VBWG. Insulin Resistance and Cardiovascular Disease: New Perspectives From Vascular Biology

Transcription

1 Insulin Resistance and Cardiovascular Disease: New Perspectives From Vascular Biology 1

2 Contents I. CV disease and insulin resistance: Challenges and opportunities II. New perspectives in cardioprotection: Focus on PPARγ activation III. Insulin sensitizers: Surrogate and clinical outcomes studies IV. Identifying and treating patients with insulin resistance 2

3 Cardiovascular Disease and Insulin Resistance: Challenges and Opportunities 3

4 The majority of Americans do not follow a healthy lifestyle 2000 Behavioral Risk Factor Surveillance System; N = 153, % Respondents Smokers BMI 25 kg/m 2 Consumes fruits/vegetables <5x/day Infrequent exercise (<5x/week) Reeves MJ, Rafferty AP. Arch Intern Med. 2005;165: The Behavioral Risk Factor Surveillance System (BRFSS) is an annual, state-wide telephone survey of randomly selected households. Reeves et al used BRFSS data from 153,805 respondents, ages 18 to 74 years, surveyed in In all, 24% to 78% of respondents smoked, had a body mass index (BMI) 25 kg/m 2, did not consume fruits and vegetables regularly, or did not engage in physical activity of moderate intensity on a regular basis. The data illustrate that the majority of Americans do not follow a healthy lifestyle. In contrast, only 16.8% of respondents (data not shown) included all four healthy lifestyle characteristics in their lifestyles: o Nonsmoking o Healthy weight (BMI 25 kg/m 2 ) o Regular consumption of fruits and vegetables (5 times daily) o Regular exercise (5 times weekly) 1. Reeves MJ, Rafferty AP. Healthy lifestyle characteristics among adults in the United States, Arch Intern Med. 2005;165:

5 Numbers of persons with diabetes will more than double by % increase 30.3 US population with diabetes (millions) Year 2030 AHA. Heart Disease and Stroke Statistics 2005 Update. Wild S et al. Diabetes Care. 2004;27: As shown previously, most Americans are sedentary and do not eat a healthy diet, suggesting that the prevalence of type 2 diabetes will continue to rise. Most recent estimates (2002 data) suggest that there are 13.9 million Americans with diagnosed diabetes. 1 Wild et al have projected that this number will rise to 30.3 million by 2030 a 118% increase. 2 With numbers this large, all communities and in particular, cardiology practices in these communities are likely to be affected. 1. American Heart Association. Heart Disease and Stroke Statistics 2005 Update. Dallas, Tex: American Heart Association; Wild S, Roglic G, Green A, Sicree R, King H. Global prevalence of diabetes: Estimates for the year 2000 and projections for Diabetes Care. 2004;27:

6 Increasing problem of obesity and diabetes among US adults Obesity (BMI 30 kg/m 2 ) 31% increase US adults (%) Diabetes 36% increase * * *Jan Sep CDC NHIS. Accessed April Unadjusted estimated prevalence data from the January to September 2004 National Health Interview Survey indicate the prevalence of both obesity and diabetes appear to have grown at comparable rates since 1997, illustrating that obesity is an important risk factor for the development of diabetes National Center for Health Statistics. Early release of selected estimates based on data from the 2004 National Health Interview Survey. Available at: Accessed August

7 Cumulative lifetime risk for diagnosis of diabetes Risk of diagnosis of diabetes (%) Hispanic females Non Hispanic black females Hispanic males Non Hispanic black males Non Hispanic white females Non Hispanic white males Age (years) Adapted from Narayan et al. JAMA. 2003;290: Narayan et al estimated the lifetime risk of diabetes based on data from the National Health Interview Survey ( ). 1 The slide shows the estimated proportion of individuals who will develop diabetes by various ages. The investigators found that 32.8% of males (or 1 in 3) and 38.5% of females (or 2 in 5) born in 2000 will eventually develop diabetes. This lifetime risk of diabetes is comparable to that associated with other chronic conditions such as hypertension and coronary heart disease. Importantly, the risk is even higher among minorities: o 40.2% of non-hispanic black males and 49% of non-hispanic black females o 45.4% of Hispanic males and 52.5% of Hispanic females 1. Narayan KMV, Boyle JP, Thompson TJ, Sorensen SW, Williamson DF. Lifetime risk for diabetes mellitus in the United States. JAMA. 2003;290:

8 Over half of patients referred to cardiologists have insulin resistance syndrome Patients with insulin resistance syndrome (%) Cardiac rehabilitation Acute MI N = 1912 Savage, 2005 N = 235 Milani, 2003 N = 85 Curran, 2004 Savage PD et al. Am Heart J. 2005;149: Milani RV, Lavie CJ. Am J Cardiol. 2003;92:50-4. Curran PJ et al. J Am Coll Cardiol. 2004;43(suppl A):249A. Savage et al analyzed data from 1912 adults with diagnosed coronary artery disease (CAD) who had entered cardiac rehabilitation programs in Burlington, VT, and Boston, Mass. 1 o 50% of these individuals had the insulin resistance syndrome. Milani et al analyzed data from 235 adults with a recent coronary event who had entered a cardiac rehabilitation program in New Orleans, La. 2 o 58% had the insulin resistance syndrome. Finally, Curran et al studied 85 young adults (ages <45 years) presenting with acute myocardial infarction (MI). 3 o 58% had the insulin resistance syndrome. o The investigators concluded that the insulin resistance syndrome is an underrecognized risk factor for MI in younger adults. 1. Savage PD, Banzer JA, Balady GJ, Ades PA. Prevalence of metabolic syndrome in cardiac rehabilitation/secondary prevention programs. Am Heart J. 2005;149: Milani RV, Lavie CJ. Prevalence and profile of metabolic syndrome in patients following acute coronary events and effects of therapeutic lifestyle change with cardiac rehabilitation. Am J Cardiol. 2003;92: Curran PJ, Chung EH, Chauhan MS, Pyne CT, Piemonte TC, Gossman DE, et al. Metabolic syndrome: An underrecognized risk factor for myocardial infarction in the young. J Am Coll Cardiol. 2004;43(suppl A):249A. Abstract

9 Almost 70% of patients with first MI have IGT or undiagnosed diabetes N = 181 consecutive patients admitted to CCU Patients (%) Glucose tolerance test results Undiagnosed diabetes Impaired glucose tolerance (IGT) Norhammar A et al. Lancet. 2002;359: Norhammar et al assessed glucose metabolism in 181 consecutive patients admitted to the coronary care units of two Swedish hospitals with acute MI. 1 All subjects had blood glucose levels <200 mg/dl and were free from a history of diabetes. Investigators administered a standard oral glucose tolerance test at discharge and 3 months later. Results of the 3-month test: o 35% had impaired glucose tolerance (IGT) (2-h glucose levels mg/dl). o 31% had diabetes (2-h glucose level 200 mg/dl). In summary, the data indicate a high prevalence of abnormal glucose metabolism in CAD patients. 1. Norhammar A, Tenerz Å, Nilsson G, Hamsten A, Efendíc S, Rydén L, Malmberg K. Glucose metabolism in patients with acute myocardial infarction and no previous diagnosis of diabetes mellitus: A prospective study. Lancet. 2002;359:

10 Role of obesity in insulin resistance Visceral Obesity Caloric intake Sedentary lifestyle Genetic factors Free fatty acids Glucose Lipids Oxidative stress Inflammation Insulin resistance Adapted from Wellen KE, Hotamisligil GS. J Clin Invest. 2005;115: The metabolic derangements of an obese lifestyle result in a state of chronic inflammation and oxidative stress and, ultimately, insulin resistance Wellen KE, Hotamisligil GS. Inflammation, stress, and diabetes. J Clin Invest. 2005;115:

11 Elevated glucose increases risk in elderly patients with acute MI Cooperative Cardiovascular Project ; N =141, Mortality rate (%) > > > >240 Glucose groups (mg/dl) Without diabetes With diabetes Kosiborod M et al. Circulation. 2005;111: Kosiborod et al conducted a retrospective analysis of data from the Cooperative Cardiovascular Project, a national program developed by the Centers for Medicare and Medicaid Services. 1 They selected a national sample of 141,680 patients age 65 years hospitalized with acute MI between 1994 and The slide shows crude 30-day mortality in patients with and without a history of diabetes, and further classified according to glucose level at hospital admission. o In patients without diabetes, the mortality risk increased as admission glucose became greater. Investigators hypothesize that many of this subgroup had undiagnosed diabetes. o In contrast, in the subgroup with a history of diabetes, a glucose-associated increase in mortality risk was seen only in severe hyperglycemia. Investigators concluded that elevated glucose is common in elderly patients with acute MI. The data are consistent with studies in other populations and suggest that strict glucose control may improve outcomes in acute MI. In conclusion, evidence suggests the components of the insulin resistance syndrome interact to place patients at high global risk for CV events. 1. Kosiborod M, Rathore SS, Inzucchi SE, Masoudi FA, Wang Y, Havranek EP, Krumholz HM. Admission glucose and mortality in elderly patients hospitalized with acute myocardial infarction: Implications for patients with and without recognized diabetes. Circulation. 2005;111:

12 Insulin resistance associated with coronary vasomotor abnormalities 75 Myocardial blood flow (MBF) response to cold pressor test MBF* (%) P = Insulin sensitive Insulin resistant *vs baseline Quiñones MJ et al. Ann Intern Med. 2004;140: Quiñones et al assessed coronary blood flow response to the cold pressor test (measured by endothelium-dependent vasodilation) in 50 insulin-resistant and 22 insulin-sensitive Mexican Americans. 1 Patients with hypertension were excluded from the study. Insulin sensitivity was measured using a euglycemic hyperinsulinemic clamp. A steady-state glucose infusion 4.0 mg/kg identified insulin-resistant subjects, and 7.5 mg/kg identified insulin-sensitive subjects. Mean baseline values Insulin sensitive Insulin resistant Fasting glucose (mg/dl) Total-C HDL-C Triglycerides Myocardial blood flow 47.6% 14.4% (P = 0.003) Myocardial blood flow (MBF) response to dipyridamole infusion (which causes endothelium-independent vasodilation) was similar in both groups. The investigators concluded that insulin resistance is associated with endothelial dysfunction in patients without hypertension, dyslipidemia, or IFG. 1. Quiñones MJ, Hernandez-Pampaloni M, Schelbert H, Bulnes-Enriquez I, Jimenez X, Hernandez G, et al. Coronary vasomotor abnormalities in insulin-resistant individuals. Ann Intern Med. 2004;140:

13 Insulin resistance to diabetes: Coronary vasomotor abnormalities progressively worsen Cold pressor test MBF* (%) Insulin sensitive 14 Insulin resistant 7 IGT 10 Diabetes Diabetes + Hypertension 2 *vs baseline P < 0.05 vs insulin sensitive Prior JO et al. Circulation. 2005;111: Prior and colleagues 1 extended the work of Quiñones et al 2 by assessing endothelial function over the spectrum of insulin resistance. MBF response to the cold pressor test was measured in insulin-sensitive subjects (n = 19) and in subjects with insulin resistance (n = 47), impaired glucose tolerance (n = 25), diabetes (n =21), and diabetes plus hypertension (n = 8). Insulin sensitivity was measured in the same manner as the study by Quiñones et al. 2 MBF increased by 44%, 14%, 7%, and 10% in the insulin-sensitive, insulin-resistant, impaired glucose tolerant, and diabetes groups, respectively. MBF changed by 2% in the group with diabetes plus hypertension. Taken together, these two studies indicate that endothelial dysfunction is present in the early stages of insulin resistance and becomes progressively worse as glucose intolerance develops. 1. Prior JO, Quiñones MJ, Hernandez-Pampaloni M, Facta AD, Schindler TH, Sayre JW, et al. Coronary circulatory dysfunction in insulin resistance, impaired glucose tolerance, and type 2 diabetes mellitus. Circulation. 2005;111: Quiñones MJ, Hernandez-Pampaloni M, Schelbert H, Bulnes-Enriquez I, Jimenez X, Hernandez G, et al. Coronary vasomotor abnormalities in insulin-resistant individuals. Ann Intern Med. 2004;140:

14 Insulin resistance increases risk of target organ damage in hypertension N = 354 with untreated hypertension 60 P = Patients (%) P = Microalbuminuria* LV hypertrophy Without insulin resistance syndrome* With insulin resistance syndrome* *Modified ATP III definition Leoncini G et al. J Intern Med. 2005;257: Leoncini et al studied the association of the insulin resistance syndrome and target organ damage in 354 adults (mean age 47 years) with untreated hypertension. 1 The investigators used modified ATP III criteria, replacing waist circumference with BMI. Microalbuminuria was defined as an albumin-to-creatinine ratio 2.38 to 19 mg/mmol (men) and 2.96 to 20 mg/mmol (women). Left ventricular (LV) hypertrophy was defined as an LV mass index >51 g/m 2.7 in both men and women. There was significantly higher prevalence of microalbuminuria (P = 0.04) and LV hypertrophy (P = 0.003) in subjects with the insulin resistance syndrome compared to those without the metabolic syndrome. Thus, subclinical as well as clinical cardiovascular (CV) disease appears to be accelerated in persons with the insulin resistance syndrome. 1. Leoncini G, Ratto E, Viazzi F, Vaccaro V, Parodi D, Parodi A, et al. Metabolic syndrome is associated with early signs of organ damage in nondiabetic, hypertensive patients. J Intern Med. 2005;257:

15 Clinical manifestations of insulin resistance Type 2 diabetes and glycemic disorders Visceral Obesity Insulin resistance Glucotoxicity Lipotoxicity Adiponectin Dyslipidemia Low HDL Small, dense LDL Hypertriglyceridemia Hypertension Endothelial dysfunction/ inflammation (hscrp) Atherosclerosis Impaired thrombolysis PAI-1 Courtesy of Selwyn AP, Weissman PN. Chronically elevated levels of insulin, glucose, and lipids, along with decreased levels of the adipokine adiponectin, lead to pancreatic -cell failure, alterations in lipoprotein structure and function, hypertension, inflammation, and a prothrombotic state. Increasing insulin sensitivity is a potentially important strategy for addressing these pathologic changes. 15

16 New perspectives in cardioprotection: Focus on PPARγ activation 16

17 Potential role of PPAR activation in CV risk reduction Food intake excess Genetic background Physical inactivity Obesity Dyslipidemia Hypertension Hyperglycemia Insulin PPAR activation resistance Hyperinsulinemia Inflammation Hypercoagulation Atherosclerosis Adapted from Tenenbaum A et al. Intl J Cardiol. 2004;97: Peroxisome proliferator-activated receptors (PPARs) are a family of steroid hormone nuclear receptors that, when activated, beneficially regulate a number of metabolic processes Tenenbaum A, Motro M, Schwammenthal E, Fisman EZ. Macrovascular complications of metabolic syndrome: An early intervention is imperative. Int J Cardiol. 2004;97:

18 Peroxisome proliferator-activator receptors (PPARs): Overview Family of steroid hormone nuclear receptors Three isotypes identified PPARα PPARγ PPARδ Ligand-activated transcription factors regulating metabolic processes Plutzky J. Science. 2003;302: Three isotypes of PPARs have been identified: PPAR, PPARγ, and PPAR. When activated (by ligand binding), they act as transcription factors regulating glucose metabolism and inflammation. 1 PPAR activation with agents such as fibrates primarily enhances free fatty acid (FFA) oxidation and controls expression of genes regulating lipoprotein concentrations. 2 PPAR activation appears to be involved in wound closure and myelination, although less is known about this PPAR subtype than the other two. 2 PPARγ activation is currently the subject of intensive research and the focus of this slide kit. 1. Plutzky J. PPARs as therapeutic targets: Reverse cardiology? Science. 2003;302: Yki-Järvinen H. Thiazolidinediones. N Engl J Med. 2004;351:

19 PPAR activation and atherosclerosis: A hypothesis Ligand endogenous or synthetic Activated PPAR receptor Direct Vascular and inflammatory cells Cytokines Chemokines Cholesterol efflux Adhesion molecules? Reduces inflammation Indirect Fat, liver, skeletal muscle? FFA Glucose Insulin sensitivity Triglycerides HDL?? Blunts atherosclerosis Adapted from Plutzky J. Science. 2003;302: The anti-inflammatory effects of PPAR activation are hypothesized to be a new approach to blunting atherosclerosis. Direct effects on the vascular wall as well as indirect effects of improving glucose and lipid metabolism are mediated via adipocytes and other peripheral tissue Plutzky J. PPARs as therapeutic targets: Reverse cardiology? Science. 2003;302:

20 Focus on PPARγ activation Reduces insulin resistance Preserves pancreatic β-cell function Improves CV risk profile Improves dyslipidemia ( HDL, LDL density, or TG) Renal microalbumin excretion Blood pressure VSMC proliferation/migration in arterial wall PAI-1 levels C-reactive protein levels Adiponectin Free fatty acids Inzucchi SE. JAMA. 2002;287: This slide kit focuses on the implications of PPARγ activation with agents such as the thiazolidinediones. Effects include improving insulin sensitivity and preserving pancreatic -cell function, as well as improvements in a number of traditional and new CV risk factors Inzucchi SE. Oral antihyperglycemic therapy for type 2 diabetes: Scientific review. JAMA. 2002;287:

21 PPARγ modulators Name Trade name Manufacturer Approval status Troglitazone Rezulin Parke-Davis 1997* Rosiglitazone Avandia GlaxoSmithKline 1999 Pioglitazone Actos Eli Lilly/ 1999 Takeda Pharmaceuticals Muraglitazar Pargluva Bristol-Myers Squibb/ NDA Merck submitted 2004 *Withdrawn March 2000 Also available in combination with metformin or sulfonylurea Also available in combination with metformin Dual PPARα/γ agonist Two thiazolidinediones are currently approved for glucose control in this country: pioglitazone and rosiglitazone. A third, troglitazone, was withdrawn from the market in Numerous clinical and experimental studies of these agents have been published in the past 5 years. Examples of major findings are discussed herein. Agents with combined PPAR/γ activity are in Phase III clinical trials. Other treatment options are currently in development Staels B, Fruchart JC. Therapeutic roles of peroxisome proliferator-activated receptor agonists. Diabetes. 2005;54:

22 PPAR activation: Newest strategy in CV risk reduction Hyperglycemia Hyperinsulinemia Dyslipidemia Hypertension Insulin PPAR activation resistance Inflammation Hypercoagulation Adapted from Tenenbaum A et al. Intl J Cardiol. 2004;97: The effects of PPAR modulation on glucotoxicity are discussed in the next slides. 22

23 Factors that may drive the progressive decline of β-cell function Hyperglycemia (glucose toxicity) Insulin resistance β-cell Lipotoxicity (elevated FFA, TG) Adapted from Kahn SE. J Clin Endocrinol Metab. 2001;86: Adapted from Ludwig DS. JAMA. 2002;287: Insulin resistance may impair β-cell function through the adverse effects associated with elevated blood glucose (a phenomenon known as glucotoxicity) or free fatty acids (a phenomenon known as lipotoxicity). 1,2 Elevated free fatty acids may also form a feedback loop, causing or worsening insulin resistance Kahn SE. The importance of β-cell failure in the development and progression of type 2 diabetes. J Clin Endocrinol Metab. 2001;86: Ludwig DS. The glycemic index: Physiological mechanisms relating to obesity, diabetes, and cardiovascular disease. JAMA. 2002;287:

24 TRIPOD: Evidence that insulin resistance causes β-cell failure N = 266 Hispanic women with gestational diabetes randomized to troglitazone 400 mg or placebo for median 30 months PPARγ activation: 55% relative risk reduction for new-onset diabetes (HR 0.45; ) Effect was most prominent in women with initial increase in insulin sensitivity and accompanying large reduction in insulin output Protection persisted 8 months after cessation of active treatment PPARγ activation associated with preserved β-cell function TRIPOD = Troglitazone in Prevention of Diabetes Buchanan TA et al. Diabetes. 2002;51: Clinical evidence that -cell failure was not preprogrammed, but was related to chronic insulin resistance came initially from the Troglitazone in Prevention of Diabetes (TRIPOD) study. 1 The main findings are summarized on this slide. 1. Buchanan TA, Xiang AH, Peters RK, Kjos SL, Marroquin A, Goico J, et al. Preservation of pancreatic -cell function and prevention of type 2 diabetes by pharmacological treatment of insulin resistance in high-risk Hispanic women. Diabetes. 2002;51:

25 DPP: Improving insulin sensitivity/ secretion prevents diabetes N = 3234 Diabetes hazard rate (per 100 pyr) Placebo Metformin Lifestyle Insulin secretion (IGR) Low Medium High 5 0 Low Medium High Low Medium High Low Medium High Insulin secretion (IGR) Insulin sensitivity (1/fasting insulin) pyr = person years IGR = insulin-to-glucose ratio DPP = Diabetes Prevention Program DPP Research Group. Diabetes. 2005;54: The Diabetes Prevention Program Research Group reported on the association of insulin sensitivity and secretion and incident diabetes. 1 As shown, subjects with the lowest baseline levels of insulin sensitivity or secretion were at highest risk for progression to diabetes. These findings support the hypothesis that reduction in both insulin sensitivity and insulin secretion (ie,-cell function) contribute to incident diabetes. 1. The Diabetes Prevention Program Research Group. Role of insulin secretion and sensitivity in the evolution of type 2 diabetes in the Diabetes Prevention Program: Effects of lifestyle intervention and metformin. Diabetes. 2005;54:

26 PPARγ activation blunts progression to diabetes Diabetes Prevention Program Cumulative incidence (%) Placebo Metformin 850 mg Lifestyle Troglitazone 400 mg* 75% vs placebo P < Years n = *Terminated early after 1.5 years DPP Research Group. Diabetes. 2005;54: The Diabetes Prevention Program (DPP) confirms the TRIPOD results in prevention of new-onset diabetes. 1 The 2343 subjects at high-risk of diabetes, as measured by elevated fasting and postload glucose concentrations, were randomized to troglitazone 400 mg, metformin 850 mg bid, intensive lifestyle modification (7% weight loss plus 150 min/wk physical activity), or placebo. The slide summarizes cumulative incidence of diabetes by subgroup for the 1.5 years before early termination of the troglitazone arm (concerns of possible liver toxicity): o Troglitazone (n = 585), metformin (n = 587), lifestyle intervention (n = 589), and placebo (n = 582) Compared with placebo, troglitazone reduced the development of diabetes by 75%, lifestyle intervention by 58%, and metformin by 44%. 1. The Diabetes Prevention Program Research Group. Prevention of type 2 diabetes with troglitazone in the Diabetes Prevention Program. Diabetes. 2005;54:

27 PPARγ activation improves β-cell function N = 17 with type 2 diabetes P = 0.02 Disposition index Insulin Rosiglitazone 8 mg Disposition index = Acute insulin response to glucose (µiu/ml/10 min) HOMA-IR HOMA-IR = Homeostasis model assessment of insulin resistance Ovalle F, Bell DSH. Diabetes Care. 2004;27: Confirmation of the TRIPOD and DPP findings comes from a study by Ovalle and Bell, who randomized 17 subjects with type 2 diabetes to insulin or rosiglitazone 8 mg once daily for 6 months. 1 All subjects had glucose inadequately controlled on maximal doses of glimepiride and metformin. A1C levels in the two groups were well matched at baseline and a study end. After 6 months, there was a significant improvement in -cell function in the thiazolidinedione group, as evidenced by a restoration of the acute-phase insulin response to glucose (AIRg, measured using the intravenous glucose tolerance test). In contrast, -cell function did not improve in the insulin group. 1. Ovalle F, Bell DSH. Effect of rosiglitazone versus insulin on the pancreatic -cell function of subjects with type 2 diabetes. Diabetes Care. 2004;27:

28 CV implications of insulin resistance and PPARγ activation Hyperglycemia Hyperinsulinemia Dyslipidemia Hypertension Insulin PPAR activation resistance Inflammation Hypercoagulation Adapted from Tenenbaum A et al. Intl J Cardiol. 2004;97: The effects of PPAR modulation on lipids are discussed in the next series of slides. 28

29 Importance of LDL particle density In insulin resistance, LDL-C levels are similar or only slightly elevated vs general population However, atherogenicity of LDL particles varies according to density More dense = more atherogenic Proportion of small, dense LDL particles greater in patients with insulin resistance or diabetes vs general population Miranda PJ et al. Am Heart J. 2005;149: In patients with insulin resistance, LDL-C levels are similar to or only slightly elevated compared with the general population. 1 However, it is important to look beyond the numbers to assess global risk in these individuals. Patients with insulin resistance have LDL particles that are more atherogenic than the general population because of a shift towards a greater proportion of small, dense particles. Small, dense LDL particles arise as follows: o Increased FFA flux to the liver stimulates the assembly and secretion of very low-density lipoproteins (VLDL). o Elevated VLDL levels promote exchange of cholesterol and triglycerides between VLDL and HDL (an exchange mediated by cholesteryl ester transfer protein). o The result is depletion of cholesterol and enrichment of triglycerides in HDL. Subsequent hydrolysis of triglycerides within HDL by either lipoprotein lipase or hepatic lipase leads to smaller, denser particles. 1. Miranda PJ, DeFronzo RA, Califf RM, Guyton JR. Metabolic syndrome: Definition, pathophysiology, and mechanisms. Am Heart J. 2005;149:

30 Greater atherogenicity of small, dense LDL vs normal LDL Susceptible to oxidation Binds to arterial wall Penetrates arterial wall Toxic to endothelial cells Promotes PAI-1 production by endothelial cells Promotes thromboxane production by endothelial cells Accumulates Ca 2+ in vascular smooth muscle cells Binds to LDL scavenger receptor Adapted from Sniderman AD et al. Ann Intern Med. 2001;135: Small, dense LDL particles have a number of characteristics that make them more atherogenic than normal LDL. 1 The clinical relevance of these properties is demonstrated in the next slide. 1. Sniderman AD, Scantlebury T, Cianflone K. Hypertriglyceridemic hyperapob: The unappreciated atherogenic dyslipoproteinemia in type 2 diabetes mellitus. Ann Intern Med. 2001;135:

31 Increased small, dense, LDL particles associated with reduced IHD survival N = 2072 men without IHD at baseline;13-year follow-up 1.00 Survival probabilities 0.90 P < Follow-up (years) Tertiles of LDL-C 255Å <1.07 mmol/l mmol/l 1.86 mmol/l IHD = ischemic heart disease St-Pierre AC et al. Arterioscler Thromb Vasc Biol. 2005;25: St-Pierre et al followed 2072 subjects for 13 years. 1 At baseline, all subjects were free from self-reported ischemic heart disease (IHD). LDL particles were classified as either large (260 Å in diameter) or small (<255 Å in diameter). Subjects with a greater proportion of small LDL particles had significantly worse survival. 1. St-Pierre AC, Cantin B, Dagenais GR, Mauriège P, Bernard P-M, Després J-P, Lamarche B. Low-density lipoprotein subfractions and the long-term risk of ischemic heart disease in men: 13-year follow-up data from the Québec Cardiovascular Study. Arterioscler Thromb Vasc Biol. 2005;25:

32 PPARγ activation increases LDL size and buoyancy N = 302; rosiglitazone 8 mg LDL particle size LDL density 8 P < Diameter vs baseline (Angstroms) Relative flotation 0.02 vs baseline P < Brunzell JD et al. Circulation. 2004;110(suppl):III-143. Brunzell et al pooled data from three studies of patients with type 2 diabetes and one study of patients with IGT. 1 All studies evaluated rosiglitazone 8 mg daily, with treatment durations ranging from 8 to 26 weeks. Rosiglitazone was associated with significant increases in LDL size and buoyancy. 1. Brunzell JD, Murdoch SJ, Deeb SS, Marcovina SM, Banerji M, Lebovitz H, et al. Rosiglitazone increases LDL size and buoyancy while decreasing CETP mass and hepatic lipase activity. Circulation. 2004;110(suppl):III-143. Abstract

33 Comparative effects of PPARγ activators on lipids in diabetes In patients not receiving statin therapy, studies suggest that pioglitazone and rosiglitazone have differing effects on lipid levels and particle size 1 In patients receiving statin therapy, some studies suggest these differences are eliminated, while other studies suggest they persist 2 Clinical implications are not known 3 1 Goldberg RB et al. Diabetes Care. 2005;28: Plotkin DJ et al. Diabetes. 2005;54(suppl 1):A Khan M et al. Diabetes. 2005;54(suppl 1):A137. Studies suggest that PPARγ activators may have different effects on lipid levels and particle size in patients not receiving concurrent statin therapy. Goldberg et al reported on a 24-week, randomized, double-blind, parallel-group study in which statin or other lipid-lowering therapy was excluded. 1 In the pioglitazone 45-mg and rosiglitazone 8-mg groups, respectively: o LDL-C increased by 23% and 16% (P < 0.001). o HDL-C increased by 15% and 8% (P < 0.001). o Triglycerides decreased 12% vs increase of 15% (P < 0.001). o Mean change in LDL diameter was 0.47 nm vs 0.31 nm (P = 0.005). Plotkin et al conducted a 24-week, randomized, placebo-controlled, parallel-group study of simvastatin 40 mg added to pioglitazone 45 mg or rosiglitazone 8 mg. 2 o There were no significant differences between groups in lipid changes, with the exception of triglycerides, where a greater reduction in the rosiglitazone group was observed. In contrast, Khan et al conducted an open-label study in 305 patients treated with statin plus rosiglitazone; the latter was switched to pioglitazone mg for 17 weeks. 3 o Decreases in total-c, LDL-C, and triglycerides were noted. o There was no change in HDL-C. Thus, the degree and clinical significance of differences among PPARγ activators with regard to their effects on lipids in patients with diabetes remains controversial. 1. Goldberg RB, Kendall DM, Deeg MA, Buse JB, Zagar AJ, Pinaire JA, et al; for the GLAI study investigators. A comparison of lipid and glycemic effects of pioglitazone and rosiglitazone in patients with type 2 diabetes and dyslipidemia. Diabetes Care. 2005;28: Plotkin DJ, Lewin AJ, Lee MW, Davies MJ, Mitchel YB. Effect of adding simvastatin to on-going thiazolidinedione (TZD) treatment on the lipid profile of patients with type 2 diabetes (T2D). Diabetes. 2005;54(suppl 1):A232. Abstract 951-P. 3. Khan M, Berhanu P, Perez A, Demissie S, Fleck P, Kupfer S. Effects of pioglitazone in combination with stable statin therapy on lipid levels in subjects with type 2 diabetes and dyslipidemia after treatment conversion from rosiglitazone: Results from an open-label study. Diabetes. 2005;54(suppl 1):A137. Abstract 553-P. 33

34 CV implications of insulin resistance and PPARγ activation Hyperglycemia Hyperinsulinemia Dyslipidemia Hypertension Insulin PPAR activation resistance Inflammation Inflammation Hypercoagulation Adapted from Tenenbaum A et al. Intl J Cardiol. 2004;97: The effects of PPAR modulation on obesity-related inflammation are discussed in the next series. 34

35 Adipokines: An overview Atherogenic CRP IL-6 PAI-1 Angiotensinogen Leptin Resistin MCP-1 Antiatherogenic Adiponectin Lau DCW et al. Am J Physiol Heart Circ Physiol. 2005;288:H Wellen KE, Hotamisligil GS. J Clin Invest. 2005;115: Adipose tissue is an active organ that secretes several biologically active molecules (adipokines). 1,2 Most adipokines have pro-inflammatory and atherogenic effects, including C-reactive protein (CRP), interleukin-6 (IL-6), plasminogen activator inhibitor-1 (PAI-1), angiotensinogen, leptin, resistin, and monocyte chemotactic protein-1 (MCP-1). Adiponectin is attracting attention, since this adipokine appears to have a number of antiatherogenic effects. Levels of this adipokine are decreased in obesity and correlate inversely with CV risk, as shown on the next slide. 1. Lau DCW, Dhillon B, Yan H, Szmitko PE, Verma S. Adipokines: Molecular links between obesity and atherosclerosis. Am J Physiol Heart Circ Physiol. 2005;288:H2031-H Wellen KE, Hotamisligil GS. Inflammation, stress, and diabetes. J Clin Invest. 2005;115:

36 Adiponectin associated with decreased risk of MI N = 18,225 men; 6-year follow-up Relative risk µg/ml Quintile of adiponectin (95% CI) Adjusted relative risk (P < 0.001) Lipid-adjusted relative risk (P < 0.02) Pischon T et al. JAMA. 2004;291: Using data from the Health Professionals Follow-up Study, Pischon et al conducted a case-control study to assess the relationship between adiponectin and CV risk. 1 N = 18,225 men were followed for a mean duration of 6 years. As shown, subjects with adiponectin levels in the highest quintile demonstrate a significantly lower risk of MI compared with those in the lowest quintile (relative risk, 0.39; 95% CI, ; P < 0.001). 1. Pischon T, Girman CJ, Hotamisligil GS, Rifai N, Hu FB, Rimm EB. Plasma adiponectin levels and risk of myocardial infarction in men. JAMA. 2004;291:

37 Improved insulin sensitivity associated with increased adiponectin N = 40 women with gestational diabetes treated with troglitazone for 3 months % Change in insulin sensitivity ( S i ) % Change in HMW/total adiponectin ( S A ) Pajvani UB et al. J Biol Chem. 2004;279: Adiponectin circulates in serum as either a hexamer of relatively molecular weight or a multimeric structure of high molecular weight (HMW form). 1 Pajvani et al measured adiponectin levels in a subgroup of 40 participants in the TRIPOD study and found that as insulin sensitivity increased, the proportion of the HMW form also increased (as measured by increasing ratio of HMW-to-total adiponectin). Investigators have also hypothesized that hyperinsulinemia, secondary to insulin resistance, downregulates adiponectin synthesis by adipocytes, while improved insulin sensitivity with PPARγ activation upregulates adiponectin synthesis. 1. Pajvani UB, Hawkins M, Combs TP, Rajala MW, Doebber T, Berger JP, et al. Complex distribution, not absolute amount of adiponectin, correlates with thiazolidinedione-mediated improvement in insulin sensitivity. J Biol Chem. 2004;279:

38 Contrasting roles of CRP and PPARγ on inflammation and insulin resistance Liver IL-6 Adipose tissue CRP PPARγ Glucose Insulin resistance Lau DCW et al. Am J Physiol Heart Circ Physiol. 2005;288:H Circulating IL-6 triggers synthesis of CRP by the liver. In addition, recent studies suggest that adipose tissue may also be a source of CRP. Chronic inflammation and hyperglycemia contribute to development of insulin resistance. 1 PPARγ activation improves insulin sensitivity by blunting both inflammation and glucotoxicity. 1. Lau DCW, Dhillon B, Yan H, Szmitko PE, Verma S. Adipokines: molecular links between obesity and atherosclerosis. Am J Physiol Heart Circ Physiol. 2005;288: H2031-H

39 Direct relationship of CRP to metabolic syndrome Women s Health Study; N = 14,719 8 Median CRP (mg/l) Components of the metabolic syndrome (n) n = Modified ATP III definition Ridker PM et al. Circulation. 2003;107: Ridker et al used data from the Women s Health Study to assess whether CRP adds prognostic information to the metabolic syndrome. 1 N= 14,719 women free from diabetes at baseline were followed-up for 8 years. The metabolic syndrome was diagnosed using modified ATP III criteria, replacing waist circumference >35 in with BMI >26.7 kg/m 2 to define obesity. 2 Incident CV events included nonfatal MI, nonfatal ischemic stroke, coronary revascularization, and CV death. Data confirmed previous studies that demonstrate an increased risk for the development of CV disease when metabolic syndrome components are added. Moreover, data show that CRP levels 3 mg/l are associated with a further increase in risk. These observational data are consistent with experimental data linking inflammation to both insulin resistance and atherosclerosis. 1. Ridker PM, Buring JE, Cook NR, Rifai N. C-reactive protein, the metabolic syndrome, and risk of incident cardiovascular events: An 8-year follow-up of initially healthy American women. Circulation. 2003;107: Grundy SM, Cleeman JI, Bairey Merz CN, Brewer HB Jr, Clark LT, Hunninghake DB, et al; for the Coordinating Committee of the National Cholesterol Education Program. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines. Circulation. 2004;110:

40 Inflammation is a contributing mechanism in diabetes development N = Incidence (%) P = 0.06 P = P = Fibrinogen CRP PAI-1 Quartiles of inflammatory proteins 1st 2nd 3rd 4th Festa A et al. Diabetes. 2002;51: Festa et al studied the association of new-onset diabetes and inflammatory activity in 1047 individuals free from diabetes at baseline. 1 Over a 5-year follow-up, subjects who developed diabetes had significantly higher baseline levels of CRP and PAI-1 (P < for upper vs lower quartiles). A similar trend was observed for fibrinogen (P = 0.06). These findings support the hypothesis that inflammation has an important role in the pathogenesis of both diabetes and atherosclerosis. 1. Festa A, D Agostino R Jr, Tracy RP, Haffner SM. Elevated levels of acute-phase proteins and plasminogen activator inhibitor-1 predict the development of type 2 diabetes: The insulin resistance atherosclerosis study. Diabetes. 2002;51:

41 PPARγ activation decreases CRP in patients with diabetes N = 357; 26 weeks 0 Placebo Rosiglitazone 4 mg Rosiglitazone 8 mg 10 Mean change from baseline (%) P < % 22% P < 0.05 Haffner SM et al. Circulation. 2002;106: Haffner et al randomized 357 patients with type 2 diabetes to receive either rosiglitazone 4 mg or 8 mg, or placebo for 26 weeks. 1 As shown, both doses of the PPARγ activator significantly reduced CRP levels compared with placebo (P < 0.05). 1. Haffner SM, Greenberg AS, Weston WM, Chen H, Williams K, Freed MI. Effect of rosiglitazone treatment on nontraditional markers of cardiovascular disease in patients with type 2 diabetes mellitus. Circulation. 2002;106:

42 CV implications of insulin resistance and PPARγ activation Hyperglycemia Hyperinsulinemia Dyslipidemia Hypertension Insulin PPAR activation resistance Inflammation Hypercoagulation Adapted from Tenenbaum A et al. Intl J Cardiol. 2004;97: The effects of PPAR modulation on hypertension in the insulin resistance syndrome are discussed in the next series of slides. 42

43 Improved insulin sensitivity associated with reduced BP N = 24 nondiabetic hypertensives; rosiglitazone 8 mg, 16 weeks 20 in 24-h systolic BP (mm Hg) P < r = Change in insulin sensitivity (mg/kg/min) Nonmodulators Low-renin hypertension Raji A et al. Diabetes Care. 2003;26: Raji et al measured 24-h ambulatory BP and insulin sensitivity in 24 hypertensive patients free from diabetes who received rosiglitazone 8 mg (along with usual antihypertensive medications) for 16 weeks. 1 Subjects were classified as either low renin (n = 12) or nonmodulators (n = 12). Previous studies had indicated that nonmodulators were a subgroup of patients with salt-sensitive hypertension who were more insulin resistant than low-renin patients. In both groups, there was a significant correlation between improvement in insulin sensitivity and modest decline in mean 24-h blood pressure. The investigators concluded that mechanisms remain to be fully elucidated. Close relationships exist between the changes in insulin sensitivity and blood pressure across hypertension subgroups. Common physiologic mechanisms are most likely responsible. 1. Raji A, Seely EW, Bekins SA, Williams GH, Simonson DC. Rosiglitazone improves insulin sensitivity and lowers blood pressure in hypertensive patients. Diabetes Care. 2003;26:

44 PPARγ activation associated with sustained BP reduction N = 668 with type 2 diabetes Rosiglitazone added to baseline therapy Baseline metformin 6 months 12 months Baseline sulfonylurea 6 months 12 months h systolic BP * Reduction from baseline (mm Hg, 95% CI) h diastolic BP * Treatment differences (mm Hg, 95% CI) * Ambulatory BP Home PD et al. Diabetes. 2005;54(suppl 1):A134. The findings by Raji et al were extended by Home and colleagues in 668 persons with type 2 diabetes and loss of glucose control. 1 Patients on metformin monotherapy were randomized to rosiglitazone or sulfonylurea. Those with loss of glucose control on sulfonylurea monotherapy were randomized to rosiglitazone or metformin. Data show that, regardless of baseline therapy, addition of rosiglitazone resulted in modest but sustained reduction in 24-h ambulatory blood pressure. 1. Home PD, Komajda M, Beck-Neilsen H, Curtis P, Zambanini A, Dargie H. Twelve months sustained efficacy of rosiglitazone combination therapy on ambulatory blood pressure (ABP) in people with type 2 diabetes mellitus. Diabetes. 2005;54(suppl 1):A134. Abstract 542-P. 44

45 CV implications of insulin resistance and PPARγ activation Hyperglycemia Hyperinsulinemia Dyslipidemia Hypertension Insulin PPAR activation resistance Inflammation Hypercoagulation Adapted from Tenenbaum A et al. Intl J Cardiol. 2004;97: The effects of PPAR modulation on thrombolytic balance in the insulin resistance syndrome are discussed in the next series of slides. 45

46 PPARγ activation blunts TNF-α induced PAI-1 secretion Human umbilical-vein endothelial cells PAI-1 (ng) * * Trog = troglitazone *P < P < TNF-α 1 ng/ml TNF-α 1 ng/ml + Trog 10 µm TNF-α TNF-α 10 ng/ml 10 ng/ml + Trog 10 µm TNF-α TNF-α 100 ng/ml 100 ng/ml + Trog 10 µm Hamaguchi E et al. J Pharmacol Exp Ther. 2003;307: Hamaguchi et al demonstrated that the inflammatory adipokine tumor necrosis factor- (TNF-) promotes secretion of PAI-1 by human umbilical-vein endothelial cells in a dose-dependent manner. 1 o PPARγ activation with troglitazone blunted this effect. Similar effects have also been demonstrated in humans, as the next two slides show. 1. Hamaguchi E, Takamura T, Shimizu A, Nagai Y. Tumor necrosis factor- and troglitazone regulate plasminogen activator inhibitor type 1 production through extracellular signal-regulated kinase- and nuclear factor-b-dependent pathways in cultured human umbilical vein endothelial cells. J Pharmacol Exp Ther. 2003;307:

47 Metformin reduces PAI-1 levels in type 2 diabetes N = 27, 12 weeks PAI-1 activity (U/mL) A1C = 1.3% FPG = 55 mg/dl * P = vs placebo Basal Placebo Metformin 2.5 g Results at 12 weeks * Nagi DK, Yudkin JS. Diabetes Care. 1993;16: Nagi et al randomized 27 persons with type 2 diabetes to metformin 2.5 g or placebo for 12 weeks. 1 At study end, PAI-1 activity was significantly lower in the metformin group than in the placebo group (difference of 5.3 U/mL, P = 0.001). 1. Nagi DK, Yudkin JS. Effects of metformin on insulin resistance, risk factors for cardiovascular disease, and plasminogen activator inhibitor in NIDDM subjects: A study of two ethnic groups. Diabetes Care. 1993;16:

48 Benefits of combined insulin sensitizer therapy: Effects on CRP, PAl-1, and MMP-9 Weeks MMP-9 * 22.2 Baseline (%) * CRP 26.9 P = PAl P < P = Metformin 2 g (n = 70) Metformin 1 g + rosiglitazone 8 mg (n = 57) *NS vs baseline Weissman PN et al. Diabetes. 2004;53(suppl 2):A28. Weissman et al treated type 2 diabetic subjects with open-label metformin 500 mg bid for at least 3 weeks then randomized the group to receive either rosiglitazone or to continue on metformin. 1 Weeks 1 through 8 (daily dose) (data not shown): o Rosiglitazone 4 mg plus metformin 1000 mg o Metformin 1500 mg Weeks 8 through 24 (daily dose): o Rosiglitazone 8 mg plus metformin 1000 mg o Metformin 2000 mg As shown, combined insulin sensitizer therapy was associated with significantly greater reductions in CRP and PAI-1. Levels of matrix metalloproteinase-9 (MMP-9) rose in the metformin group and decreased in the thiazolidinedione group. 1. Weissman PN, Goldstein BJ, Campbell JC, Gould EM, Waterhouse BR, Strow LJ, Cobitz AR. Rosiglitazone plus metformin combination effects on CV risk markers suggest potential CV benefits in type 2 diabetic patients. Diabetes. 2004;53(suppl 2):A28. Abstract 121-OR. 48

49 Insulin Sensitizers: Surrogate and Clinical Outcomes Studies This section summarizes provocative new data that suggests PPARγ activation may be associated with reduction in CV events as well as the ongoing clinical studies that are testing this hypothesis. 49

50 Metformin improves endothelial function Metformin 1000 mg (3 months) * Placebo Increase in forearm blood flow (%) * * Acetylcholine (µg/min) Before treatment After treatment * P = vs placebo Mather KJ et al. J Am Coll Cardiol. 2001;37: Endothelial function is impaired early in insulin resistance. Mather et al randomized 44 patients with type 2 diabetes to metformin 1 g or placebo for 12 weeks. 1 Before and after treatment, endothelium-dependent and endothelium-independent vasodilation was assessed by intra-arterial administration of acetycholine or sodium nitroprusside, respectively. As shown, metformin was associated with a significant improvement in endothelium-dependent vasodilation compared with placebo. This finding supports a link between insulin resistance and endothelial dysfunction. 1. Mather KJ, Verma S, Anderson TJ. Improved endothelial function with metformin in type 2 diabetes mellitus. J Am Coll Cardiol. 2001;37:

51 PPARγ activation improves renal endothelial function and reduces proteinuria N = 19 with type 2 diabetes with/without microalbuminuria GFR 80 (ml/min) P < P < Treatment with rosiglitazone was followed by 60% reductions in albuminuria and proteinuria in diabetic patients with microalbuminuria. 0 Placebo Rosiglitazone Nateglinide Rosiglitazone Microalbuminuria No microalbuminuria Pistrosch F et al. Diabetes. 2005;54: Pistroch et al conducted 12-week double-blind crossover trial in 19 patients with type 2 diabetes. 1 Subjects with microalbuminuria remained on their baseline oral hypoglycemic drug and were crossed over from placebo to rosiglitazone. Those without microalbuminuria were crossed over from nateglinide to rosiglitazone. In both groups, rosiglitazone was associated with improvements in GFR and reduction in proteinuria. 1. Pistrosch F, Herbrig K, Kindel B, Passauer J, Fischer S, Gross P. Rosiglitazone improves glomerular hyperfiltration, renal endothelial dysfunction, and microalbuminuria of incipient diabetic nephropathy in patients. Diabetes. 2005;54:

52 PPARγ activation normalizes coronary vasomotor abnormalities in insulin resistance N = 16 with insulin resistance; rosiglitazone 8 mg for 3 months 50 P < 0.01 P < 0.01 MBF* (%) (±24.3) 40.3 (±31.3) 8.7 (±18.9) Pre-Treatment Post-Treatment Off-Treatment * from rest Quiñones MJ et al. Ann Intern Med. 2004;140: Quiñones et al treated 16 insulin-resistant patients with rosiglitazone 8 mg for 3 months. Endothelial function improved with treatment, as shown by increased coronary vasodilation in response to the cold pressor test. 1 Following cessation of treatment, endothelial function declined. 1. Quiñones MJ, Hernandez-Pampaloni M, Schelbert H, Bulnes-Enriquez I, Jimenez X, Hernandez G, et al. Coronary vasomotor abnormalities in insulin-resistant individuals. Ann Intern Med. 2004;140:

53 PPARγ activation: Consistent reduction in carotid atherosclerosis Study (year) Minamikawa (1998) Treatments Troglitazone 400 mg Usual care Patients (n) duration Type 2 diabetes (n = 135) 6 mos IMT (mm) 0.080, troglitazone 0.027, usual care P < Koshiyama (2001) Pioglitazone 30 mg Usual care Type 2 diabetes (n = 106) 6 mos 0.084, troglitazone 0.022, usual care P < Sidhu (2004) Langenfeld (2005) Rosiglitazone 8 mg Placebo Pioglitazone 45 mg Glimepiride 2.7 mg Stable CAD (n = 92) 12 mos Type 2 diabetes (n = 173) 6 mos 0.012, rosiglitazone , placebo P = , pioglitazone 0.011, glimepiride P < Minamikawa J et al. J Clin Endocrinol Metab. 1998;83: Koshiyama H et al. J Clin Endocrinol Metab. 2001;86; Sidhu JS et al. Arterioscler Thromb Vasc Biol. 2004;24: Langenfeld MR et al. Circulation. 2005;111: Accumulated data indicate that reduction in carotid atherosclerosis is common to all thiazolidinediones. 1 Minamikawa et al randomized 135 patients with type 2 diabetes to troglitazone 400 mg plus usual care (sulfonylureas or diet) or usual care alone for 6 months. 1 Koshiyama et al randomized 106 patients with type 2 diabetes to pioglitazone 30 mg plus usual care (sulfonylureas or diet) or usual care alone for 6 months. 2 Sidhu et al randomized 92 patients with stable CAD but no diabetes to rosiglitazone or placebo for 12 months. 3 Langenfeld et al randomized 173 patients with type 2 diabetes to pioglitazone 45 mg or glimepiride 1 to 6 mg (average of 2.7 mg) for 6 months Minamikawa J, Tanaka S, Yamauchi M, Inoue D, Koshiyama H. Potent inhibitory effect of troglitazone on carotid arterial wall thickness in type 2 diabetes. J Clin Endocrinol Metab. 1998;83: Koshiyama H, Shimono D, Kuwamura N, Minamikawa J, Nakamura Y. Inhibitory effect of pioglitazone on carotid arterial wall thickness in type 2 diabetes. J Clin Endocrinol Metab. 2001;86; Sidhu JS, Kaposzta Z, Markus HS, Kaski JC. Effect of rosiglitazone on common carotid intimamedia thickness progression in coronary artery disease patients without diabetes mellitus. Arterioscler Thromb Vasc Biol. 2004;24: Langenfeld MR, Forst T, Hohberg C, Kann P, Lübben G, Konrad T, et al. Pioglitazone decreases carotid intima-media thickness independently of glycemic control in patients with type 2 diabetes: Results from a controlled randomized study. Circulation. 2005;111:

54 PPARγ activation blunts progression of carotid atherosclerosis in stable CAD N = 92 without diabetes Carotid IMT (mm) Placebo Progression rate = mm/48 wks Rosiglitazone 8 mg Progression rate = mm/48 wks Time (weeks) P = 0.03 Adapted from Sidhu JS et al. Arterioscler Thromb Vasc Biol. 2004;24: Sidhu et al randomized 92 consecutive nondiabetic subjects with stable CAD to placebo or rosiglitazone 4 mg once daily for 8 weeks, followed by 8 mg daily for 40 weeks. 1 The data on the slide are from the 80 subjects who completed the study. The PPARγ-activator group showed reduced progression of carotid intima-media thickness (IMT) compared with the placebo group (decrease of mm vs increase of mm, respectively, P = 0.03). 1. Sidhu JS, Kaposzta Z, Markus HS, Kaski JC. Effect of rosiglitazone on common carotid intima-media thickness progression in coronary artery disease patients without diabetes mellitus. Arterioscler Thromb Vasc Biol. 2004;24:

55 PPARγ activation blunts progression of carotid atherosclerosis N = 173 with type 2 diabetes ns Carotid IMT (mm) P < P < Weeks Pioglitazone 45 mg Glimepiride 2.7 mg Langenfeld MR et al. Circulation. 2005;111: A study by Langenfeld et al provided further insight into the antiatherosclerotic effect of PPARγ activation. 1 N = 173 adults with type 2 diabetes were randomized to pioglitazone 45 mg or glimepiride 2.7 mg for 24 weeks. Carotid IMT was measured via B-mode ultrasound. Both treatments were associated with similar glucose control: A1C decreased from 7.52% to 6.72% in the PPARγ-activator group and from 7.44% to 6.84% in the sulfonylurea group (P = for between-group comparison). Carotid IMT was significantly reduced from baseline in the PPARγ-activator group (0.033 mm; P < 0.005), but not in the sulfonylurea group (0.002 mm reduction) (P < 0.001, between-group comparison). Thus, the effect of PPARγ activation on atherosclerotic progression is independent of glucose lowering. 1. Langenfeld MR, Forst T, Hohberg C, Kann P, Lübben G, Konrad T, et al. Pioglitazone decreases carotid intima-media thickness independently of glycemic control in patients with type 2 diabetes mellitus: Results from a controlled randomized study. Circulation. 2005;111:

56 Additive effect of statin and PPARγ activation on atherosclerosis Rabbit model (%) Highcholesterol diet (n = 6) P < 0.01 Changes in maximal vessel wall thickness Normal diet (n = 6) Normal diet + PPARγagonist* (n = 7) Normal diet + simvastatin (n = 6) P = 0.04 P = 0.03 Normal diet + simvastatin + PPARγ agonist * (n = 6) *L P < 0.05 vs high-cholesterol diet P < 0.05 vs normal diet Corti R et al. J Am Coll Cardiol. 2004;43: Studies have convincingly demonstrated the reduction of atherosclerosis progression with statins. Since statins and PPARγ activation blunt disease progression via different mechanisms, it is logical to expect that their effects would be additive. Corti et al tested this hypothesis in rabbits. 1 Aortic atherosclerosis was induced by a high-cholesterol diet in conjunction with injury to the vessel wall. The animals were randomized to either continue a highcholesterol diet, a normal diet, or normal diet augmented with the statin simvastatin with and without the experimental PPARγ activator L The investigators used vessel wall area (visualized by magnetic resonance imaging [MRI]) as a measure of atherosclerosis progression. A significant progression in vessel wall area of 15% was observed in the highcholesterol diet group (P < 0.01). Progression was blunted or reversed in the other groups: o Normal diet, 2.5% reduction o PPARγ activator, 4.5% reduction o Statin, 12% reduction o PPARγ activator plus statin, 22% reduction (P = 0.03 vs PPARγ activator alone and P = 0.04 vs statin alone) 1. Corti R, Osende JI, Fallon JT, Fuster V, Mizsei G, Jneid H, et al. The selective peroxisomal proliferator-activated receptor-gamma agonist has an additive effect on plaque regression in combination with simvastatin in experimental atherosclerosis: In vivo study by high-resolution magnetic resonance imaging. J Am Coll Cardiol. 2004;43:

57 PPARγ activation reduces intimal hyperplasia Balloon injury in mouse model Control Rosiglitazone 8 mg/kg I/M ratio (%) 2 1 P < Intimal area I/M = Medial area 0 Control Rosiglitazone Wang C-H et al. Circulation. 2004;109: Wang et al induced neointimal hyperplasia in mice via femoral angioplasty. 1 The animals also received either rosiglitazone 8 mg/kg or saline for 2 weeks prior to and 4 weeks after angioplasty. The investigators used the ratio of intimal area to medial area (I/M ratio) as a measure of neointimal proliferation. The I/M ratio was 3.1 in controls and 0.98 in the PPARγ-activator group (P < 0.001). The arrows in the cross-sectional images above the graph indicate the vascular medial layer. The antiproliferative effects of PPARγ activation have also been demonstrated in humans, as the next slide demonstrates. 1. Wang C-H, Ciliberti N, Li S-H, Szmitko PE, Weisel RD, Fedak PWM, et al. Rosiglitazone facilitates angiogenic progenitor cell differentiation toward endothelial lineage: A new paradigm in glitazone pleiotropy. Circulation. 2004;109: