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Editorial Commentary: The metabolic syndrome: What does the clinician need to know and do?
Author's Accepted Manuscript
The Metabolic Syndrome: what Does the Clinician Need to Know and Do? Paul D. Thompson MD
www.elsevier.com/locate/tcm
PII: DOI: Reference:
S1050-1738(15)00251-0 http://dx.doi.org/10.1016/j.tcm.2015.11.001 TCM6227
To appear in: trends in cardiovascular medicine
Cite this article as: Paul D. Thompson MD, The Metabolic Syndrome: what Does the Clinician Need to Know and Do?, trends in cardiovascular medicine, http://dx.doi.org/10.1016/j.tcm.2015.11.001 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
The Metabolic Syndrome: What Does the Clinician Need to Know and Do? Paul D. Thompson, MD Chief of Cardiology, Hartford Hospital Address for Correspondence: Paul D. Thompson, MD Cardiology, 7th Floor Jefferson Hartford Hospital 80 Seymour Street Hartford, CT 06102 Tel: 860 729 4806 [email protected] Conflicts of interest: Dr. Thompson has received research support from Roche, Sanofi, Regeneron, Esperion, Amarin and Pfizer; has served as a consultant for Amgen, Regeneron, Merck, Esperion and Sanolfi; has received speaker honoraria from Merck, Astra Zenica, Regeneron, Sanofi, and Amgen; owns stock in Abbvie, Abbott Labs, CVS, General Electric , Johnson & Johnson, Medtronic and JA Willey; and has provided expert legal testimony on exercise-related cardiac events and statin myopathy.
In this issue of Trends in Cardiovascular Medicine, Scott Grundy, MD, reviews the “metabolic syndrome” and summarizes its possible pathogenesis, clinical importance, and treatment.1 It is appropriate that Dr. Grundy assumed this task. He chaired both the second and third National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) reports on managing lipids,2, 3 and ATP III was the first of these reports to note the importance of the metabolic syndrome. Dr. Grundy subsequently firstauthored a position paper from the National Heart and Lung Institute and the American Heart Association on the importance of the metabolic syndrome.4 So, what do clinicians need to know about the metabolic syndrome? Clinicians need to know the markedly increased risk conferred by the metabolic syndrome, its diagnostic parameters, as well
as its probable pathogenesis and possible treatment strategies. This editorial seeks to provide this information for clinicians based on Dr. Grundy’s review, other literature and clinical experience. The metabolic syndrome doubles the risk of atherosclerotic cardiovascular disease (ASCVD) in individuals with or without diabetes and increases the risk of stroke four-fold. The mechanisms for this markedly increased risk are probably both the risk components of the syndrome itself as well as the observation that thrombotic and inflammatory factors are also increased in metabolic syndrome patients. The metabolic syndrome is typically diagnosed when 3 of the 5 following risk factors are present: a waist circumference measured at the iliac crests of ≥ 102 cm (40 inches) in men or ≥ 80 cm (31 inches) in women; blood triglycerides ≥1.7 mmol/L (150 mg/dl); a high density lipoprotein cholesterol (HDL-C) level ≤1.03 mmol/L ( 40 mg/dl) in men and ≤ 1.3 mmol/L (50 mg/dl ) in women; systolic blood pressure ≥ 130 mmHg or diastolic blood pressure ≥85 mmHg; and a fasting blood glucose ≥5.5mmol/L (100 mg/dl).4 The exact etiology of the metabolic syndrome is not clear, but most authorities consider insulin resistance, often due to increased body weight, to be the ultimate culprit. How could insulin resistance alone produce such disparate risk factors? Many clinicians are unaware that either more insulin, or greater insulin sensitivity, is required to regulate fat and triglycerides than to regulate glucose metabolism. Insulin drives free fatty acids into the fat cell, probably one of the reasons that treatments that increase insulin levels, such as insulin itself or sulfonylureas, often increase body weight.
With insufficient insulin or with insulin resistance, circulating free fatty acids are ingested by the liver to produce triglyceride-rich, very low density lipoprotein (VLDL) particles. Lipoprotein lipase (LPL) removes fatty acids from VLDL for use in peripheral tissue, such as muscle during exercise, but insulin resistance reduces LPL activity contributing to the accumulation of triglycerides in the blood. Elevated triglyceride levels, in turn, increase the TG concentration in the HDL particle, which facilitates HDL catabolism. Insulin resistance may also increase blood pressure since excess insulin concentrations are one of the hallmarks of insulin resistance and insulin increases renal sodium reabsorption. Thus, increasing abdominal obesity, evidenced by increased waist circumference, reduces insulin sensitivity, which increases glucose, triglycerides and blood pressure and reduces HDL-C. Management of patients with the metabolic syndrome requires treating both the risk and the individual risk factors. Statins are not the “go to” drugs for triglycerides, but they are the cornerstone of treatment of the metabolic syndrome because they are the best medications for reducing ASCVD risk. This is probably best evidenced by the JUPITER trial, which required participants to have high sensitivity C-reactive protein values >2 mg/dl, and >40% of participants had the metabolic syndrome.5 The fact that so many JUPITER participants had the metabolic syndrome is probably also the reason that JUPITER demonstrated so clearly that statins increase the risk of diabetes. The component risk factors of the metabolic syndrome including abdominal obesity, blood pressure and glucose levels should also be addressed. We routinely perform oral glucose tolerance tests (OGTTs) in metabolic syndrome patients with glucose or
hemoglobin A1c levels borderline for diabetes, looking for an excuse to use metformin. In the Diabetes Prevention Program (DPP) metformin alone reduced the risk of developing diabetes over the next 3 years by 31% in individuals with 2 hour OGTT glucose values ≥ 140 mg/dl compared to usual care.6 Metformin also typically reduces body weight, which addresses one of the primary causes of the metabolic syndrome. Metformin administered alone does not produce hypoglycemia, and reduced the risk of myocardial infarction and death mortality by 33 and 27%, respectively, in obese participants in the United Kingdom Diabetes Prevention Program (UKDPP).7 Both exercise and diet reduce body weight and increase insulin sensitivity, although exercise alone rarely produces weight loss in short-term studies, such as those lasting less than several years. Nevertheless, it is important for patients to understand that exercise promptly and acutely increases insulin sensitivity so that exercise should have a beneficial effect in the metabolic syndrome even before someone has “gotten in shape”. We recommend daily exercise of at least 30 minutes of brisk walking daily and more if possible. Walking has the additional benefit of consuming the more calories per mile in the heaviest individuals because heavy patients expend more calories transporting their increased body weight. It is one way for patients to turn “their lemons into lemonade”. Exercise and dietary weight loss reduced the risk of subsequent diabetes 51% in the DPP, significantly more than the 31% reduction produced my metformin alone,5 but exercise and weight loss strategies are difficult to implement outside of study protocols for both patients and physicians. Many patients are unable to follow consistent exercise and dietary regiments because of life pressures
that impede adherence to both strategies and because of orthopedic problems, likely exacerbated by years of being overweight. Dr. Grundy recommends weight loss intestinal surgery for the heaviest patients with the metabolic syndrome who cannot achieve weight loss goals by exercise and diet alone. Such surgery and subsequent weight loss often cure the metabolic syndrome. Even in those patients who ultimately “eat through” their surgery and regain all or some of their weight, we suspect that even they benefit form their years with weight loss and without the metabolic syndrome. Metabolic syndrome is a growing problem (pun intended) because of the increasing obesity in many cultures. The best approach is to prevent obesity in the first place by encouraging patients to adopt an active lifestyle and to avoid obesity throughout their lifespan. Physicians have a role in this effort and should weigh all patients at every visit and address even small gains in weight. We tell patients that “it’s easier to lose one pound fifty times than fifty pounds once”. In the absence of such preventive efforts, aggressive statin therapy, weight loss, and risk factor modification are the second best approach.
Reference List (1) Grundy SM. Metabolic Syndrome Update. Trends in Cardiovascular Medicine. 2015. In Press (1) 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 December 17;106(25):3143-421. (2) National Cholesterol Education Program. Second Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II). Circulation 1994 March;89(3):1333-445. (3) 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 October 25;112(17):2735-52. (4) Ridker PM, Danielson E, Fonseca FA et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008 November 20;359(21):2195-207. (5) 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 February 7;346(6):393-403. (6) Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 2008 October 9;359(15):1577-89.
The Metabolic Syndrome: what Does the Clinician Need to Know and Do? Paul D. Thompson MD
www.elsevier.com/locate/tcm
PII: DOI: Reference:
S1050-1738(15)00251-0 http://dx.doi.org/10.1016/j.tcm.2015.11.001 TCM6227
To appear in: trends in cardiovascular medicine
Cite this article as: Paul D. Thompson MD, The Metabolic Syndrome: what Does the Clinician Need to Know and Do?, trends in cardiovascular medicine, http://dx.doi.org/10.1016/j.tcm.2015.11.001 This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting galley proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
The Metabolic Syndrome: What Does the Clinician Need to Know and Do? Paul D. Thompson, MD Chief of Cardiology, Hartford Hospital Address for Correspondence: Paul D. Thompson, MD Cardiology, 7th Floor Jefferson Hartford Hospital 80 Seymour Street Hartford, CT 06102 Tel: 860 729 4806 [email protected] Conflicts of interest: Dr. Thompson has received research support from Roche, Sanofi, Regeneron, Esperion, Amarin and Pfizer; has served as a consultant for Amgen, Regeneron, Merck, Esperion and Sanolfi; has received speaker honoraria from Merck, Astra Zenica, Regeneron, Sanofi, and Amgen; owns stock in Abbvie, Abbott Labs, CVS, General Electric , Johnson & Johnson, Medtronic and JA Willey; and has provided expert legal testimony on exercise-related cardiac events and statin myopathy.
In this issue of Trends in Cardiovascular Medicine, Scott Grundy, MD, reviews the “metabolic syndrome” and summarizes its possible pathogenesis, clinical importance, and treatment.1 It is appropriate that Dr. Grundy assumed this task. He chaired both the second and third National Cholesterol Education Program (NCEP) Adult Treatment Panel (ATP) reports on managing lipids,2, 3 and ATP III was the first of these reports to note the importance of the metabolic syndrome. Dr. Grundy subsequently firstauthored a position paper from the National Heart and Lung Institute and the American Heart Association on the importance of the metabolic syndrome.4 So, what do clinicians need to know about the metabolic syndrome? Clinicians need to know the markedly increased risk conferred by the metabolic syndrome, its diagnostic parameters, as well
as its probable pathogenesis and possible treatment strategies. This editorial seeks to provide this information for clinicians based on Dr. Grundy’s review, other literature and clinical experience. The metabolic syndrome doubles the risk of atherosclerotic cardiovascular disease (ASCVD) in individuals with or without diabetes and increases the risk of stroke four-fold. The mechanisms for this markedly increased risk are probably both the risk components of the syndrome itself as well as the observation that thrombotic and inflammatory factors are also increased in metabolic syndrome patients. The metabolic syndrome is typically diagnosed when 3 of the 5 following risk factors are present: a waist circumference measured at the iliac crests of ≥ 102 cm (40 inches) in men or ≥ 80 cm (31 inches) in women; blood triglycerides ≥1.7 mmol/L (150 mg/dl); a high density lipoprotein cholesterol (HDL-C) level ≤1.03 mmol/L ( 40 mg/dl) in men and ≤ 1.3 mmol/L (50 mg/dl ) in women; systolic blood pressure ≥ 130 mmHg or diastolic blood pressure ≥85 mmHg; and a fasting blood glucose ≥5.5mmol/L (100 mg/dl).4 The exact etiology of the metabolic syndrome is not clear, but most authorities consider insulin resistance, often due to increased body weight, to be the ultimate culprit. How could insulin resistance alone produce such disparate risk factors? Many clinicians are unaware that either more insulin, or greater insulin sensitivity, is required to regulate fat and triglycerides than to regulate glucose metabolism. Insulin drives free fatty acids into the fat cell, probably one of the reasons that treatments that increase insulin levels, such as insulin itself or sulfonylureas, often increase body weight.
With insufficient insulin or with insulin resistance, circulating free fatty acids are ingested by the liver to produce triglyceride-rich, very low density lipoprotein (VLDL) particles. Lipoprotein lipase (LPL) removes fatty acids from VLDL for use in peripheral tissue, such as muscle during exercise, but insulin resistance reduces LPL activity contributing to the accumulation of triglycerides in the blood. Elevated triglyceride levels, in turn, increase the TG concentration in the HDL particle, which facilitates HDL catabolism. Insulin resistance may also increase blood pressure since excess insulin concentrations are one of the hallmarks of insulin resistance and insulin increases renal sodium reabsorption. Thus, increasing abdominal obesity, evidenced by increased waist circumference, reduces insulin sensitivity, which increases glucose, triglycerides and blood pressure and reduces HDL-C. Management of patients with the metabolic syndrome requires treating both the risk and the individual risk factors. Statins are not the “go to” drugs for triglycerides, but they are the cornerstone of treatment of the metabolic syndrome because they are the best medications for reducing ASCVD risk. This is probably best evidenced by the JUPITER trial, which required participants to have high sensitivity C-reactive protein values >2 mg/dl, and >40% of participants had the metabolic syndrome.5 The fact that so many JUPITER participants had the metabolic syndrome is probably also the reason that JUPITER demonstrated so clearly that statins increase the risk of diabetes. The component risk factors of the metabolic syndrome including abdominal obesity, blood pressure and glucose levels should also be addressed. We routinely perform oral glucose tolerance tests (OGTTs) in metabolic syndrome patients with glucose or
hemoglobin A1c levels borderline for diabetes, looking for an excuse to use metformin. In the Diabetes Prevention Program (DPP) metformin alone reduced the risk of developing diabetes over the next 3 years by 31% in individuals with 2 hour OGTT glucose values ≥ 140 mg/dl compared to usual care.6 Metformin also typically reduces body weight, which addresses one of the primary causes of the metabolic syndrome. Metformin administered alone does not produce hypoglycemia, and reduced the risk of myocardial infarction and death mortality by 33 and 27%, respectively, in obese participants in the United Kingdom Diabetes Prevention Program (UKDPP).7 Both exercise and diet reduce body weight and increase insulin sensitivity, although exercise alone rarely produces weight loss in short-term studies, such as those lasting less than several years. Nevertheless, it is important for patients to understand that exercise promptly and acutely increases insulin sensitivity so that exercise should have a beneficial effect in the metabolic syndrome even before someone has “gotten in shape”. We recommend daily exercise of at least 30 minutes of brisk walking daily and more if possible. Walking has the additional benefit of consuming the more calories per mile in the heaviest individuals because heavy patients expend more calories transporting their increased body weight. It is one way for patients to turn “their lemons into lemonade”. Exercise and dietary weight loss reduced the risk of subsequent diabetes 51% in the DPP, significantly more than the 31% reduction produced my metformin alone,5 but exercise and weight loss strategies are difficult to implement outside of study protocols for both patients and physicians. Many patients are unable to follow consistent exercise and dietary regiments because of life pressures
that impede adherence to both strategies and because of orthopedic problems, likely exacerbated by years of being overweight. Dr. Grundy recommends weight loss intestinal surgery for the heaviest patients with the metabolic syndrome who cannot achieve weight loss goals by exercise and diet alone. Such surgery and subsequent weight loss often cure the metabolic syndrome. Even in those patients who ultimately “eat through” their surgery and regain all or some of their weight, we suspect that even they benefit form their years with weight loss and without the metabolic syndrome. Metabolic syndrome is a growing problem (pun intended) because of the increasing obesity in many cultures. The best approach is to prevent obesity in the first place by encouraging patients to adopt an active lifestyle and to avoid obesity throughout their lifespan. Physicians have a role in this effort and should weigh all patients at every visit and address even small gains in weight. We tell patients that “it’s easier to lose one pound fifty times than fifty pounds once”. In the absence of such preventive efforts, aggressive statin therapy, weight loss, and risk factor modification are the second best approach.
Reference List (1) Grundy SM. Metabolic Syndrome Update. Trends in Cardiovascular Medicine. 2015. In Press (1) 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 December 17;106(25):3143-421. (2) National Cholesterol Education Program. Second Report of the Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults (Adult Treatment Panel II). Circulation 1994 March;89(3):1333-445. (3) 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 October 25;112(17):2735-52. (4) Ridker PM, Danielson E, Fonseca FA et al. Rosuvastatin to prevent vascular events in men and women with elevated C-reactive protein. N Engl J Med 2008 November 20;359(21):2195-207. (5) 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 February 7;346(6):393-403. (6) Holman RR, Paul SK, Bethel MA, Matthews DR, Neil HA. 10-year follow-up of intensive glucose control in type 2 diabetes. N Engl J Med 2008 October 9;359(15):1577-89.