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Lingering questions about intentional weight loss
EDITORIAL
COMMENTS
819
Lingering Questions About Intentional Weight Loss I recently received an advertisement for a $2,800 marketdata report on “emerging obesity therapies.” The advertisement stated, “Pharmaceutical help may be on the horizon for the estimated 40 million Americans (aged 15-74) considered obese.” ’ By most standards this is a very large market. But the actual market may be even larger, as it is currently estimated that nearly half of U.S. women and one-quarter of U.S. men are attempting to lose weight at any time, regardless of their body weight.’ In spite of its commonness, the magnitude and direction of the long-term health impact of intentional weight loss is unknown. Until relatively recently, the proposition that weight loss will improve an obese person’s morbidity and longevity was accepted as dogma by the clinical community, for the understandable reason that clinical trials quite consistently found that weight loss was associated with marked improvement in the cardiovascular risk factors blood pressure, lipoproteins, and glucose.3 In 1989, however, two prospective observational studies were published that raised fundamental questions about the long-term safety of intentional weight loss. Independent groups in Chicago and Sweden found mortality was higher for persons with variable body weight compared to those with relatively stable weight.4.5 These papers were followed by two additional “weight cycling” studies in the Framingham cohort and the Multiple Risk Factor Intervention Trial cohort, with similar findings.6,7 In an additional analysis of the Framingham cohort, weight loss was associated with the expected improvements in blood pressure and cholesterol levels, but it was also associated with continued cigarette smoking, prevalent and incident cardiovascular disease, diabetes mellitus, other diseases, and ultimately death.8 In none of these epidemiologic studies was intentionality of weight loss directly assessed.’ One published observational study of weight loss and mortality directly assessed intentionality of weight loss, and this study may have raised more questions than answers.” This analysis of the never-smoker women participants in the American Cancer Society’s Cancer Prevention Study-I cohort found that in those with obesity-related comorbidities intentional weight loss was associated with a statistically significant 20% reduction in total mortality. This mortality reduction was largely driven by reduced cancer mortality rather than reduced cardiovascular disease mortality. In the women without comorbidities there was no consistent association between intentional weight loss and mortality, except in those whose weight loss occurred over more than a l-y period; their total and cardiovascular mortality was increased above those with no weight loss. There are also two published intervention studies relating weight loss to morbidity and mortality. Singh and colleagues ” published results of a l-y randomized controlled trial of a ’‘cardioprotective diet’ ’ in Indian patients hospitalized with recent myocardial infarction (mean age 50 y and mean body mass index [BMI] about 24 kg/m’). Compared to controls, incidence of cardiac events, as well as cardiovascular and total
mortality, were markedly reduced in the patients who received the dietary intervention. Although this study was not designed to test the efficacy of weight loss per se, the authors carried out post-hoc analyses within the dietary intervention arm. They found that those who lost 20.5 kg had a 50% lower risk of any cardiac event (95% confidence interval [CI] -70% to -19%). and a 54% lower risk of dying from any cause (95% CI -80% to +6%) compared with their counterparts who lost ~0.5 kg (relative risks and CIs ” were calculated by this writer using the data reported by Singh et al.“). Acknowledging the limitations of these post-hoc analyses, the study of Singh et al. does support the premise that intentional weight loss can improve long-term health, albeit in nonobese persons with severe cardiovascular comorbidities. The ongoing Swedish Obesity Study (SOS) is a controlled trial of surgically induced weight loss and subsequent morbidity and mortality over a 10-y follow-up period (ages 37-57 y, BMI ~34 kg/m* in men, and 238 kg/m’ in women ).I3 This study is not randomized as participants self-select for surgery. however. Nevertheless controls, who receive a behavioral weight loss program, are computer-matched to surgical participants by a large number of potential confounders. In a preliminary report the SOS study found that the 2-y incidence of diabetes was 16% in the control group and only 0.5% in the surgery group. In addition, hypertension incidence was 15% and 5%, hypertriglyceridemia incidence was 23% and 6%, and hypo-high density lipoproteinemia incidence was 16% and 5% in the control and surgery groups, respectively (statistical significance not reported) .I3 Thus there may be substantial reductions in morbidity and mortality associated with surgically induced weight loss when this study is over. Because of the limitations and inconsistencies in the observational and experimental literature, true randomized controlled trials have been advocated to directly test the efficacy of intentional weight loss on disease incidence and mortality.‘4 There are, however, four putative problems with the randomized controlled trial approach. The first problem is that randomized controlled trials are unethical because the physiologic benefits have already been proved.14 This assertion is challenged by StemI who points outthat, “. . . the clinical trials’ literature is full of unexpected, adverse side effects of theoretically appealing therapies (e.g., higher mortality with clofibrate and higher cardiovascular disease rates with estrogen treatment in men).” The second problem is that too few study participants will successfully maintain weight 10~s.‘~ This “problem” is in fact a major underlying rationale for a randomized controlled trial because the deleterious effects of weight variability may be caused by the frequent regain of weight that was initially lost.’ The third problem is that no “control group” of obese persons will refrain from intentional weight loss for any extended period.’ This will be a significant difficulty for any controlled trial that seeks to answer the purist question of whether any weight loss is better than none. However, if the question is
820
EDITORIAL
whether a new therapy is more efficacious than standard therapy, then a “control group” could be assigned to a more traditional behavioral weight loss program, as in the SOS study, or in the case of a drug trial, the control group would be given a placebo. The fourth problem, which has been raised in the context of the economics of pharmaceutical development, is that randomized controlled trials of disease and mortality endpoints will require too much time, making drug development unprofitable and hence not feasible.15 This may be the most serious of the problems associated with randomized controlled trials of intentional weight loss, although an appropriate modification of the approach taken by Singh and colleagues ” may have important cost savings. The problem of money, however, leads me back to the beginning of this editorial. The U.S. population is not a potential market for weight loss pharmacotherapy, it is an already active and growing market. In 1995, 1.1 million prescriptions were written for d,l fenfluramine (the less potent racemer of dexfenhutamine, the drug recently approved by the Food and Drug Administration). This represents more than a 17-fold increase in the number of prescriptions written for this drug since 1992.16 In parallel with this, the business community has noted a growing trend in the establishment of special clinics for prescription of weight-loss medications.” Even if we could all agree that intentional weight loss had long-term benefits, would any of us have a clue as to the actual magnitude of the benefit, as well as its incremental cost-effectiveness in our population? Will “lack of money,” coupled with insatiable consumer demand for thinner bodies, negate the public health imperative that adequate outcome data be collected and reported to payers, providers, and consumers of such widely used therapies? Should the definitive randomized controlled trial be the “price of admission” to enter this enormous and lucrative market? DAVID F. WILLIAMSON, PHD Centers for Disease Control and Prevention Division of Diabetes Translation (K- 10) Atlanta, GA, USA REFERENCES 1. Sannes LJ. Obesity: prospects for emerging therapies. In: Decision resources reports. Waltham, MA: Decision Resources, Inc, 1995
COMMENTS
2. Williamson DF, Serdula MK, Anda RF, Levy A, Byers T. Current weight loss attempts in adults: goal, duration, and rate of weight loss. Am J Pub Health 1992;82:1251 3. Pi-Sunyer FX. Short-term medical benefits and adverse effects of weight loss. Ann Intern Med 1993; 119(7 pt 2):722 4. Hamm P, Shekelle RB, Stamler J. Large fluctuations in body weight during young adulthood and twenty-five-year risk of coronary death in men. Am J Epidemiol 1989; 129:312 5. Lissner L, Bengtsson C, Lapidus L, et al. Body weight variability and mortality in Gothenburg prospective studies of men and women. In Bjomtorp P, Rossner B, eds. Obesity in Europe 88: Proceedings of the First European Conference on Obesity. London: Libbey, 1989:55 6. Lissner L, Ode11P, D’Agostino R, et al. Variability in body weight and health outcomes in the Framingham population. N Engl J Med 1991;324:1839 I. Blair SN, Shaten J, Brownell K, Collins G, Lissner L. Body weight change, all-cause mortality, and cause-specific mortality in the Multiple Risk Factor Intervention Trial. Ann Intern Med 1993; 119(7 pt 2):749 8. Higgins M, D’Agostino R, Kannel W. Cobb J. Benefits and adverse effects of weight loss: Observations from the Framingham study. Ann Int Med 1993;119(7 pt 2):758 9. Williamson DF. “Weight cycling” and mortality: How do the epidemiologists explain the role of intentional weight loss? J Am Co11Nutr 1996; 15:6 10. Williamson DF, Pamuk E, Thun M, et al. Prospective study of intentional weight loss and mortality in never-smoking overweight US white women aged 40-64 years. Am J Epidemiol 1995; 141:1128 11. Singh RB, Rastogi SS, Verma R, et al. Randomised controlled trial of cardioprotective diet in patients with recent acute myocardial infarction: results of one year follow up. Br Med J 1992;304:1015 12. Rothman KJ. Modern epidemiology. Boston: Little, Brown and Co., 1986 13. Sjostrom L. Natural history of massive obesity (abstract). Obesity Res 1995;3:317s 14. Stem MP. The case for randomized clinical trials on the treatment of obesity. Obesity Res 1995:3(suppl 2):299s 15. Pi-Sunyer FX. Drug therapy for obesity: What’s needed in a drug. 1BC Second Annual International Symposium on Obesity: Advances in Understanding and Treatment. Southborough, MA: International
Business Communications, 1996: I 16. Statement of Dr. Bruce Stadel, Food and Drug Administration Endocrinologic and Metabolic Drugs Advisory Committee Meeting Condensed Transcript and Concordance. SAG Corporation: Washington, D.C. September 28, 1995:261 17. Stipp D. New weapons in the war on fat. Fortune. December 11, 1995, 164
How Much Energy Consumed and Spent for Optimal Growth and Development? Positive imbalance between energy intake and output during growth has been regarded as one of the most important risk factors for present and/or future obesity and other metabolic complications’-6 that lead to serious diseases, such as atherosclerosis, later in life. ’ Reducing the Recommended Daily Allowance has even been suggested, as children have been found to grow normally with an energy intake lower than what has actually been recommended.8
Engaging in a high level of spontaneous physical activity is an important characteristic for children of all ages.4,9Significant changes occur on entering primary school and during puberty4 and adequate exercise is indispensable for optimal growth and development, especially of the cardiovascular and neuromotor systems. The increased energy output of active children renders possible a higher, more desirable food intake, preventing complications from nutritional deficiencies that occur more easily
COMMENTS
819
Lingering Questions About Intentional Weight Loss I recently received an advertisement for a $2,800 marketdata report on “emerging obesity therapies.” The advertisement stated, “Pharmaceutical help may be on the horizon for the estimated 40 million Americans (aged 15-74) considered obese.” ’ By most standards this is a very large market. But the actual market may be even larger, as it is currently estimated that nearly half of U.S. women and one-quarter of U.S. men are attempting to lose weight at any time, regardless of their body weight.’ In spite of its commonness, the magnitude and direction of the long-term health impact of intentional weight loss is unknown. Until relatively recently, the proposition that weight loss will improve an obese person’s morbidity and longevity was accepted as dogma by the clinical community, for the understandable reason that clinical trials quite consistently found that weight loss was associated with marked improvement in the cardiovascular risk factors blood pressure, lipoproteins, and glucose.3 In 1989, however, two prospective observational studies were published that raised fundamental questions about the long-term safety of intentional weight loss. Independent groups in Chicago and Sweden found mortality was higher for persons with variable body weight compared to those with relatively stable weight.4.5 These papers were followed by two additional “weight cycling” studies in the Framingham cohort and the Multiple Risk Factor Intervention Trial cohort, with similar findings.6,7 In an additional analysis of the Framingham cohort, weight loss was associated with the expected improvements in blood pressure and cholesterol levels, but it was also associated with continued cigarette smoking, prevalent and incident cardiovascular disease, diabetes mellitus, other diseases, and ultimately death.8 In none of these epidemiologic studies was intentionality of weight loss directly assessed.’ One published observational study of weight loss and mortality directly assessed intentionality of weight loss, and this study may have raised more questions than answers.” This analysis of the never-smoker women participants in the American Cancer Society’s Cancer Prevention Study-I cohort found that in those with obesity-related comorbidities intentional weight loss was associated with a statistically significant 20% reduction in total mortality. This mortality reduction was largely driven by reduced cancer mortality rather than reduced cardiovascular disease mortality. In the women without comorbidities there was no consistent association between intentional weight loss and mortality, except in those whose weight loss occurred over more than a l-y period; their total and cardiovascular mortality was increased above those with no weight loss. There are also two published intervention studies relating weight loss to morbidity and mortality. Singh and colleagues ” published results of a l-y randomized controlled trial of a ’‘cardioprotective diet’ ’ in Indian patients hospitalized with recent myocardial infarction (mean age 50 y and mean body mass index [BMI] about 24 kg/m’). Compared to controls, incidence of cardiac events, as well as cardiovascular and total
mortality, were markedly reduced in the patients who received the dietary intervention. Although this study was not designed to test the efficacy of weight loss per se, the authors carried out post-hoc analyses within the dietary intervention arm. They found that those who lost 20.5 kg had a 50% lower risk of any cardiac event (95% confidence interval [CI] -70% to -19%). and a 54% lower risk of dying from any cause (95% CI -80% to +6%) compared with their counterparts who lost ~0.5 kg (relative risks and CIs ” were calculated by this writer using the data reported by Singh et al.“). Acknowledging the limitations of these post-hoc analyses, the study of Singh et al. does support the premise that intentional weight loss can improve long-term health, albeit in nonobese persons with severe cardiovascular comorbidities. The ongoing Swedish Obesity Study (SOS) is a controlled trial of surgically induced weight loss and subsequent morbidity and mortality over a 10-y follow-up period (ages 37-57 y, BMI ~34 kg/m* in men, and 238 kg/m’ in women ).I3 This study is not randomized as participants self-select for surgery. however. Nevertheless controls, who receive a behavioral weight loss program, are computer-matched to surgical participants by a large number of potential confounders. In a preliminary report the SOS study found that the 2-y incidence of diabetes was 16% in the control group and only 0.5% in the surgery group. In addition, hypertension incidence was 15% and 5%, hypertriglyceridemia incidence was 23% and 6%, and hypo-high density lipoproteinemia incidence was 16% and 5% in the control and surgery groups, respectively (statistical significance not reported) .I3 Thus there may be substantial reductions in morbidity and mortality associated with surgically induced weight loss when this study is over. Because of the limitations and inconsistencies in the observational and experimental literature, true randomized controlled trials have been advocated to directly test the efficacy of intentional weight loss on disease incidence and mortality.‘4 There are, however, four putative problems with the randomized controlled trial approach. The first problem is that randomized controlled trials are unethical because the physiologic benefits have already been proved.14 This assertion is challenged by StemI who points outthat, “. . . the clinical trials’ literature is full of unexpected, adverse side effects of theoretically appealing therapies (e.g., higher mortality with clofibrate and higher cardiovascular disease rates with estrogen treatment in men).” The second problem is that too few study participants will successfully maintain weight 10~s.‘~ This “problem” is in fact a major underlying rationale for a randomized controlled trial because the deleterious effects of weight variability may be caused by the frequent regain of weight that was initially lost.’ The third problem is that no “control group” of obese persons will refrain from intentional weight loss for any extended period.’ This will be a significant difficulty for any controlled trial that seeks to answer the purist question of whether any weight loss is better than none. However, if the question is
820
EDITORIAL
whether a new therapy is more efficacious than standard therapy, then a “control group” could be assigned to a more traditional behavioral weight loss program, as in the SOS study, or in the case of a drug trial, the control group would be given a placebo. The fourth problem, which has been raised in the context of the economics of pharmaceutical development, is that randomized controlled trials of disease and mortality endpoints will require too much time, making drug development unprofitable and hence not feasible.15 This may be the most serious of the problems associated with randomized controlled trials of intentional weight loss, although an appropriate modification of the approach taken by Singh and colleagues ” may have important cost savings. The problem of money, however, leads me back to the beginning of this editorial. The U.S. population is not a potential market for weight loss pharmacotherapy, it is an already active and growing market. In 1995, 1.1 million prescriptions were written for d,l fenfluramine (the less potent racemer of dexfenhutamine, the drug recently approved by the Food and Drug Administration). This represents more than a 17-fold increase in the number of prescriptions written for this drug since 1992.16 In parallel with this, the business community has noted a growing trend in the establishment of special clinics for prescription of weight-loss medications.” Even if we could all agree that intentional weight loss had long-term benefits, would any of us have a clue as to the actual magnitude of the benefit, as well as its incremental cost-effectiveness in our population? Will “lack of money,” coupled with insatiable consumer demand for thinner bodies, negate the public health imperative that adequate outcome data be collected and reported to payers, providers, and consumers of such widely used therapies? Should the definitive randomized controlled trial be the “price of admission” to enter this enormous and lucrative market? DAVID F. WILLIAMSON, PHD Centers for Disease Control and Prevention Division of Diabetes Translation (K- 10) Atlanta, GA, USA REFERENCES 1. Sannes LJ. Obesity: prospects for emerging therapies. In: Decision resources reports. Waltham, MA: Decision Resources, Inc, 1995
COMMENTS
2. Williamson DF, Serdula MK, Anda RF, Levy A, Byers T. Current weight loss attempts in adults: goal, duration, and rate of weight loss. Am J Pub Health 1992;82:1251 3. Pi-Sunyer FX. Short-term medical benefits and adverse effects of weight loss. Ann Intern Med 1993; 119(7 pt 2):722 4. Hamm P, Shekelle RB, Stamler J. Large fluctuations in body weight during young adulthood and twenty-five-year risk of coronary death in men. Am J Epidemiol 1989; 129:312 5. Lissner L, Bengtsson C, Lapidus L, et al. Body weight variability and mortality in Gothenburg prospective studies of men and women. In Bjomtorp P, Rossner B, eds. Obesity in Europe 88: Proceedings of the First European Conference on Obesity. London: Libbey, 1989:55 6. Lissner L, Ode11P, D’Agostino R, et al. Variability in body weight and health outcomes in the Framingham population. N Engl J Med 1991;324:1839 I. Blair SN, Shaten J, Brownell K, Collins G, Lissner L. Body weight change, all-cause mortality, and cause-specific mortality in the Multiple Risk Factor Intervention Trial. Ann Intern Med 1993; 119(7 pt 2):749 8. Higgins M, D’Agostino R, Kannel W. Cobb J. Benefits and adverse effects of weight loss: Observations from the Framingham study. Ann Int Med 1993;119(7 pt 2):758 9. Williamson DF. “Weight cycling” and mortality: How do the epidemiologists explain the role of intentional weight loss? J Am Co11Nutr 1996; 15:6 10. Williamson DF, Pamuk E, Thun M, et al. Prospective study of intentional weight loss and mortality in never-smoking overweight US white women aged 40-64 years. Am J Epidemiol 1995; 141:1128 11. Singh RB, Rastogi SS, Verma R, et al. Randomised controlled trial of cardioprotective diet in patients with recent acute myocardial infarction: results of one year follow up. Br Med J 1992;304:1015 12. Rothman KJ. Modern epidemiology. Boston: Little, Brown and Co., 1986 13. Sjostrom L. Natural history of massive obesity (abstract). Obesity Res 1995;3:317s 14. Stem MP. The case for randomized clinical trials on the treatment of obesity. Obesity Res 1995:3(suppl 2):299s 15. Pi-Sunyer FX. Drug therapy for obesity: What’s needed in a drug. 1BC Second Annual International Symposium on Obesity: Advances in Understanding and Treatment. Southborough, MA: International
Business Communications, 1996: I 16. Statement of Dr. Bruce Stadel, Food and Drug Administration Endocrinologic and Metabolic Drugs Advisory Committee Meeting Condensed Transcript and Concordance. SAG Corporation: Washington, D.C. September 28, 1995:261 17. Stipp D. New weapons in the war on fat. Fortune. December 11, 1995, 164
How Much Energy Consumed and Spent for Optimal Growth and Development? Positive imbalance between energy intake and output during growth has been regarded as one of the most important risk factors for present and/or future obesity and other metabolic complications’-6 that lead to serious diseases, such as atherosclerosis, later in life. ’ Reducing the Recommended Daily Allowance has even been suggested, as children have been found to grow normally with an energy intake lower than what has actually been recommended.8
Engaging in a high level of spontaneous physical activity is an important characteristic for children of all ages.4,9Significant changes occur on entering primary school and during puberty4 and adequate exercise is indispensable for optimal growth and development, especially of the cardiovascular and neuromotor systems. The increased energy output of active children renders possible a higher, more desirable food intake, preventing complications from nutritional deficiencies that occur more easily