The Metabolic Syndrome

The Metabolic Syndrome Advances in Internal Medicine David D. Waters, MD May 21, 27 UCSF Metabolic Syndrome: Definition abdominal obesity increased waist circumference atherogenic dyslipidemia low HDL-C, high triglycerides, increased remnant lipoproteins, small LDL and HDL particles elevated blood pressure insulin resistance glucose intolerance type II diabetes proinflammatory state increased CRP prothrombotic state increased fibrinogen and PAI-1 Grundy et al, Circulation 24;19:433 Criteria for Clinical Identification of the Metabolic Syndrome According to ATP III Factors That Contribute to the Metabolic Syndrome 1. waist circumference >4 inches for men or 35 inches for women 2. triglycerides 15 mg/dl 3. HDL-C <4 mg/dl for men or <5 mg/dl for women 4. BP 13/ 85 mm Hg 5. fasting glucose 11 mg/dl 3 of 5 required for diagnosis Adapted from Kahn R, Circulation 27;115:186 Truncal Obesity Is a Key Component of the Metabolic Syndrome Insulin sensitive Insulin resistant Sironi AM et al, Hypertension 24;44:127 Mediastinal and Abdominal Fat Is Related to Hypertension and Insulin Resistance 13 hypertensives compared to 26 age and BMI-matched men intra-abdominal and intrathoracic fat measured by MRI intra-abdominal and intrathoracic fat was significantly greater in hypertensives insulin sensitivity was and total insulin output in hypertensives Conclusion: visceral adiposity is related to both height of BP and insulin resistance

Impact of the Metabolic Syndrome on Coronary Heart Disease Mortality in US Adults Clinical Management of the Metabolic Syndrome Prospective cohort study of 6255 subjects aged 3-75 from NHANES II Followed for a mean of 13 years Adjusted hazard ratio for CHD mortality in metabolic syndrome was 2. (95% CI 1.4-2.9) Those with even 1-2 risk factors for metabolic syndrome had increased CHD mortality Deaths/1, Person Years 2 18 16 14 12 1 8 6 4 2 No MS or DM MS only MS + DM DM only CVD CVD + DM 6.3 4.3 4.8 2.6 CHD Mortality 1.9 17 The underlying risk factors that promote development of the metabolic syndrome are overweight and obesity, physical inactivity, and an atherogenic diet. All current guidelines on the management of the individual components of the metabolic syndrome emphasize that lifestyle modification (weight loss and physical activity) is first-line therapy. Grundy et al, Circulation 24;19:551 Malik et al, Circulation 24;11:1245 Obesity Trends* Among U.S. Adults BRFSS, 199 (*BMI 3, or ~ 3 lbs overweight for 5 4 person) Obesity Trends* Among U.S. Adults BRFSS, 1992 (*BMI 3, or ~ 3 lbs overweight for 5 4 person) No Data <1% 1% 14% No Data <1% 1% 14% 15% 19% Obesity Trends* Among U.S. Adults BRFSS, 1994 (*BMI 3, or ~ 3 lbs overweight for 5 4 person) Obesity Trends* Among U.S. Adults BRFSS, 1996 (*BMI 3, or ~ 3 lbs overweight for 5 4 person) No Data <1% 1% 14% 15% 19% No Data <1% 1% 14% 15% 19%

Obesity Trends* Among U.S. Adults BRFSS, 1998 (*BMI 3, or ~ 3 lbs overweight for 5 4 person) Obesity Trends* Among U.S. Adults BRFSS, 2 (*BMI 3, or ~ 3 lbs overweight for 5 4 person) No Data <1% 1% 14% 15% 19% 2% No Data <1% 1% 14% 15% 19% 2%

Diabetes Trends* Among Adults in the U.S., (Includes Gestational Diabetes) BRFSS, 199,1995 and 21 199 1995 21 No Data <4% 4%-6% 6%-8% 8%-1% >1% Source: Mokdad et al., Diabetes Care 2;23:1278-83; J Am Med Assoc 21;286:1. Portion Sizes Are Enormous High-powered ambulance chaser, Milford Godfrey, Manhattan, New York, snacks on a full-size rotisserie chicken while conducting business on his cell phone. He keeps a Rotisserie basting oven in his Lincoln Navigator and a George Foreman Grill in his brief case to squeeze in feedings between malpractice trials.

Lack of Physical Activity Does Urban Sprawl Contribute to Obesity? A typical white male living in an isolated residential only neighborhood weighs about 1 pounds more than one living in a walkable, mixed-use community. Lawrence Frank, 24 Densely built urban areas such as Vancouver s downtown may encourage pedestrian traffic and promote physical activity. Metropolitan Atlanta, often called a poster child for urban sprawl, has undergone rapid geographical expansion. Harder B, Science News Online, 27;171:43 Age: 44 years Weight: 26 lbs Height: 5 4 BMI: 35.4 BP: 142/88 mmhg Fasting blood sugar 116 mg/dl Total C: 24 mg/dl HDL-C: 36 mg/dl Triglycerides: 42 mg/dl LDL-C: 134 mg/dl hs-crp: 2.6 mg/dl Non-smoker What Is the 1-Year Risk of Cardiac Death or MI in This Patient According to Framingham? 2% 4% 6% 1% 14% 18% What Is the 1-Year Risk of Cardiac Death or MI in This Patient According to Framingham? 2% 4% 6% 1% 14% 18% 2% is the correct answer. However, the Framingham calculator does not count hs-crp, triglycerides or BMI, and does not include other coronary events or any cerebrovascular events in the endpoint. Effects of Diet and Exercise in Men and Postmenopausal Women with Low HDL-C 18 postmenopausal women aged 45-64 with HDL-C <6 mg/dl and 197 men aged 3-64 with HDL-C <45 mg/dl randomized to NCEP step 2 diet, exercise (equivalent to 1 miles of jogging/walking per week), both, or neither interventions continued for 1 year mean baseline HDL-C was 47 mg/dl in women and 36 mg/dl in men; baseline LDL-C averaged 158 mg/dl Stefanick M et al, N Engl J Med 1998;339:12

Effects of Diet and Exercise in Women with Low HDL-C mg/dl 5-5 -1-15 -2 p<.1 p=ns p=.3 Wt (kg) HDL-C LDL-C Control Exercise Diet D + E Prevention of Type 2 Diabetes by Lifestyle Changes Among Subjects with Impaired Glucose Tolerance 522 patients with impaired glucose tolerance (mean age 55, mean BMI 31) randomly assigned to weight reduction and exercise or to control group mean weight loss of 4.2 Kg in intervention group versus.8 Kg in control group at one year (p<.1) diabetes defined by 1985 WHO criteria cumulative incidence of diabetes at 4 years was 11% in the intervention group and 25% in the control group, a 58% reduction (p<.1) the reduction in the incidence of diabetes was directly associated with changes in lifestyle Stefanick M et al, N Engl J Med 1998;339:12 Tuomilehto et al, N Engl J Med 21;344:1343 Effect of Smoking Cessation on HDL-Cholesterol Levels meta-analysis of 27 studies from 1966-2 smoking cessation increased HDL-C by 1.8 mg/dl (95% CI 1.4-2.2) increase greater in women and subjects with higher baseline HDL-C no change in total or LDL-cholesterol, or triglycerides Maeda et al, Prev Med 23;37:283 Relationship of Alcohol Intake to Change in HDL-C: a Meta-Analysis 36 data records from 25 studies on average, 41 g/day of alcohol increased HDL-C by 5.1 mg/dl 2 drinks (3 g of alcohol) will increase HDL-C by 4 mg/dl, or 8.3% 2 drinks will reduce the predicted risk of CHD by 24.7%, based on changes in biomarkers (fibrinogen, tpa, Lp(a), apo A1, etc) Rimm et al, BMJ 1999;319:1523 Potential Drug Therapy for Metabolic Syndrome fibrate niacin statin glitazone rimonabant antihypertensive aspirin Helsinki Heart Study 4,81 men with no evidence of coronary disease randomized to gemfibrozil 6 mg BID or placebo and followed for 5 years mean HDL-C increased from 47 to 52 mg/dl (1.2 to 1.3 mmol/l) and triglycerides decreased from 175 to 13 mg/dl ( 2. to 1.2 mmol/l); LDL-C decreased from 189 to 173 mg/dl (4.9 to 4.5 mmol/l) primary endpoint, cardiac death + nonfatal MI, reduced by 34%, from 84 to 56 (p=.2) Frick MH et al, N Engl J Med 1987;317:1237

Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial (VA-HIT) 2,531 men with coronary disease, an HDL-C 4 mg/dl and an LDL-C 14 mg/dl randomized to gemfibrozil 1,2 mg/day or placebo median follow-up = 5.1 years primary endpoint = coronary death + nonfatal MI HDL-C 6% higher and triglycerides 31% lower at 1 year in gemfibrozil group; no difference in LDL-C event rate 21.7% in placebo and 17.3% in gemfibrozil group, a 22% relative risk reduction (p=.6) Rubins et al, N Engl J Med 1999;341:41 Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Trial 9,795 patients with type II diabetes randomized to micronized fenofibrate 2 mg/day or to placebo and followed for 5 years total cholesterol 3.-6.5 mmol/l with either a TC/HDL-C ratio 4 or triglycerides 1.-5. mmol/l primary outcome (coronary death or nonfatal MI) occurred in 5.2% of fenofibrate and 5.9% of placebo patients (HR.89, 95% CI.75-1.5, p=.16) 24% reduction in nonfatal MI (HR.76, 95% CI.62-.94) but a 22% increase in coronary death (HR 1.19, 95% CI.9-1.57) total coronary events reduced with treatment in the 7,664 patients without previous CAD, 8.9% vs 1.8%, p<.1 benefit seen in patients with low HDL-C, 13.% vs 15.1%, p=.2 The Field Study Investigators, Lancet 25;366:1849 Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) Trial 9,795 patients with type II diabetes randomized to micronized fenofibrate 2 mg/day or to placebo and followed for 5 years total cholesterol 3.-6.5 mmol/l with either a TC/HDL-C ratio 4 or triglycerides 1.-5. mmol/l primary outcome (coronary death or nonfatal MI) occurred in 5.2% of fenofibrate and 5.9% of placebo patients (HR.89, 95% CI.75-1.5, p=.16) 24% reduction in nonfatal MI (HR.76, 95% CI.62-.94) but a 22% increase in coronary death (HR 1.19, 95% CI.9-1.57) total coronary events reduced with treatment in the 7,664 patients without previous CAD, 8.9% vs 1.8%, p<.1 benefit seen in patients with low HDL-C, 13.% vs 15.1%, p=.2 The Field Study Investigators, Lancet 25;366:1849 What Are the Clinical Differences Between Gemfibrozil and Fenofibrate? fenofibrate causes fewer problems when used with a statin gemfibrozil reduced events in both the Helsinki Heart Study and the VA-HIT Trial (both primary and secondary prevention) fenofibrate failed to significantly reduce events in FIELD as-yet-unpublished data indicate that fenofibrate increased creatinine and homocysteine levels in FIELD, negating a significant event reduction CLINICAL LIMITATION: Gemfibrozil is effective, but must be used cautiously with a statin Fenofibrate is safer with a statin, but has no proven efficacy Potential Drug Therapy for Metabolic Syndrome fibrate niacin statin glitazone rimonabant antihypertensive aspirin

Niacin in the Coronary Drug Project 8,341 men aged 3-64 with previous MI randomized to low or high dose estrogen, dextrothyroxine, clofibrate, niacin 3 gm/day or placebo between 1966-69 the 2 estrogen arms and the dextrothyroxine arm were discontinued early due to excess adverse events, and clofibrate showed no benefit niacin (n=1,119) and placebo (n=2,789) patients followed for 6.2 years primary endpoint, total mortality, was 24.8% in niacin group and 25.9% in placebo group (p=ns) however, MI was significantly reduced in the niacin group (1.4% versus 14.7%) Coronary Drug Project Research Group, JAMA 1975;231:36 Niacin After the Coronary Drug Project 5 years after publication of the results, the investigators followed up the patients to assess long term adverse effects of treatment on mortality with a mean follow-up of 15 years, nearly 9 years after the end of the trial, all-cause mortality in the other drug groups were all similar to placebo but in the niacin group, mortality was reduced by 11% (52.% versus 58.2%, p=.4) the investigators estimated that only 1 of the 69 fewer deaths in the niacin group could be attributed to the lower infarction rate during the trial Canner PL et al, J Am Coll Cardiol 1986;8:1245 Niacin in Trials With Surrogate Endpoints HATS the combination of simvastatin + naicin lowered LDL-C by 42%, increased HDL-C by 26%, and halted progression of coronary disease by angiography compared to placebo over 3 years in a study of 16 patients Brown BG et al, N Engl J Med 21;345:1583 ARBITER 2 adding 1, mg of extended-release niacin to statintreated patients with CAD halted progression of carotid intima-media thickness over 12 months, while progression occurred in placebo-treated statin patients despite LDL-C of 86 mg/dl Taylor AJ et al, Circulation 24;11:3512 Change in Carotid IMT ARBITER 2: Carotid IMT Results.5.4.3.2.1 -.1 p=.8 p<.1 p=ns Taylor AJ et al, Circulation 24;11:3512 p=.26 All Pts No DM/MS DM/MS Placebo Niacin p=ns AIM HIGH: Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides and Impact on Global Health Outcomes 33 patients Men and women Aged 45 years Established vascular disease and atherogenic dyslipidemia (low HDL-C and high triglycerides) Primary End Point Composite of CHD death, nonfatal MI, ischemic stroke, or hospitalization for highrisk ACS with objective evidence of ischemia Simvastatin 4 mg + ER niacin 2 g Simvastatin 4 mg 4-year follow-up Key Secondary End Points Composite of CHD death, nonfatal MI, or ischemic stroke HPS2 THRIVE: Heart Protection Study 2 Treatment of HDL to Reduce the Incidence of Vascular Events 2 patients Statin therapy Men and women to optimal Aged 5-8 years LDL-C level History of MI, stroke, or PAD ~7 patients with diabetes Coordinating centers in UK, China, and Scandinavia Primary End Point MI, stroke, revascularization procedures ER niacin+mk-524a combination tablet Placebo 4-year follow-up ER, extended release Estimated completion: 21 Estimated completion: 212

Potential Drug Therapy for Metabolic Syndrome fibrate niacin statin glitazone rimonabant antihypertensive aspirin Major Randomized Statin Trials in CAD Primary Prevention WOSCOPS, AFCAPS/TexCAPS Secondary Prevention - Stable CAD 4S, CARE, LIPID, TNT, IDEAL Acute Coronary Syndromes MIRACL, PROVE-IT, A to Z Populations at Risk - Heart Protection Study Hypertension: ALLHAT, ASCOT Diabetes: CARDS, ASPEN Elderly: PROSPER Stroke: SPARCL Potentially Beneficial Effects of Statins in the Metabolic Syndrome lowering LDL-C and shifting LDL particle size upward lowering high triglyceride levels minor increase in HDL-C levels improvement in endothelial dysfunction reduction in levels of inflammatory markers such as hs-crp normalization of platelet hyperaggregability Furthermore, statins have been shown to reduce events in patients with diabetes (CARDS, HPS), hypertension (ASCOT), and low HDL-C (AFCAPS/TexCAPS) AFCAPS/TexCAPS: Primary Endpoint: First Acute Major Coronary Event* Cumulative incidence.7.6.5.4.3.2.1. Placebo Lovastatin 1 2 3 4 5 >5 Years of follow-up 37% Risk Reduction (p<.1) Includes unstable angina, fatal and nonfatal MI and sudden cardiac death Downs JR et al, JAMA 1998;279;1615 Event rate AFCAPS/TexCAPS: Primary End Point Events by HDL-C C Tertile at Entry and by Treatment 14 12 1 8 6 4 2 34 35-39 4 HDL-C mg/dl Downs JR et al, JAMA 1998;279:1615 Placebo Lovastatin % of patients Heart Protection Study: Major Vascular Events by HDL-C C and by Treatment 3 25 2 15 1 5 <35 35-43 >43 HDL-C mg/dl Heart Protection Study Collaborative Group. Lancet. 22;36:7 Placebo Simvastatin

Major Cardiovascular Events in Patients With Metabolic Syndrome Proportion of patients experiencing major cardiovascular event*.2.15.1.5 HR =.71 (95% CI.61,.84) P <.1 Atorvastatin 1 mg Atorvastatin 8 mg Relative risk reduction = 29% 1 2 3 4 5 6 Time (years) *CHD death, nonfatal non procedure-related MI, resuscitated cardiac arrest, fatal or nonfatal stroke Deedwania P et al, Lancet 26;368:919 Potential Drug Therapy for Metabolic Syndrome fibrate niacin statin glitazone rimonabant antihypertensive aspirin Prevention of Diabetes by Rosiglitazone Among Subjects with Impaired Fasting Glucose or Glucose Tolerance The DREAM Trial 5269 adults with impaired fasting glucose, impaired glucose tolerance, or both, and no evidence of cardiovascular disease were randomized to placebo or rosiglitazone 8 mg/day and followed for 3 years primary endpoint was composite of death or diabetes primary endpoint occurred in 36 rosiglitazone and 686 placebo pts (11.6% vs 26.%, HR.4, 95% CI.36-.46, p<.1) 133 rosiglitazone and 798 placebo pts became normoglycemic (5.5% vs 3.3%, HR 1.71, 95% CI 1.57-1.87, p<.1) heart failure developed in 14 rosiglitazone and 2 placebo patients (p=.1) Gerstein HC et al, Lancet 26;368:196 Effects of Pioglitazone on Lipoproteins, Inflammatory Markers and Adipokines in Non-Diabetic Subjects with Metabolic Syndrome 6 non-diabetic subjects with the metabolic syndrome and low HDL-C randomized to pioglitazone 3 45 mg/day or placebo for 12 weeks no change in body weight, blood glucose, insulin, or LDL-C HDL-C Small HDL particles Large HDL particles Small LDL particles Large LDL particles hs-crp HOMA-IR adiponectin Change vs Placebo +14% -16% +36% -18% +83% -31% -22% +111% p value <.1.1.6.6.6.3.5 <.1 Effect of Rimonabant on Metabolic Risk Factors in Obese Subjects with Dyslipidemia rimonabant is a selective cannabinoid-1 receptor blocker 1,36 obese subjects with hypertriglyceridemia and high TC/HDL-C ratio randomized to placebo or rimonabant 5 or 2 mg/day and followed for 52 weeks rimonabant 2 mg/day versus placebo 6.7 Kg weight loss, 5.8 cm decrease in waist circumference, 1.% increase in HDL-C, and 13.% decrease in triglycerides (all p<.1) prevalence of metabolic syndrome decreased from 54 to 25.8% no change in LDL-C but decrease in hs-crp Després JP et al, N Engl J Med 25;353:2121 Szapary PO et al, ATVB 26;26:182

Effect of Rimonabant on Body Weight, Waist Circumference, Plasma Triglycerides, and HDL-Cholesterol Levels Després JP et al, N Engl J Med 25;353:2121 Age: 44 years Weight: 26 lbs Height: 5 4 BMI: 35.4 BP: 142/88 mmhg Fasting blood sugar 116 mg/dl Total C: 24 mg/dl HDL-C: 36 mg/dl Triglycerides: 42 mg/dl LDL-C: 134 mg/dl hs-crp: 2.6 mg/dl Summary metabolic syndrome is an expanding epidemic portending disastrous consequences in terms of diabetes and vascular disease the causes, excess caloric intake and lack of exercise, are cultural and environmental the optimal treatment, diet and exercise, is usually ineffective drug therapy can ameliorate components of the metabolic syndrome and reduce the risk of vascular disease and diabetes patients with metabolic syndrome present an enormous challenge to their physicians