METABOLIC SYNDROME DONALD FELITTO, M.D.

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1 METABOLIC SYNDROME DONALD FELITTO, M.D.

2 DEFINITIONS

3 WHO Defini:on 1999 Diabetes or impaired fas/ng glycemia or IGT or insulin resistance Plus any two: Obesity: BMI > 30, WTH ra/o>0.9 male or >0.85 female. Dyslipidemia: TG >or= 1.7mmol/liter or HDL cholesterol <0.9 mmol/l male or <1.0mmol/l female. Hypertension: BP > 140/90 mmhg Microalbuminuria: albumin excre/on >20mcg/min

4 European Group for the Study of Insulin Resistance 1999 Insulin Resistance: hyperinsulinemia: top 25% of the fas/ng insulin values from the non- diabe/c popula/on. Plus 2 or more of the following: Central obesity: waist circumference > or = to 94 cm for male and 84 cm female Dyslipidemia: TG > 2.0mmol/L or HDL cholesterol > 1.0mmol/L Hypertension: BP 140/90 and/or medica/on Fas/ng plasma glucose > 6.1mmol/l

5 Na:onal Cholesterol Educa:on Program s Adult Treatment Panel III (2001) Three or more of the following: Central Obesity: waist > 40 in. male and waist > 34 in. female. TG > or = to 150 Low HDL cholesterol: < 40 male and less than 50 female. Hypertension: BP > or = 135/85mm/Hg Fas/ng plasma glucose > 110

6 American Associa:on of Endocrinology - Statement Insulin Resistance Syndrome (2002) Four Iden/fying Abnormali/es: High Triglycerides Low HDL cholesterol Hypertension Elevated fas/ng or post load (75g) glucose. OBESITY is not a component of the defini/on.

Comparison of Defini:ons WHO 1999 Risk Factor

IGT, DM Central Obesity BP > 140/90 TG >150 or HDL.

Factor (any 3 of 5 risk factors) Blood Sugar >/=

Triglyceride >/= 150 HDL <40M, <50F Am. Assoc.

load (75g) glucose Hypertension Elevated

Interna/onal Diabetes Federa/on 2005 Risk Factor

7 Comparison of Defini:ons WHO 1999 Risk Factor Impaired glucose regula/on (+2 other risks,) IR, IGT, DM Central Obesity BP > 140/90 TG >150 or HDL. M <35, F <39 Mcroalbuminuria ATP III 2001 Risk Factor (any 3 of 5 risk factors) Blood Sugar >/= 100 Central obesity BPS >/=130, BPD >/= 85 Triglyceride >/= 150 HDL <40M, <50F Am. Assoc. of Endo 2002 Risk factor Elevated fas/ng or post load (75g) glucose Hypertension Elevated Triglycerides Low HDL (no men/on of obesity) Interna/onal Diabetes Federa/on 2005 Risk Factor Central Obesity (plus >/= 2 factors) BS>/=100 or DM BPS>/=135, BPD >/ =85 TG > 150 HDL <40M,,50F

9 Table 2: AHA/NHLBI criteria for diagnosis of metabolic syndrome

10 Commonali:es A large waistline: Central Obesity/ Visceral Obesity For women a waistline > 35 and for men >40 Dyslipidemia: High Triglyceride and low HDL in the blood Hypertension: 135/85 or 140/90 Some form of insulin resistance

11 Case Report Mr. B. is a 63 year old man with a past medical history for Hypertension, Dyslipidemia, Obesity and family history of Type 2 Diabetes Mellitus was evaluated for weight loss. The BMI was 36 kg/m2, BP was 144/84, fas/ng blood sugar was 125, TC was 183, LDL cholesterol 112, TG 171, HDL cholesterol 37. The EKG showed old MI.

12 Prevalence of Metabolic Syndrome USA Na/ve Americans 45-49y/o: (58% women and 45% men) USA Filipina- Americans: 50-69y/o (35%) USA 30-79y/o: 25+% (>60y/o 40+%) USA non- Hispanic white:30-79y/o (25%) USA Mexican American 30-79y/o (30%)

13 Prevalence of Metabolic Syndrome Weiss et al. (2004) Severely obese children/adolescents, the prevalence is 50%! NHANES III 12-19y/o using ATPIII criteria for metabolic syndrome the prevalence is 4.2%.

14 Risk factors for developing Metabolic Syndrome Overweight Obesity Lack of physical ac/vity (sedentary lifestyle) Insulin resistance Gene/cs Older age NHLBI 2007

15 Condi:ons that may play a role Fajy Liver (NASH) Polycys/c Ovarian Syndrome Gallstones Sleep Apnea NHLBI 2007

16 The diagnosis of metabolic syndrome requires a tape measure or accurate eye; fasting lipogram and plasma glucose measurements; and BP measurements. Opie L H Circulation. 2007;115:e32-e35 Copyright American Heart Association, Inc. All rights reserved.

17 Mechanisms Abdominal adipose /ssue is an endocrine organ which releases into circula/on FFA, Angiotensin II and adipokines. Increased FFA in the blood inhibit uptake of glucose by muscle. Excess FFA and AT II damage the pancreas. The pancreas makes extra insulin, it is an insufficient to counter hyperglycemia So, there is increased insulin levels and increased glucose. This is insulin resistance. AT II increases BP through vasoconstric/on. Inflammatory cytokines are responsible IR and Hypertension Hyperglycemia and increased circula/ng FFA contribute to increased manufacture of TG by the liver. Circula/ng TG increase so that lipoproteins carry more TG and less HDL. Circulation 2007;115:e32-e35

18 Mechanisms Insulin resistance: Increased postprandial insulin to maintain euglycemia. Increased fas/ng insulin secre/on to maintain euglycemia. Eventually, hyperglycemia in many. Hyperglycemia and increased FFA will increase insulin levels further. Beta cell dysfunc/on, defec/ve insulin secre/on

19 Pathophysiology AT II increases Blood Pressure The adipose /ssue liberates Tumor Necrosis Factor alpha and interleukins that provoke an inflammatory reac/on which promotes insulin resistance and promotes and promotes hypertension. Hyperglycemia and elevated levels of circula/ng FFA foster the manufacture of triglycerides by the liver. Lipoproteins carry triglyceride and TG level rises. HDL molecules are small and they are easily secreted. These physiologic reac/ons cause the high TG: HDL lipid abnormality. Opie L H Circulation. 2007;115:e32-e35

20 Inflama:on Inflamma/on associated with Insulin resistance: IL 6, TNF a, CRP, are increased. IL 6 and other cytokines increase hepa/c glucose produc/on, inc. hepa/c produc/on of VLDL and increase insulin resistance in muscle /ssue. Cytokines plus FFA increase fibrinogen and plasminogen ac/vator inhibitor 1 (from the liver) promote a prothrombo/c state.

21 Adiponec:n Adiponec/n: An/- inflammatory cytokine produced by adipose /ssue. Enhances insulin sensi/vity and inhibits the inflammatory process. Inhibits hepa/c glucose produc/on. Enhances glucose transport to muscle. It is reduced with insulin resistance. Some associate low concentra/ons with progression of subclinical CAD and MI.

22 The diagnosis of metabolic syndrome requires a tape measure or accurate eye; fasting lipogram and plasma glucose measurements; and BP measurements. Opie L H Circulation. 2007;115:e32-e35 Copyright American Heart Association, Inc. All rights reserved.

24 Manifesta:ons Obesity and Physical Inac/vity Dyslipidemia Insulin Resistance/IGT/Hyperinsulinemia (Na reten/on, SNS s/mula/on, HTN, increased circula/ng FFA). Prothrombo/c state Pro- inflammatory state Hyperuricemia defects in insulin ac/on on the renal tubular reabsorp/on of uric acid. Asymmetric dimethylarginine (endothelial dysfunc/on) Homocysteinemia Microalbuminuria Non- alcoholic fajy liver OSA? Lep/n deficiency/dysfunc/on (TG accumula/on and?hyperinsulinism) NHLBI 2007

25 Diagnosis of Metabolic Syndrome Large waistline High TG and low HDL (3:1) Blood Pressure >130/85 High FBS About 85% of people with Type 2 Diabetes Mellitus have Metabolic Syndrome NHLBI 2007

26 Case Report A 45 year old man with a PHx significant for MCD, Obesity, Hyperlipidemia, HTN who despite counseling developed Type 2 DM. BP controlled with ACEI. Total cholesterol 303, TG 1498, Abnormal LFT s, TC/HDL cholesterol 9.2

27 A pa:ent is found to have Metabolic Syndrome; so what?

28 Metabolic Syndrome Lifestyle High Sodium Intake High Caloric Intake Atherogenic diet Carbohydrate abuse Sedentary living plus Predisposi/on Tobacco Abuse Hypertension Obesity Insulin Resistance Premature Coronary Heart Disease Hyperlipidemia Metabolic Syndrome Type 2 Diabetes Mellitus Neuropathy Nephropathy Retinopathy Vasculopathy

29 Metabolic Syndrome is associated with risk of cardiovascular disease The risk of vascular complica/ons (CHD, Type 2 Diabetes Mellitus and Stroke) increase with the number of risk factors. People with Metabolic Syndrome are twice as likely to develop CHD and 5 /mes as likely to develop Type 2 Diabetes Mellitus when compared to pa/ents who do not have Metabolic Syndrome. Coagulopathy (propensity for blood clonng) and inflamma/on (elevated C- Reac/ve Protein) The risk must be added to finding of high LDL and smoking NHLBI 2007

30 Risk of Metabolic Syndrome Although the metabolic syndrome unequivocally predisposes to type 2 diabetes mellitus, 48,58 62 many inves/gators of cardiovascular diseases consider this syndrome to be a mul/dimensional risk factor for ASCVD. 1,58 Several recent reports show that the metabolic syndrome is associated with greater risk for cardiovascular disease, but once type 2 diabetes mellitus emerges, cardiovascular risk increases even more. Ann Intern Med. doi: /m

31 Metabolic Syndrome- Risk Other metabolic risk factors likewise appear individually to be: atherogenic diet Hypertension Elevated blood glucose prothrombo:c state proinflammatory state. Indeed, 3 of the metabolic risk factors elevated apob- containing lipoproteins, 1 low HDL- C levels, 1 and hypertension 91 are well established, major risk factors. Each imparts increased risk even when only marginally abnormal. Ann Intern Med. doi: /m

32 THERAPY

33 Treatments Healthy Lifestyle Ea/ng a healthy diet/losing weight Increasing physical ac/vity Quinng the cigareje smoking habit

34 The Diabetes Preven:on Program A randomized clinical trial tes/ng strategies to prevent Type 2 Diabetes Mellitus. High risk individuals with elevated fas/ng glucose and impaired glucose tolerance. 3,234 par/cipants 27 centers in the U.S.- 20% of whom were over 65y/o. Mean age 51y/o, BMI 34m/kg2. Three interven/ons: intensive lifestyle interven/on, Merormin, Placebo.

35 Diabetes Preven:on Program Primary outcome was development of Type 2 DM Secondary outcomes: CVD, changes in glycemia, Beta cell func/on, insulin sensi/vity, obesity, diet, physical ac/vity, health related QOL, occurrence of adverse events.

36 Diabetes Preven:on Program Inclusion Criteria: Age greater than or equal to 25y/o. BMI >/= 24kg/m2. IGT 2h plasma glucose Elevated FPG (95-125mg/dl)

37 Diabetes Preven:on Program ILS reduced the incidence of Type 2 DM by 58%. Merormin reduced the incidence of Type 2 DM by 31% over 2.8 years. 6.9 par/cipants with IGT would need to be treated with ILS for 3 years to prevent one case of Type 2 DM. For Merormin 14.3 par/cipants for 3 yrs to prevent one case Type 2 DM. Cost analysis shows both therapies to be cost effec/ve. Diabetes Care 9/03

38 Lifestyle changes Losing weight Reduce salt in the diet DASH diet (Dietary Approaches to Stop Hypertension) Increase ac/vity/fitness

40 Therapy: Finnish Study Study design: Reduce fat intake Reduce saturated fat Increase Fiber Increase exercise Yield was a 60% reduc/on of Type II Diabetes. Finnish Diabetes Preven/on Study Group. Preven/on of type- 2 diabetes mellitus by changes in lifestyle among subjects with impaired glucose tolerance.tuomilehto et al. N Engl J Med. 2001;344:

41 Treatment of Metabolic Syndrome Therapeu/c Strategies: 1. Lifestyle changes, exercise, adherence to the Mediterranean diet, and weight loss less new diabetes 2. Merormin (less new diabetes, not as good as lifestyle changes) 3. Glitazones, for non- diabe/cs with high cardiovascular risk: reduce fajy free acids, reduce insulin resistance, Increase HDL, must balance these against possible weight gain and heart failure 4. Choice of an/hypertensives: - blocker/diure/c much more likely to cause metabolic syndrome than calcium channel blockers/angiotensin- conver/ng enzyme inhibitors32 Opie L H Circulation. 2007;115:e32-e35

42 BEHAVIORAL COUNSELING TO PROMOTE A HEALTHFUL DIET AND PHYSICAL ACTIVITY FOR CARDIOVASCULAR DISEASE PREVENTION IN ADULTS WITH CARDIOVASCULAR RISK FACTORS CLINICAL SUMMARY OF U.S. PREVENTIVE SERVICES TASK FORCE RECOMMENDATION Ann Intern Med. doi: /m

43 Importance of the Recommenda:ons 1. Obesity is associated with increased CVD mortality 2. Adults who adhere to na/onal guidelines for a healthy diet and physical ac/vity have a lower cardiovascular morbidity and mortality than those who do not 3. All persons, regardless of CVD risk status, can accrue the health of improved nutri/on, healthy ea/ng behaviors and increased physical ac/vity. AnnInternMed.doi: /M

44 Proof of Efficacy The task force found adequate evidence that intensive behavioral counseling interven/ons have moderate benefits for CVD risk in overweight or obese adults who are at increased risk for CVD, including: Ø Decreases in blood pressure, lipid and fas/ng glucose levels, and body mass index (BMI). Ø Increases in levels of physical ac/vity. Ø The reduc/on in glucose levels was large enough to decrease the incidence of a diabetes diagnosis. Ann Intern Med. doi: /m

46 Case Report A 45 year old man with a PHx significant for MCD, Obesity, Hyperlipidemia, HTN who despite counseling developed Type 2 DM. BP controlled with ACEI. Total cholesterol 303, TG 1498, Abnormal LFT s, TC/HDL cholesterol 9.2

47 Case Report: 57lb. Weight Loss Total Protein 1.6g/ 24h Cholesterol 303mg/ dl HDL 32.9 Tc/HDL 9.2 LDL CNC TG mg/24h Cholesterol 191mg/ dl HDL 49mg/dl Tc/HDL 3.89 LDL 95mg/dl TG 236mg/dl

48 Treatments/Medica:ons If lifestyle changes are inadequate; medica/on may be necessary: Hypertension (Ace Inhibitors/Angiotensin Receptor Blockers) Dyslipidemia (Sta/ns and fibrates) High Blood Sugar (Merormin) Excessive blood clonng (ASA may be indicated) Ann Intern Med. doi: /m

49 Disease Burden Cardiovascular disease is the leading cause of death in the US CVD risk factors are common in adults Ann Intern Med. doi: /m

50 Disease Burden The Center for Disease Control and Preven/on es/mates that nearly half of all U.S. adults aged 20 years or older have at least of the following CVD risk factors: Uncontrolled hypertension Elevated low density lipoprotein Current smoking Ø Nearly 70% of U.S. adults are either overweight or obese Ann Intern Med. doi: /m

51 Low carbohydrate vs. Low fat diet 1.Foster GD, et al. A randomized trial of a low- carbohydrate diet for obesity. New England Journal of Medicine, Details: 63 individuals were randomized to either a low- fat diet group, or a low- carb diet group. The low- fat group was calorie restricted. This study went on for 12 months. Weight Loss: The low- carb group lost more weight, 7.3% of total body weight, compared to the low- fat group, which lost 4.5%. The difference was sta/s/cally significant at 3 and 6 months, but not 12 months. Conclusion: There was more weight loss in the low- carb group, significant at 3 and 6 months, but not 12. The low- carb group had greater improvements in blood triglycerides and HDL, but other biomarkers were similar between groups. authoritynutrition.com

52 Low carbohydrate vs. Low fat diet 2. Samaha FF, et al. A low- carbohydrate as compared with a low- fat diet in severe obesity. New England Journal of Medicine, Details: 132 individuals with severe obesity (mean BMI of 43) were randomized to either a low- fat or a low- carb diet. Many of the subjects had metabolic syndrome or type II diabetes. The low- fat dieters were calorie restricted. Study dura/on was 6 months. Weight Loss: The low- carb group lost an average of 5.8 kg (12.8 lbs) while the low- fat group lost only 1.9 kg (4.2 lbs). The difference was sta/s/cally significant. authoritynutrition.com

53 Low carbohydrate vs. Low carbohydrate diet Conclusion: The low- carb group lost significantly more weight (about 3 /mes as much). There was also a sta/s/cally significant difference in several biomarkers: Triglycerides went down by 38 mg/dl in the LC group, compared to 7 mg/dl in the LF group. Insulin sensi/vity improved on LC, got slightly worse on LF. Fas/ng blood glucose levels went down by 26 mg/dl in the LC group, only 5 mg/dl in the LF group. Insulin levels went down by 27% in the LC group, but increased slightly in the LF group. Overall, the low- carb diet had significantly more beneficial effects on weight and key biomarkers in this group of severely obese individuals. authoritynutrition.com

54 Low carbohydrate vs. Low fat diet 8. Meckling KA, et al. Comparison of a low- fat diet to a low- carbohydrate diet on weight loss, body composi/on, and risk factors for diabetes and cardiovascular disease in free- living, overweight men and women. The Journal of Clinical Endocrinology & Metabolism, Details: 40 overweight individuals were randomized to a low- carb and a low- fat diet for 10 weeks. The calories were matched between groups. Weight Loss: The low- carb group lost 7.0 kg (15.4 lbs) and the low- fat group lost 6.8 kg (14.9 lbs). The difference was not sta/s/cally significant. authoritynutrition.com

55 Low carbohydrate vs. Low fat diet Conclusion: Both groups lost a similar amount of weight. A few other notable differences in biomarkers: Blood pressure decreased in both groups, both systolic and diastolic. Total and LDL cholesterol decreased in the LF group only. Triglycerides decreased in both groups. HDL cholesterol went up in the LC group, but decreased in the LF group. Blood sugar went down in both groups, but only the LC group had decreases in insulin levels, indica/ng improved insulin sensi/vity. authoritynutrition.com

56 Low carbohydrate vs. Low Carbohydrate diet 19. Volek JS, et al. Carbohydrate restric/on has a more favorable impact on the metabolic syndrome than a low fat diet. Lipids, Details: 40 subjects with elevated risk factors for cardiovascular disease were randomized to a low- carb or a low- fat diet for 12 weeks. Both groups were calorie restricted. Weight Loss: The low- carb group lost 10.1 kg (22.3), while the low- fat group lost 5.2 kg (11.5 lbs). authoritynutrition.com

57 Low carbohydrate vs. Low fat diet Conclusion: The low- carb group lost almost twice the amount of weight as the low- fat group, despite ea/ng the same amount of calories. This study is par/cularly interes/ng because it matched calories between groups and measured so- called advanced lipid markers. Several things are worth no/ng: Triglycerides went down by 107 mg/dl on LC, but 36 mg/dl on the LF diet. HDL cholesterol increased by 4 mg/dl on LC, but went down by 1 mg/dl on LF. Apolipoprotein B went down by 11 points on LC, but only 2 points on LF. LDL size increased on LC, but stayed the same on LF. On the LC diet, the LDL par/cles partly shixed from small to large (good), while they partly shixed from large to small on LF (bad). authoritynutrition.com

58 Case Report Mrs. D. is a 46 year old woman with a PMH significant for Type 2 Diabetes Mellitus, Hypertension, Dyslipidemia, microalbuminuria, and morbid obesity who was seen in the clinic for weight loss management. BP was 126/80, BMI 54.3kg/m2, : HbA1C : TC 163, LDL 89, HDL 56, TG : weight 356 lbs Axer weight loss of 60lbs, 70/30 insulin requirement has dropped. From 70/ units bid to 30 units bid : HbA1C has likewise dropped to 6.4

59 Physical Ac:vity

Figure 1. A, Joint associations of waist circumference and physical activity with CHD, the Nurses Health Study 1986 to 2000.

60 Figure 1. A, Joint associations of waist circumference and physical activity with CHD, the Nurses Health Study 1986 to *Adjusted for age (<50, 50 to 54, 55 to 59, 60 to 64, 65), parental history of CHD, postmenopausal status and hormone use (never-use, past, current), physical activity (5 categories), aspirin use (<1, 1 to 2, 3 to 6, 7 to 14, 15+/wk), BMI (<25, 25 to 29.9, 30 kg/m2), and alcohol consumption (0, 0.1 to 4.9, 5 to 14.9, 15 g/d). Li T Y et al. Circulation. 2006;113: Copyright American Heart Association, Inc. All rights reserved.

Figure 2. Joint associations of WHR and BMI and CHD, the Nurses Health Study 1986 to 2000.

61 Figure 2. Joint associations of WHR and BMI and CHD, the Nurses Health Study 1986 to *Adjusted for age (<50, 50 to 54, 55 to 59, 60 to 64, 65), parental history of CHD, postmenopausal status and hormone use (never-use, past, current), physical activity (5 categories), aspirin use (<1, 1 to 2, 3 to 6, 7 to 14, 15+/wk), and alcohol consumption (0, 0.1 to 4.9, 5 to 14.9, 15 g/d). Li T Y et al. Circulation. 2006;113: Copyright American Heart Association, Inc. All rights reserved.

62 Goals of Therapy Prevent risk of heart disease Prevent Type 2 Diabetes Mellitus Manage risk factors that can be controlled (weight and sedentary lifestyle) and smoking Ann Intern Med. doi: /m

63 Preven:on and Delay of Metabolic Syndrome Regular follow up with the primary care physician A lifelong commitment to a healthy lifestyle (ea/ng habits and exercise) Long- term effort Because of the rise in the prevalence of obesity, Metabolic Syndrome may overtake smoking as the leading cause of Coronary Heart Disease. Ann Intern Med. doi: /m

64 Summary Onset of Type 2 DM can be delayed. The results have been replicated in Finland and China. Assess CVD risks in each pa/ent Managing each cardiac risk factor with ILS interven/ons and the appropriate medica/ons can reduce CVD morbidity and mortality.

65 Thank you.

66 Pathophysiology Adipose /ssue is an endocrine organ. It liberates excess FFA, AT II and adipokines The rise of FFA in the blood inhibit uptake of glucose by muscle. Excess FFA + AT II damage the pancreas (Lipotoxicity) Pancreas increases insulin but not enough to counter the rise of blood sugar, therefore; both insulin and blood sugar rise. Opie L H Circulation. 2007;115:e32-e35

Obesity Comorbidi.es: It s About Your Health, Not Your Weight. Elizabeth Estrada, MD Pediatric Endocrinology

Obesity Comorbidi.es: It s About Your Health, Not Your Weight Elizabeth Estrada, MD Pediatric Endocrinology Conflict of Interest NOTHING TO DISCLOSE Objec.ves 1. Recognize the most common comorbidi.es