The Metabolic Syndrome and Cardiovascular Risk

The Metabolic Syndrome andd Cardiovascular Risk Vivian Fonseca Tulane University Texas A & M University Scott and White Clinic

Type 2 Diabetes Mellitus Is a yp Progressive Disease Diagnosis 350 Postprandial 300 Glucose Glucose (mg/dL) 250 Fasting 200 Glucose 150 G ( 100 50 250 Insulin Resistance 200 150 Insulin Relative 100 Level L l Insulin 50 Inadequate Resistance β-Cell Function Decreasing β-Cell Function 0 Uncontrolled Obesity y IGT Diabetes Hyperglycemia Clinical Macrovascular Changes Features Microvascular Changes Years –10 –5 0 5 10 15 20 25 30 Adapted from Type 2 Diabetes BASICS. International Diabetes Center; 2000.

Insulin Resistance Syndrome and Risk Factors for CVD in Type 2 Diabetes Hypertension Hyperglycemia Hyperinsulinemia yp Dyslipidemia – decreased HDL Altered – increased fibrinolysis, triglycerides Inflammation, Insulin Endothelial resistance i t Genetics dysfunction Aging Obesity Ob it Sedentary lifestyle

Metabolic Syndrome: NCEP Criteria Diagnosis requires three or more of the following features • Waist ≥40” in males or ≥35” females ≥40 ≥35 • Triglycerides ≥150 mg/dL (or treatment) • HDL <40 mg/dL in males and <50 mg/dL in females (or t t ( treatment) t) • SBP ≥130 or DBP ≥85 mmHg (or treatment) • Fasting plasma glucose (FPG) ≥100 mg/dL (or treatment) 100 Issues • Great G t concept for professional and patient education: tf f i l d ti t d ti clustering of risk factors relate to poor lifestyle habits • Providers do not measure waist and many lipid panels are non-fasting f ti Grundy S, et al. Circulation 2005;112:2735

WHO and NCEP ATP III Criteria for the Metabolic Syndrome Criteria WHO NCEP Glucose status or IR plus 3 or more of others: 3 or more of: Glucose Status IGT/IFG/DM IFG/DM HOMA IR Highest 25% g N/A Blood Pressure (mmHg) ≥140/90 ≥130/85 Triglycerides (mg/dL) ≥150 ≥150 HDL (mg/dL) <35 (M) <40 (M) <39 (F) ( ) <50 (F) ( ) Obesity WHR>0.9 (M) WC>102 cm (M) WHR>0.85 (F) WC>88 cm (F) or BMI>30 kg/m^2 Microalbuminuria ≥30 mg/g N/A

Nuances in the definitions can have huge effects SBP>130 AND DBP>85 or SBP>130 OR DBP>85 The latter scoops up about 60% more people than the former Does it matter? We don’t know. 6 of 22

Associated with insulin resistance? Then how about adding… Adiponectin p C-reactive protein Age Others? Oth ? 7 of 22

Insulin resistance in those with MS Author Sensitivity Specificity PPV Comment Cheal et al. 46% 93% 76% N=443, no diabetes, Diabetes 40% overweight 53:1195,2004 3 119 2004 Liao et al. 20 - 50% 92% 56% N=74, Diabetes Care no diabetes 27:978,2004 McLaughlin 52% 85% 78% N=258, N=258 et al. Ann no diabetes, Intern Med 100% overweight , 139:802,2003 or obese Sierra-Johnson 42% 94% 72% N=256, et al. no HBP, Diabetes C Di b t Care no diabetes 29:668,2006 8 of 22

Likelihood of IR* in overweight / obese people Marker Positive Predictive Value Overweight / Obese alone 50% Triglyceride > 130 mg/dl 70% Triglyceride / HDL ratio >3.0 67% ATP III Criteria 78% *Insulin resistance = highest tertile McLaughlin T et al. Ann Intern Med 139:802,2003 9 of 22

Prevalence of Metabolic Syndrome One in four Americans have metabolic syndrome by NCEP criteria Approximately 80% of adults over the age of 20 have one or more of th components of metabolic syndrome f the t f t b li d In addition to 21 million people with diabetes, there are approximately 50 million people with pre-diabetes or metabolic syndrome Ford et al. JAMA 2002;287:356 http://www.diabetes.org/diabetes-statistics/prevalence.jsp

CHD Associated with High Insulin Levels in Nondiabetic Subjects 1.00 0.95 Proportion Q1 0.90 0 90 Increasing Without Major CHD insulin 0.85 Q2 Event levels 0.80 Log rank: associated Overall P=.001 Q3 with insulin Q5 vs. Q1 P <.001 Q4 resistance 0.75 Q5 0 0 5 10 15 20 25 Years Pyörälä M et al. Circulation 1998;98:398

Cardiovascular Disease Mortality and the Metabolic Syndrome 15 Metabolic RR=3.55 Syndrome 10 (95% CI, 1.96-6.43) Cumulative Hazard Ratio 5 Controls 0 0 2 4 6 8 10 12 Follow-up (Years) Metabolic Yes 866 852 834 292 Syndrome? No 288 279 234 100 Lakka HM et al. JAMA 2002;288:2709

Dysglycemia in Patients with Acute MI y gy Consecutive patients presenting with acute MI, n = 181 Oral Glucose Tolerance Test 20% 25% 80% 40% 35% Diabetic DM by OGTT No DM (by History) IGT by OGTT Normal OGTT Norhammar A et al. Lancet. 2002;359:2140

Metabolic Syndrome and the risk of di b t f diabetes (San Antonio Heart Study) Sens. Spec. PPV ATP III 53 85 31 WHO 43 87 30 FPG ≥ 97 mg/dl 43 92 39 Lorenzo C, et al. Diabetes Care. 26:3153, 2003. 14 of 22

Metabolic Syndrome and the risk of diabetes (Insulin Resistance Atherosclerosis Study*) Variable OR** (95% CI) ATPIII 4.14 (2.79 6.16) 4 14 (2 79 – 6 16) 3.84 (2.59 – 5.69) AHA/NHLBI 3.40 (2.28 – 5.06) IDF IGT alone 5.42 (3.60 – 8.17) * Incident of diabetes in 822 subjects followed for a mean of 5.2 years j y ** Adjusted for age, sex and ethnicity Hanley et al., Circulation 112:3713-3721,2005 15 of 22

Does the Metabolic Syndrome Predict CVD? (Data from San Antonio Heart Study*) Variable Odds Ratio**(CI) P-Value ATP III definition 1.56 .028 Adjusted for diabetes Adj t d f di b t 1.11 1 11 .658 658 Diabetes 2.63 2 63 <0.0001 <0 0001 * CVD mortality i 5 158 people f ll t lit in 5,158 l followed f 7 8 years d for 7-8 ** Adjusted for age and gender Stern MP et al. Atheroscler Suppl. 6:3-6, 2005. 16 of 22

Glucose Levels and Cardiovascular Events 3 3 2 h Glucose Fasting Glucose 2.5 2.5 2 RR 2 RR 1.5 1.5 1 1 72 108 144 180 198 72 90 108 126 144 163 2hPG = 140 mg/dL; RR = 1 58 (1.19-2.10) 1.58 (1 19 2 10) 19- FPG = 110 mg/dL; RR = 1 33 (1 06-1.67) 1.33 (1.06 1 67) 06- 2hPG=2-hour plasma glucose; FPG=fasting plasma glucose; RR=risk ratio Yellow lines are 95% Confidence Intervals Coutinho MS et al. Diabetes Care. 1999;22:233-242 17 of 22

Relation of Waist:Hip Ratio to MI and Mortality in Women dM li i W 20 15 Mortality MI Incidence 10 (%) 5 0 0-20 21-40 41-60 61-80 81-90 91-95 96-100 Centiles of waist-to-hip ratio Lapidus L et al. BMJ. 1984;289:1257-1261. 18 of 22

Relationship between insulin resistance and obesity Helke MF et al., Am J Clin Nutr 83:47, 2006 19 of 22

The Adipocyte as an Endocrine Cell FFA adiponectin PAI-1 leptin RPB-4 resistin omentin apelin li adipsin di i SAA TNF-α IL-6 visfatin MCP-1

Metabolic Syndrome: ADA/EASD View Adults with any major CVD risk factor should be evaluated for the presence of other CVD risk factors Lifestyle modification should be advised for patients with CVD risk factors above the “normal” cut-point p Pharmacological treatment should be administered if the CVD risk factor is indicative of frank disease All CVD risk factors should be treated individually Until randomized controlled trials have been completed, there is no indication for the pharmacological treatment for the metabolic syndrome Kahn R et al. ADA/EASD. Diabetes Care 2005;28:2289

Prevention of Type 2 Diabetes: Results f Recent R d i d T i l R l of R Randomized Trials Relative Risk Study Subjects Intervention Reduction NNT Behavioral Finnish DPS IGT Lifestyle 58% 4-8 US DPP IGT y Lifestyle 58% % US DPP IGT Metformin 31% 14 STOP-NIDDM IGT Acarbose 32% 11 edication TRIPOD Troglitazone Prior 56% 6 GDM Orlistat 45% XENDOS Me 10 IGT Ramipril / DREAM Rosiglitazone NS / 62% 7 IGT Nathan DM et al. Diabetes Care 2007 30:753

Steps to Obesity Management p y g Recognition BMI, waist circumference obesity-related complications BMI circumference, obesity- Commitment Patient, and nutrition team (MD, NP-PA, RD, PhD) NP- Realistic expectations Reduction in health risks, 5% to10% initial weight loss A multi-disciplined treatment approach multi- Behavior modification Physical activity y y Diet Pharmacotherapy

What is Known about Weight Management? • Modest weight loss is beneficial especially in the prevention o chronic diseases c ud g of c o c d seases including type 2 d abetes a d for diabetes and o lowering blood pressure • At ~6 months individuals can lose 5% to 10% of their 6 starting weight • Regardless of the intervention, plateaus and regain of weight loss are expected; compensatory mechanisms protect against weight loss • If treatment is discontinued, weight gain occurs • With support modest weight loss can be maintained support, Franz M et al. J Am Diet Assoc 2007:107:1736

Being Fit Reduces the Hazards of Obesity in Males 25,389 males followed for 8 years Physical fitness, regardless of body mass index (BMI) fitness (BMI), decreases risk of mortality from all chronic diseases 3 RR Of All-Cause Mortality including CVD 2.5 Relative 2 Risk Fit 1.5 Unfit 1 0.5 0 Lean Normal Obese Lee CD et al. Am J Clin Nutr 1999;69:373; Sui X et al. JAMA 2007;298:2507

Comparison of Popular Weight Loss Diets • Subjects (n=160) utilized one of the following diets – Atkins (carbohydrate restricted) – Zone (macronutrient balanced) – Weight Watchers (calorie restriction) – O i h (fat restriction) Ornish (f t t i ti ) • Weight loss and completers at 1 year – Atkins 2.1 kg (4.6 lb) [53%] – Zone 3.2 kg (7.0 lb) [65%] – Weight Watchers 3 0 kg (6 6 lb) [65%] 3.0 (6.6 – Ornish 3.3 kg (7.3 lb) [50%] • Each popular diet modestly reduced body weight weight. Amount of weight lost was associated with self- Dansinger M et al. JAMA 2005;293:43 diet but not with diet type reported adherence to

Predictors of Successful Weight Loss Maintenance in National Weight Control Registry • Continue to eat lower energy diets (average energy intake ~1400 kcal/day); eat a low-fat, moderate-carbohydrate diet (24% of energy from fat) •F Frequently self-monitor weight and f d i t k tl lf it i ht d food intake • Participant in a minimum of 60 to 90 minutes of physical activity nearly every d of th week ti it l day f the k (2800 kcal/week; 28 miles of walking/week) • Eat breakfast every day (contrary to the typical eating pattern for dieters) Wing RR, Hill JO. Ann Rev Nutr 2001;21:323. Wyatt H et al. Obes Res 2002;2:78

What is the Effect of Weight Loss and Weight Loss Medications on A1C in Type 2 Diabetes? 12-mo 12 mo Weight 12-mo 12 mo Weight Change (Type 2 12-mo A1C Change (Without Interventions Diabetes) Change Diabetes) Weight Loss Diet g – 2.6 kg ( g (5.7 lb) ) – 0.4% –4.6-7.6 kg ( g (10-17 lb) ) (n=532) Orlistat 120 mg tid – 5.0 kg (11 lb) – 0.8% –8.2 kg (18 lb) (n=574) (Alli) Sibutramine 15-20 – 7.2 kg (15.8 lb) – 0.4% –8.2 (18 lb) mg (n=152) Franz M. On the Cutting Edge. Diabetes Care and Education 2006;6:27

Strategies for Changing Behavior • Self-monitoring (recording behaviors): always rated by participants as most helpful • Individuals who recorded food intake frequently lost more than twice as much weight as those who did so infrequently1 • Realistic goals: 8% to 10% weight loss improves risk f % % factors • Stimulus control: environmental restructuring for modification of eating cues • Cognitive restructuring: moving from self-rejection to self-acceptance p • Contingency management: rewards by self or professionals (rated as least helpful) • Stress management: #1 predictor of relapse Foreyt JP, Pendleton VR. Primary Care Reports 2000;6:19 1Wadden TA et al. N Eng J Med 2005;353:2111

Strategies for Maintenance of Behavior Change • Physical activity: major p y y j predictor of maintenance • Social support: family “set p , peer support, pp y point,” p pp , self-help or work-site groups • Relapse prevention: relapse is expected; coping strategies are needed – Stress management – Social situations – Continuing support from health professionals Foreyt JP, Pendleton VR. Primary Care Reports 2000;6:19

Bariatric Surgery and Diabetes Swedish Obese Subjects Study (SOS) • Weight loss at: 10 Years Post Bariatric Surgery • 1 year: 38% • 2 years: 23% Post g y Surgery Control • 10 years: 16% • All studied risk factors Resolution 36% 13% improved, except of DM hypercholesterolemia and cardiovascular risk Newly 7% 24% Developed • Decreased overall mortality DM Sjostrom L et al. N Engl J Med 2004;351:2683; Sjostrom L et al. N Engl J Med 2007;357:741

The STOP-NIDDM Study: Reduction in Risk of Cardiovascular Disease 0.06 0.05 Probability 0.04 Hazards Ratio RRR of Any Placebo 0.51 49% 0.03 Cardiovascular Event 0.02 Acarbose 0.01 0 01 P=0.04 (log-rank test) 0 P=0.03 (Cox proportional model) Days After Randomization Patients at risk Acarbose 686 675 667 658 643 638 633 627 615 611 604 519 424 332 232 Placebo 682 659 635 622 608 601 596 590 577 567 558 473 376 286 203 Chiasson JL, et al. JAMA. 2003;290(4):486-494.

NAVIGATOR 2 x 2 Factorial Design Valsartan comparison Valsartan/Nateglinide Placebo/Nateglinide (n = 2,288) (n = 2,288) Nateglinide comparison Valsartan/Placebo Placebo/Placebo (n = 2,288) (n = 2,288) Dosages Nateglinide 60 mg PO ac Valsartan 160 mg PO qd All subjects will receive a lifestyle advice program

Exenatide + Oral Agents Summary of Weight Changes Placebo “THE 3 AMIGOS TRIALS” TRIALS” Exenatide 5 μg 30- 30-Week, Randomized, Placebo-Controlled Placebo- Exenatide 10 μg 0.0 -0.5 -0.3 -0.6 -1.0 -0.9 ght -0.9 g) Δ weig (kg -1.5 -1.6 -1.6 -1.6 -1.6 -2.0 * * * * -2 5 2.5 -3.0 -2.8 * *P<0 05 vs placebo <0.05 Exenatide + SU Exenatide + Met Exenatide + SU + Met (n=377) (n=336) (n=733) Buse JB, et al. Diabetes Care. 2004;27:2628-2635. Defronzo RA, et al. Diabetes Care. 2005;28:1092-1100. Kendall DM, et al. Diabetes Care. 2005;28:1083-1091.

Rimonabant:Changes From Baseline for Body Weight for Year 1 0 Change from baseline, kg , -2 -4 b -6 es -8 Placebo 5 mg Rim. 20 mg Rim. -10 0 12 24 36 52 No. at Risk Weeks Placebo 590 496 413 347 309 5 mg Rim. 1191 1104 833 711 619 20 mg Rim. 1189 1017 863 750 672 Pi-Sunyer, F. et al., JAMA 2006; 295:761-75.

Source of Proinflammatory Risk Factors Adipose Tissue CD40L Adhesion Interleukins molecules TNF- TNF-alpha IL- IL-1 IL- IL-6 IL- IL-8 Matrix Inflammation Metalloproteinases Liver Acute phase proteins Plaque destabilization Serum CRP Fibrinogen amyloid A

Selected NF-κB responsive genes with potential roles in insulin resistance and T2D (•) or CHD (♦) IKKβ NF-κB Cytokines Chemokines Surface Proteins Others •♦IL-6 •♦MCP-1 ♦E-Selectin •♦PAI1 •♦IL 1β •♦IL-1β ♦MIP 1α, ♦MIP-1α, β ♦P Selectin ♦P-Selectin •♦SAA •♦TNF-α ♦MIP-2 ♦ICAM1 •♦CRP •Resistin ♦MIP-3α ♦VCAM1 ♦Cox2 ♦IFN-γ ♦CD40 ligand •♦iNOS Receptors ♦Lymphotoxins ♦IgGs ♦VEGF ♦CD40 IL-7, 8 ♦A20 IL-6R, IL-1R Transcription IL-11, 12 ♦MMPs •TNFR p75 p •IKKβ IL-13, IL 13 15 •TNFR p55 •♦NF-κB RelA, p50 IL-4 IFNα,β,γR c-Jun, FosB, JunB

Effect of Pioglitazone on Cardiovascular Risk Markers rom baseline % change fr pioglitazone glimepiride hsCRP h CRP MCP-1 MCP 1 MMP-9 MMP 9 IMT Pfützner A J Am Coll Cardiol. 2005;45(12):1925-31

Glucose Metabolism Before and After Aspirin Hundal RS et al. J Clin Invest. 2002;109:1321-1326.

TINSAL T2D – Targeting Inflammation with Salsalate in Type 2 Diabetes Salsalate is a covalent, head-to-tail dimer between two salicylic acid moieties. Salsalate is insoluble at acidic pH so it doesn’t irritate the stomach pH, stomach. OH CH 3 CO 2 OH CO 2 H CO 2 H CO 2 H CO 2 Salicylic Aspirin Salsalate Acid (Disalcid)

4.5 vs. 3.0 g/day Salsalate in patients with T2D Glucose utilization Salicylate FBS (mg/dl) C-peptide (nM) (mg/kg/min) (mg/dl) 3 8 200 Pre * * 20 Post 6 2 * 4 Pre 100 * 1 * 10 2 Post 19% 9% 40% 50% 15% 0 0 0 0 4.5 3.0 4.5 3.0 4.5 3.0 4.5 3.0 Adiponectin FFA (mEq/l) TG (mg/dl) CRP (mg/dl) (mg/dl) 1.2 12 6 200 20 0.8 * * * * 4 * 100 10 0.4 2 28% 40% 50% 40% 35% 0 0 0 0 4.5 45 30 3.0 4.5 45 30 3.0 4.5 45 30 3.0 4.5 45 30 3.0 Salsalate dose (g/d) Goldfine & Shoelson et al, Clinical and Translational Science, 2008;1;36

Salsalate Improves Glycemia During Oral Glucose Tolerance Testing in Ob it Gl T l T ti i Obesity Salsalate Placebo * p<0 01 p<0.01 10 ** ** 9 9 Percent Change e 5 ** mol/L) 8 8 0 lucose (mm 7 7 5 -5 -10 6 6 -15 15 Gl 5 5 Baseline Post Therapy -20 0 60 120 0 60 120 Salsalate Placebo Time (minutes) Fleischman et al Diabetes Care 2008; 31:289

Free Fatty Acids and Inflammatory Mediators Improve With Salsalate in Obesity ** 0.6 20 6 * p<0.05 * Salsalate * 0.3 10 3 ** p<0.01 14% 34% 56% FFA CRP Adiponectin 0.6 20 6 Placebo 0.3 3 10 3 Baseline Salsalate FFA CRP Adiponectin (mEq/L) (mg/L) (mg/L) Fleischman et al Diabetes Care 2008; 31:289

TINSAL- TINSAL-T2D Stage 1: HbA1c (primary endpoint) 0.2 hange fro baseline) Placebo 0 om -0.2 *P vs placebo vs. ercent HbA1c (ch 3.5 g *0.02 -0.4 3.0 g *0.02 4.0 g *0.001 Pe -0.6 *Holm’s procedure 0 4 8 14 Trial week

TINSAL- TINSAL-T2D Trial Design Stage I: 14-week multicenter, double-masked, placebo-controlled dose ranging study in inadequately controlled T2D (7.0 ≤ HbA1c ≤ 9.5) Screen n=240, Randomize n=108 Placebo 3.0g 3.5g 4.0g n=27 n=27 n=27 n=27 52 Stage II: 26-week multicenter, double-masked, placebo-controlled phase III trial Screen n=564 Randomize n=282 n=564, Placebo Salsalate 3.5 g/d n=141 randomized n=141 randomized Placebo Salsalate n=113 complete n=113 complete

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The Metabolic Syndrome and Cardiovascular Risk

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