonabant 20 mg/day, or placebo likewise reported a higher rate of discontinuation due to adverse effects, including anxiety, in patients receiving rimonabant 20 mg/day.48 Therefore, the use of rimonabant may be limited in clinical practice, particularly in patients with preexisting depression.50

SUMMARY Obesity is a major public health concern and requires effective treatment strategies to reduce cardiometabolic risk factors that can lead to substantial morbidity and early mortality. Although strategies exist to achieve modest weight loss that can substantially reduce cardiometabolic risk, many individuals continue to be resistant to long-term weight loss. Challenges persist in achieving and sustaining weight loss in obese individuals. Individualizing weight loss plans, use of meal replacements, and increased exercise seem to show improvement in outcome measurements. Current data suggest that combining behavior modification and pharmacotherapy in treating obese individuals may offer better outcomes than does either modality alone. Novel therapeutic strategies may be available in the future that will offer hope to patients combating obesity.

AUTHOR DISCLOSURES The authors who contributed to this article have disclosed the following industry relationships: Louis J. Aronne, MD, has received financial support for research from Amylin Pharmaceuticals, Inc, GlaxoSmithKline, Medtronic, Inc, Merck & Co, Inc, Obecure Ltd, Orexigen Therapeutics, Inc, Pfizer Inc, sanofi-aventis Pharmaceuticals, Inc, and Transneuronix, Inc; is a consultant for Manhattan Pharmaceuticals, Inc, Metabolic Therapeutics, Inc, and sanofi-aventis Pharmaceuticals, Inc; is a member of a Speakers’ Bureau for Pfizer Inc and sanofi-aventis Pharmaceuticals, Inc; and has received grant support or consulted for Arena Pharmaceuticals, Inc, GI Dynamics, Johnson & Johnson, Novo Nordisk, TransTech Pharma, Inc, and Vivus Inc. Thomas Wadden, PhD, is a consultant for Abbott Laboratories.

S31 Kathy Keenan Isoldi, MS, RD, CDE, has no relevant financial relationships with a commercial entity producing healthcare-related products and/or services. Kristina A. Woodworth has no relevant financial relationships with a commercial entity producing healthcarerelated products and/or services.

References 1. Flegal KM, Carroll MD, Ogden CL, Johnson CL. Prevalence and trends in obesity among US adults, 1999-2000. JAMA. 2002;288:17231727. 2. National Heart, Lung, and Blood Institute (NHLBI). The Practical Guide: Identification, Evaluation, and Treatment of Overweight and Obesity in Adults. Bethesda, MD: National Heart, Lung, and Blood Institute, National Institutes of Health, Dept of Health and Human Services, October 2000. NIH Publication No. 00-4084. 3. Knowler WC, Barrett-Connor E, Fowler SE, et al, for the Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N Engl J Med. 2002;346:393-403. 4. Tuomilehto J, Lindström J, Eriksson JG, et al, for the Finnish Diabetes Prevention Study Group. Prevention of type 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance. N Engl J Med. 2001;344:1343-1350. 5. Wadden TA, Berkowitz RI, Sarwer DB, Prus-Wisniewski R, Steinberg C. Benefits of lifestyle modification in the pharmacologic treatment of obesity: a randomized trial. Arch Intern Med. 2001;161:218-227. 6. Wadden TA, Berkowitz RI, Womble LG, et al. Randomized trial of lifestyle modification and pharmacotherapy for obesity. N Engl J Med. 2005;353:2111-2120. 7. Li Z, Maglione M, Tu W, et al. Meta-analysis: pharmacologic treatment of obesity. Ann Intern Med. 2005;142:532-546. 8. Leslie WS, Hankey CR, Lean ME. Weight gain as an adverse effect of some commonly prescribed drugs: a systematic review. QJM. 2007; 100:395-404. 9. Ness-Abramof R, Apovian CM. Drug-induced weight gain. Timely Top Med Cardiovasc Dis. 2005;9:E31. 10. Waitman JA, Aronne LJ. Pharmacological treatment. In: Foster G, Nonas C, eds. Managing Obesity: A Clinical Guide. Chicago: American Dietetic Association; 2004:151-173. 11. National Heart, Lung, and Blood Institute (NHLBI). The Evidence Report: Clinical Guidelines on the Identification, Evaluation, and Treatment of Overweight and Obesity in Adults. Bethesda, MD: National Heart, Lung, and Blood Institute, National Institutes of Health, Dept of Health and Human Services, September 1998. NIH Publication No. 98-4083. 12. Scheen AJ, Van Gaal LF, Brohet C, de Backer G, Vissers E, Vandenhoven G. Belgian Evaluation of Screening and Treatment of high risk patients based on waist and age (BEST): focus on diabetes mellitus and metabolic syndrome. Presented at the 65th Annual Scientific Sessions of the American Diabetes Association; June 12, 2005; San Diego, CA. 13. Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III) final report. Circulation. 2002;106:3143-3421. 14. International Diabetes Federation. The IDF Consensus worldwide definition of the metabolic syndrome. [IDF Website.] Brussels, Belgium: International Diabetes Federation, April 14, 2005. Available at: http:// www.idf.org/webdata/docs/Metabolic_syndrome_definition.pdf. Accessed April 16, 2007. 15. Executive Summary of the Third Report of the National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel III). JAMA. 2001;285:2486-2497. 16. Foster G. The behavioral approach to treating obesity. Am Heart J. 2006;151:625-627.

S32 17. Nordmann AJ, Nordmann A, Briel M, et al. Effects of low-carbohydrate vs low-fat diets on weight loss and cardiovascular risk factors: a meta-analysis of randomized controlled trials. Arch Intern Med. 2006; 166:285-293. 18. Ebbeling CB, Leidig MM, Feldman HA, Lovesky MM, Ludwig DS. Effects of a low-glycemic load vs low-fat diet in obese young adults: a randomized trial. JAMA. 2007;297:2092-2102. 19. Gilden Tsai A, Wadden TA. The evolution of very-low-calorie diets: an update and meta-analysis. Obesity (Silver Spring). 2006;14:12831293. 20. Apfelbaum M, Vague P, Ziegler O, Hanotin C, Thomas F, Leutenegger E. Long-term maintenance of weight loss after a very-low-calorie diet: a randomized blinded trial of the efficacy and tolerability of sibutramine. Am J Med. 1999;106:179-184. 21. Mathus-Vliegen EM. Long-term maintenance of weight loss with sibutramine in a GP setting following a specialist guided very-lowcalorie diet: a double-blind, placebo-controlled, parallel group study. Eur J Clin Nutr. 2005;59(suppl 1):S31-S38. 22. Ditschuneit HH, Flechtner-Mors M, Johnson TD, Adler G. Metabolic and weight-loss effects of a long-term dietary intervention in obese patients. Am J Clin Nutr. 1999;69:198-204. 23. Flechtner-Mors M, Ditschuneit HH, Johnson TD, Suchard MA, Adler G. Metabolic and weight loss effects of long-term dietary intervention in obese patients: four-year results. Obes Res. 2000;8:399-402. 24. US Department of Health and Human Services (HHS), US Department of Agriculture (USDA). Dietary Guidelines for Americans. [HHS Website.] Updated October 16, 2006. Washington, DC: Office of Disease Prevention and Health Promotion, US Dept of Health and Human Services, 2005. Available at: www.healthierus.gov/ dietaryguidelines. Assessed June 21, 2007. 25. Lee CD, Blair SN, Jackson AS. Cardiorespiratory fitness, body composition, and all-cause and cardiovascular disease mortality in men. Am J Clin Nutr. 1999;69:373-380. 26. Stevens J, Cai J, Evenson KR, Thomas R. Fitness and fatness as predictors of mortality from all causes and from cardiovascular disease in men and women in the Lipid Research Clinics Study. Am J Epidemiol. 2002;156:832-841. 27. Redman LM, Heilbronn LK, Martin CK, Alfonso A, Smith SR, Ravussin E. Effect of calorie restriction with or without exercise on body composition and fat distribution. J Clin Endocrinol Metab. 2007;92: 865-872. 28. Orchard TJ, Temprosa M, Goldberg R, et al. The effect of metformin and intensive lifestyle intervention on the metabolic syndrome: the Diabetes Prevention Program randomized trial. Ann Intern Med. 2005; 142:611-619. 29. Wadden TA, Crerand CE, Brock J. Behavioral treatment of obesity. Psychiatr Clin North Am. 2005;28:151-170. 30. Korner J, Aronne LJ. Pharmacological approaches to weight reduction: therapeutic targets. J Clin Endocrinol Metab. 2004;89:2616-2621. 31. Lowe MR. Self-regulation of energy intake in the prevention and treatment of obesity: is it feasible? Obes Res. 2003;11(suppl):44S-59S. 32. Ryan DH, Espeland MA, Foster GD, et al. Look AHEAD (Action for Health in Diabetes): design and methods for a clinical trial of weight loss for the prevention of cardiovascular disease in type 2 diabetes. Control Clin Trials. 2003;24:610-628. 33. Jones LR, Wilson CI, Wadden TA. Lifestyle modification in the treatment of obesity: an educational challenge and opportunity. Clin Pharmacol Ther. 2007;81:776-779.

The American Journal of Medicine, Vol 122, No 4A, April 2009 34. Lyznicki JM, Young DC, Riggs JA, Davis RM. Obesity: assessment and management in primary care. Am Fam Physician. 2001;63:21852196. 35. Gadde KM, Xiong GL. Bupropion for weight reduction. Expert Rev Neurother. 2007;7:17-24. 36. Stenlof K, Rossner S, Vercruysse F, Kumar A, Fitchet M, Sjostrom L. Topiramate in the treatment of obese subjects with drug-naive type 2 diabetes. Diabetes Obes Metab. 2007;9:360-368. 37. Riddle MC, Henry RR, Poon TH, et al. Exenatide elicits sustained glycaemic control and progressive reduction of body weight in patients with type 2 diabetes inadequately controlled by sulphonylureas with or without metformin. Diabetes Metab Res Rev. 2006;22:483-491. 38. Buse JB, Klonoff DC, Nielsen LL, et al. Metabolic effects of two years of exenatide treatment on diabetes, obesity, and hepatic biomarkers in patients with type 2 diabetes: an interim analysis of data from the open-label, uncontrolled extension of three double-blind, placebocontrolled trials. Clin Ther. 2007;29:139-153. 39. Scholze J, Grimm E, Herrmann D, Unger T, Kintscher U. Optimal treatment of obesity-related hypertension: the Hypertension-ObesitySibutramine (HOS) study. Circulation. 2007;115:1991-1998. 40. Kyrou I, Valsamakis G, Tsigos C. The endocannabinoid system as a target for the treatment of visceral obesity and metabolic syndrome. Ann N Y Acad Sci. 2006;1083:270-305. 41. Kirkham TC, Williams CM, Fezza F, Di Marzo V. Endocannabinoid levels in rat limbic forebrain and hypothalamus in relation to fasting, feeding and satiation: stimulation of eating by 2-arachidonoyl glycerol. Br J Pharmacol. 2002;136:550-557. 42. Jamshidi N, Taylor DA. Anandamide administration into the ventromedial hypothalamus stimulates appetite in rats. Br J Pharmacol. 2001;134:1151-1154. 43. Ravinet Trillou C, Delgorge C, Menet C, Arnone M, Soubrie P. CB1 cannabinoid receptor knockout in mice leads to leanness, resistance to diet-induced obesity and enhanced leptin sensitivity. Int J Obes Relat Metab Disord. 2004;28:640-648. 44. Cota D, Marsicano G, Tschop M, et al. The endogenous cannabinoid system affects energy balance via central orexigenic drive and peripheral lipogenesis. J Clin Invest. 2003;112:423-431. 45. Cani PD, Montoya ML, Neyrinck AM, Delzenne NM, Lambert DM. Potential modulation of plasma ghrelin and glucagon-like peptide-1 by anorexigenic cannabinoid compounds, SR141716A (rimonabant) and oleoylethanolamide. Br J Nutr. 2004;92:757-761. 46. Pi-Sunyer FX, Aronne LJ, Devin J, Rosenstock J. Effect of rimonabant, a cannabinoid-1 receptor blocker, on weight and cardiometabolic risk factors in overweight or obese patients, RIO-North America: a randomized controlled trial. JAMA. 2006;295:761-775. 47. Van Gaal LF, Rissanen AM, Scheen AJ, Ziegler O, Rossner S. Effects of the cannabinoid-1 receptor blocker rimonabant on weight reduction and cardiovascular risk factors in overweight patients: 1-year experience from the RIO-Europe study. Lancet. 2005;365:1389-1397. 48. Després JP, Golay A, Sjöstrom L. Effects of rimonabant on metabolic risk factors in overweight patients with dyslipidemia. N Engl J Med. 2005;353:2121-2134. 49. Scheen AJ, Finer N, Hollander P, Jensen MD, Van Gaal LF, for the RIO-Diabetes Study Group. Efficacy and tolerability of rimonabant in overweight or obese patients with type 2 diabetes: a randomised controlled study. Lancet. 2006;368:1660-1672. 50. Gadde KM, Allison DB. Cannabinoid-1 receptor antagonist, rimonabant, for management of obesity and related risks. Circulation. 2006; 114:974-984.

Supplement issue

An Obesity/Cardiometabolic Risk Reduction Disease Management Program: A Population-Based Approach Victor G. Villagra, MD Ethel Donaghue Center for Translating Research into Practice and Policy at the University of Connecticut Health Center, Farmington, Connecticut, USA; and Health & Technology Vector, Inc., Hartford, Connecticut, USA

ABSTRACT Obesity is a critical health concern that has captured the attention of public and private healthcare payers who are interested in controlling costs and mitigating the long-term economic consequences of the obesity epidemic. Population-based approaches to obesity management have been proposed that take advantage of a chronic care model (CCM), including patient self-care, the use of community-based resources, and the realization of care continuity through ongoing communications with patients, information technology, and public policy changes. Payer-sponsored disease management programs represent an important conduit to delivering population-based care founded on similar CCM concepts. Disease management is founded on population-based disease identification, evidence-based care protocols, and collaborative practices between clinicians. While substantial clinician training, technology infrastructure commitments, and financial support at the payer level will be needed for the success of disease management programs in obesity and cardiometabolic risk reduction, these barriers can be overcome with the proper commitment. Disease management programs represent an important tool to combat the growing societal risks of overweight and obesity. © 2009 Elsevier Inc. All rights reserved. • The American Journal of Medicine (2009) 122, S33–S36 KEYWORDS: Cardiometabolic risk; Chronic care model; Disease management; Obesity; Population-based

There is increasing concern among employers about the adverse cost and productivity impact of the obesity epidemic. In the United States, the impact of obesity on the cost of care among Medicare beneficiaries has also received attention. A study conducted by the RAND Corporation predicted that medical innovation will result in a healthier population that lives longer but will likely also result in increased Medicare spending because beneficiaries will be accumulating costs over a longer period.1 The study concludes that improving treatments for chronic diseases, or even eliminating some chronic diseases, will not mitigate the projected increase in costs. However, obesity may be an important exception because, unlike other common chronic conditions, obesity results in a 40% increase in disability and a 35% higher cost, without a concomitant reduction in life expectancy, among 70-year-old beneficiaries compared Statement of author disclosure: Please see the Author Disclosures section at the end of this article. Requests for reprints should be addressed to Victor G. Villagra, MD, 674 Prospect Ave, Hartford, CT 06105. E-mail address: [email protected]

0002-9343/$ -see front matter © 2009 Elsevier Inc. All rights reserved. doi:10.1016/j.amjmed.2009.01.006

with their nonobese counterparts.1 This suggests that reducing the number of obese patients reaching Medicare age could result in significant savings. Although there is a general understanding that the obesity epidemic is the result of a complex interaction of social, behavioral, and economic factors and that solutions will also require a broad array of strategies, the “medical problem” of obesity presents itself to healthcare professionals as a distinct management challenge. As employers become aware of the adverse health and economic burden of obesity, requests for effective interventions amenable to large-scale, “population-based” deployment are becoming more common. There is a growing body of evidence demonstrating which components of disease management programs are most effective2; however, the complex, multifactorial nature of obesity poses unique challenges. Any sustainable program designed to address obesity and reductions in related health risks will require a well-coordinated plan—an organization of care capable of reaching tens of thousands of individuals and a suitable financial base to deliver it costeffectively. This article outlines the ideal conditions for the

S34 development of an obesity/cardiometabolic risk reduction disease management program, its necessary components, and the role of patients, providers, and payers in such an effort.

THEORETICAL FRAMEWORK The chronic care model (CCM)3 provides a useful theoretical framework for a population-based solution to the obesity epidemic, and disease management offers an efficient operational platform to put it into effect on a large scale. Disease management is a unique expression of the CCM and an innovative strategy for the diffusion of evidencebased interventions across large, geographically dispersed populations.4,5 The components of the CCM include patient self-care, community-based resources, continuity of care beyond traditional sites of care using telephonic and other forms of communication, information technology, decision support tools for patients and providers, delivery system redesign, and enabling public policy (Figure 1).3 The elements of disease management include population-based identification methods, evidence-based contents, collaborative relationships with physicians, and ongoing evaluation and feedback to patients, providers, and payers (Figure 2).6

The American Journal of Medicine, Vol 122, No 4A, April 2009 able and expanding rapidly. Use of Web-based distancelearning technology and case-based training are examples of recent advances in the science of knowledge transfer.

At the Payer Level Appropriate financial support for an obesity/cardiometabolic risk reduction initiative is needed. An increasingly popular mechanism for potentially stimulating behavior change is physician pay-for-performance.10 Some programs are stimulating the management of isolated cardiometabolic risks, such as hypertension, dyslipidemia, and tobacco use, but those efforts must be coordinated and expanded so that efforts converge in a patient-centric direction rather than persist as isolated, risk-oriented initiatives. A logical next step would be to stimulate better management of overweight and obesity. An obesity/cardiometabolic risk reduction disease management program could catalyze and expand current pay-for-performance efforts to encompass all of the elements of the metabolic syndrome. Financial benefits would accrue to physicians, and patients would realize clinical benefits. However, it remains to be seen whether the RAND study suggestion that obesity prevention efforts will translate into cost savings for payers is correct.

At a Population Level BARRIERS AND OPPORTUNITIES FOR AN OBESITY/CARDIOMETABOLIC RISK REDUCTION DISEASE MANAGEMENT PROGRAM A number of barriers to an effective obesity/cardiometabolic risk reduction disease management program can be identified; however, solutions are also emerging.

At the Physician Practice Level Physicians report a number of barriers to effective management of obesity. Cited barriers include a lack of time to address obesity during routine office visits, a lack of reimbursement for these services,7 a sense that obesity is a chronic disease with high recidivism rates, and inadequate training and lack of training mechanisms for physicians in the medical management of obesity. The CCM provides a helpful template for practice redesign that would eventually overcome some of those barriers, but transforming physician practices would represent a lengthy process that is out of step with the sense of urgency that the obesity epidemic represents. A more desirable approach would be a collaborative arrangement between existing payer-sponsored disease management programs and individual physician practices. Such an arrangement would offer multiple advantages,8 including shortening the time required to deploy large-scale programs.9 The solution to the perceived gap of physician low selfefficacy would be the development of effective obesity/ cardiometabolic risk reduction physician-training vehicles. The knowledge base for effective treatments across the entire continuum of therapeutic alternatives spanning behavior modification, pharmacotherapy, and bariatric surgery is avail-

A systematic, population-based identification of at-risk individuals is critical for the success of any disease management program.10 To that end, clinicians develop patient registries11 at the point of service, and payers query their claims databases.12,13 Traditional lack of reimbursement for obesity-related services has discouraged use of obesity International Classification of Diseases–9th Revision (ICD-9) codes in claims submission. Use of codes identifying the metabolic syndrome also is very infrequent. For these reasons, cost-effective identification of obesity/cardiometabolic risk reduction program candidates using administrative databases is not possible. Alternative means of patient identification are needed. Examples include increased use of health risk assessment by employers and insurance companies, development of patient self-referral mechanisms, and expansion of practice-based patient registries. A coordinated, collaborative effort between payers and providers could combine strategies to identify and electronically register large numbers of obese individuals amenable to disease management programs in a relatively short period.8

WHAT WILL AN OBESITY/CARDIOMETABOLIC RISK REDUCTION DISEASE MANAGEMENT PROGRAM OFFER TO PATIENTS? An obesity/cardiometabolic risk reduction disease management program can offer patients a variety of concrete benefits. Specifically: ●

Information: Disease management programs provide patients with information about their condition and its treatment. The information is of the highest scientific quality, but it is presented in simple-to-understand lay terms.

Villagra

Obesity Disease Management Program

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The Chronic Care Model Health System Health Care Organization

Community Resources and Policies Self-Management Support

Delivery System Design

Decision Support

Clinical Information Systems

Informed, Activated Patient Supportive, Integrated Community

Productive Interactions

Prepared, Proactive Practice Team

Figure 1 The chronic care model of healthcare delivery. (Adapted from Health Aff (Millwood).3)

Disease Management Claims

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UM

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Population-Based Patient identification Identification Population-based patient Interventions Available

Interventions Applied

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Care Management Workstation Figure 2 Components of the disease management concept of healthcare delivery. HRA ⫽ health risk assessment; Lab ⫽ laboratory; QOL ⫽ quality of life; Rx ⫽ prescriptions; UM ⫽ utilization. (Adapted from the Disease Management Association of America.6)

●

Self-care skills: Disease management promotes greater control and independence in patients by encouraging development of their self-care skills, including self-monitoring practices such as use of food diaries.

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Motivation: Care managers— highly trained nurses and other clinicians who interact regularly with patients, usually over the phone—provide a source of ongoing patient motivation to adopt healthful lifestyles.

S36 ●

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Support: Care managers actually support patients through their efforts to quit smoking, increase physical activity levels, adhere to diets, and manage their stress. Self-efficacy: Through repetition, attainment of short-term realistic goals, and encouragement, patients attain progressively higher levels of self-efficacy. Perception of self-efficacy is among the strongest predictors of success in lifestyle modification. Self-care tools: Disease management programs provide tools for self-care, such as scales for patients with congestive heart failure, blood pressure cuffs for patients with hypertension, and, for individuals with access to computers, software for tracking and transmitting key information to their physicians. Visit planning: Care managers provide visit-planning coaching so that patients are able to maximize the value of each physician visit. Physicians also benefit from more effective and efficient patient visits.

PROGRAM LEADERSHIP AND COORDINATION Under the guidance of physicians, an obesity/cardiometabolic risk reduction program would provide ongoing patient self-care education and support—a critical component for long-term success of obesity/cardiometabolic risk reduction treatment plans. Program contents would be supported by the best-available scientific evidence. This approach has been shown to improve adherence to behavioral and pharmacologic treatment plans among patients with chronic conditions. In many cases, it has been shown to reduce use of the emergency room and hospital admissions and to lower overall cost of care.14,15 These performance indicators align well with employers expectations.

SUMMARY The implementation of comprehensive obesity/cardiometabolic risk reduction disease management programs faces barriers that can be readily overcome. Disease management programs can result in a wider adoption of evidence-based treatments, a significant reduction in long-term treatment failures, and potentially lower overall costs of care. A coordinated disease management initiative would represent a sensible response to employers’ and other payers’ demands for action.

AUTHOR DISCLOSURES The author of this article has disclosed the following industry relationships:

The American Journal of Medicine, Vol 122, No 4A, April 2009 Victor G. Villagra, MD, is a member of the Board of Directors of Genomas, Inc, a consultant for Healthways, Inc, and sanofi-aventis Pharmaceuticals, Inc, and an independent contractor for the Disease Management Association of America.

References 1. Lakdawalla DN, Goldman DP, Shang B. The health and cost consequences of obesity among the future elderly. Health Aff (Millwood). 2005;24(suppl 2):W5R30-W5R41. 2. Health & Technology Vector/Disease Management Association of America (DMAA). Disease Management Literature Finder (DM LitFinder) [DMAA Website database]. Available at: http://www.dmaa. org/dmlibrary/start.asp. Accessed October 10, 2007. 3. Wagner EH, Austin BT, Davis C, Hindmarsh M, Schaefer J, Bonomi A. Improving chronic illness care: translating evidence into action. Health Aff (Millwood). 2001;20:64-78. 4. Ellrodt G, Cook DJ, Lee J, Cho M, Hunt D, Weingarten S. Evidencebased disease management. JAMA. 1997;278:1687-1692. 5. Weingarten SR, Henning JM, Badamgarav E, Knight K, Hasselblad V, Gano A Jr, et al. Interventions used in disease management programmes for patients with chronic illness—which ones work? Metaanalysis of published reports. BMJ. 2002;325:925. 6. Disease Management Association of America. Definition of disease management. [DMAA Website.] Available at: http://www.dmaa.org/ definition.html. 7. Tsai AG, Asch DA, Wadden TA. Insurance coverage for obesity treatment. J Am Diet Assoc. 2006;106:1651-1655. 8. Villagra VG. Integrating disease management into the outpatient delivery system during and after managed care. Health Aff (Millwood). 2004;Web Exclusives(suppl):W4-281–W4-283. 9. Casalino LP. Disease management and the organization of physician practice. JAMA. 2005;293:485-488. 10. Villagra V. Strategies to control costs and quality: a focus on outcomes research for disease management. Med Care. 2004;42:III24-III30. 11. Wagner EH, Grothaus LC, Sandhu N, et al. Chronic care clinics for diabetes in primary care: a system-wide randomized trial. Diabetes Care. 2001;24:695-700. 12. Koroukian SM, Cooper GS, Rimm AA. Ability of Medicaid claims data to identify incident cases of breast cancer in the Ohio Medicaid population. Health Serv Res. 2003;38:947-960. 13. Solz H, Gilbert K. Health claims data as a strategy and tool in disease management. J Ambul Care Manage. 2001;24:69-85. 14. Villagra VG, Ahmed T. Effectiveness of a disease management program for patients with diabetes. Health Aff (Millwood). 2004;23:255266. 15. Sidorov J, Shull R, Tomcavage J, Girolami S, Lawton N, Harris R. Does diabetes disease management save money and improve outcomes? A report of simultaneous short-term savings and quality improvement associated with a health maintenance organization–sponsored disease management program among patients fulfilling health employer data and information set criteria. Diabetes Care. 2002;25: 684-689.

Supplement to

The American Journal of Medicine

The Obesity Epidemic: Strategies in Reducing Cardiometabolic Risk

CME SECTION ASSESSMENT TEST

Provided by:

Release Date: April 2009

Expiration Date: April 30, 2010

CME ASSESSMENT TEST The Obesity Epidemic: Strategies in Reducing Cardiometabolic Risk Please circle the correct response to each question on the Answer Sheet provided. A passing score of ⱖ70% must be achieved to receive CME credit. 1. Approximately what percentage of Americans are currently classified as overweight or obese based on body mass index (BMI)? a. 30% b. 25% c. 66% d. 75% 2. The use of which assessment tool may be helpful in assessing health risks in individuals evaluated for overweight and obesity? a. BMI b. Waist circumference c. Waist-to-hip ratio d. All of the above 3. In its definition of the metabolic syndrome, a joint statement by the American Heart Association and the National Heart, Lung, and Blood Institute suggested that the threshold for ______ be reduced from the threshold identified by the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III) to more accurately capture diabetic risk. a. Triglycerides b. Fasting blood glucose c. Abdominal obesity d. Hypertension 4. Both the San Antonio Heart Study and a large population-based study of familial type 2 diabetes found that the metabolic syndrome is associated with an increased risk of important health effects, including: a. Stroke b. Myocardial infarction c. All-cause mortality d. All of the above

c. Abstinence from alcohol d. Regular exercise regimen 7. In a trial conducted by the Diabetes Prevention Program Research Group that studied a population of individuals with elevated fasting glucose, which of the following interventions had the greatest impact on lowering the risk of developing type 2 diabetes: a. Metformin therapy b. Lifestyle interventions that achieved weight loss c. Weight loss medications d. Exercise alone 8. Which of the following hormone levels increase(s) proportionately with body fat? a. Leptin b. Insulin c. a and b d. Cholecystokinin 9. Which of the following organs or tissues produces inflammatory cytokines that have been linked to insulin resistance and cardiovascular risk? a. Liver b. Small intestine c. Adipose tissue d. Kidney 10. As defined by the NCEP ATP III, the metabolic syndrome includes all of the following traits except: a. Elevated waist circumference b. Elevated fasting triglyceride levels c. Decreased high-density lipoprotein cholesterol levels d. Increased low-density lipoprotein cholesterol levels

5. Abnormal lipid metabolism is a manifestation of obesity and increases the risk of: a. Cardiovascular events b. Gout c. Diabetes d. Inflammation

11. The 2005 US Department of Agriculture (USDA) Dietary Guidelines for Americans suggests that those with a target diet of 2,000 calories per day should consume: a. 1 cup fruits, 2 cups vegetables b. 5 or more daily servings of fruits c. 9 or more daily servings of fruits and vegetables d. 4 or more daily servings of fruits and vegetables

6. In a study of female nurses followed over a period of 16 years, which trait did not contribute to lower risk of type 2 diabetes: a. Maintenance of BMI ⱕ25 b. High-fiber, low-fat, low-glycemic-load diet

12. Rolls et al demonstrated that which of the following factors significantly correlated with the amount of one type of food consumed during a meal? a. The amount of food offered b. The perceived palatability of the food

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c. The individual’s perceived hunger prior to meal initiation d. The caloric content of the food 13. Which of the following dietary changes in the American population has been linked to rising obesity rates in recent decades? a. Increased fat content of food b. Increased fruit and vegetable consumption c. Increased sodium content of food d. Increased consumption of dairy products 14. In a meta-analysis by Nordmann et al, which dietary strategy was able to more effectively sustain weight loss over 12 months? a. Low-fat diet b. Low-carbohydrate diet

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c. There was no difference between the 2 diets at 12 months d. Neither diet achieved measurable weight loss at 12 months 15. The National Heart, Lung, and Blood Institute Practical Guide suggests considering the addition of pharmacotherapy to an otherwise comprehensive strategy of behavioral therapy, dietary changes, and increased physical activity to induce weight loss in individuals falling within which of the following groups? a. BMI of 27 to 29.9 with comorbidities b. BMI ⱖ30 c. All individuals with a BMI ⱖ25 d. a and b

MEDICINE姞 Vol 122 (4A)

The Obesity Epidemic: Strategies for Reducing Cardiometabolic Risk Instructions for Continuing Medical Education Credit: This activity should take approximately 4.0 hours to complete. To receive AMA PRA Category 1 Credits™ for your participation in this educational activity, you must complete both the posttest and the evaluation form. The participants should review the educational objectives listed in the front of this supplement to determine if the content relates to their individual learning needs. They should read the supplement carefully, paying particular attention to the tables and other illustrative materials, and then circle the best answer for each of the 15 multiple-choice posttest questions and complete the evaluation form on the following page. Evaluation of this activity is an integral part of the CME process. CME certificate requests cannot be processed if the evaluation form is not complete. To receive credit for this activity, follow the instructions provided on the posttest. Credit is valid through April 30, 2010. No credit will be given after that date. Mail completed posttest and evaluation to: American Medical Association Science, Research, and Technology 515 N. State Street, 8th Floor Chicago, IL 60654 Or fax to: 312-464-5841, attn: Obesity CME Coordinator

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MEDICINE姞 Vol 122 (4A) S45

CME Evaluation Form The Obesity Epidemic: Strategies in Reducing Cardiometabolic Risk To assist us in evaluating the effectiveness of this activity and to make recommendations for future educational offerings, please take a few minutes to complete this evaluation form. You must complete this evaluation form to receive acknowledgment for completing this activity. Please circle the appropriate number for each of the items below:

Overall Evaluation ● Overall, I am satisfied with the quality of this educational activity ● This activity presented scientifically rigorous, unbiased, and balanced information ● This activity changed my knowledge and attitudes about obesity ● The learning objectives were clearly stated and achieved

1 ⫽ Strongly Disagree

2 ⫽ Disagree

3 ⫽ Neutral

4 ⫽ Agree

5 ⫽ Strongly Agree

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Which of the following best describes the impact of this activity on your clinical practice (check one)? 䊐 This activity will not change my behavior because my current practice is consistent with what was taught 䊐 This activity will not change my behavior because I do not agree with the information presented 䊐 I need more information before I change my practice behavior 䊐 I will implement the information in my practice Low Moderate High Level of learning Overall knowledge/skill level before the activity 1 2 3 4 5 Overall knowledge/skill level after the activity 1 2 3 4 5 Ability to describe the impact of obesity on public health, resource utilization, healthcare expenditures and mortality risk, and quality of life Before the activity 1 2 3 4 5 After the activity 1 2 3 4 5 Ability to recognize the role of adipose tissue as an endocrine organ and the effect that alterations in energy homeostasis may have on fat storage and function Before the activity 1 2 3 4 5 After the activity 1 2 3 4 5 Ability to discuss the endogenous endocannabinoid system and its effect on energy balance, fat storage, and the adipose endocrine system Before the activity 1 2 3 4 5 After the activity 1 2 3 4 5 Ability to identify effective strategies for recognizing patients at risk of cardiovascular and metabolic disease Before the activity 1 2 3 4 5 After the activity 1 2 3 4 5 Ability to specify current and future options, including behavioral and pharmacologic strategies, to reduce risk factors for cardiovascular and metabolic disease in the community setting Before the activity 1 2 3 4 5 After the activity 1 2 3 4 5

Did you perceive commercial bias during this activity? If yes, please specify: How could this activity be improved? Other comments:

Yes

No