Relationship of Glycemia to Cardiovascular Disease ... - Lipids Online

Relationship of Glycemia to 

Cardiovascular Disease: Role of 

Antidiabetic Agents in 

Cardiovascular Risk Reduction 

Richard W. Nesto, MD 

Slide Source 

Lipids Online Slide Library 

www.lipidsonline.org 

Relationship of Glycemia to Cardiovascular Disease: Role of Antidiabetic Agents in 


Unadjusted Mortality According to 

Glucose Metabolism: Data from AusDiab 

Cumulative Incidence of 

All-cause Mortality 

0.15 

0.10 

0.05 

All-Cause Mortality 

KDM 

NDM 

IGT 

IFG 

NGT 

0.00 

0 2 4 6 

Time (years) 

Cumulative Incidence of 

CVD Mortality 

0.05 

0.04 

0.03 

0.02 

0.01 

0.00 

Reprinted from Barr EL, et al. Circulation. 2007;116:151–157, 

with permission from Lippincott Williams & Wilkins. 

CVD Mortality 

0 2 4 6 

Time (years) 

AusDiab = Australian Diabetes, Obesity, and Lifestyle Study; CVD = cardiovascular; 

KDM = known diabetes mellitus; NDM = newly diagnosed diabetes mellitus; IFG = 

impaired fasting glucose; IGT = impaired glucose tolerance; NGT = normal glucose 

tolerance 

KDM 

NDM 

IFG 

IGT 

NGT 

Slide Source 



Unadjusted Mortality According to Glucose Metabolism: Data from AusDiab 

In The Australian Diabetes, Obesity, and Lifestyle (AusDiab) Study, the status of glucose 

intolerance was related to both all-cause mortality and cardiovascular disease (CVD) 

mortality over a 6-year follow-up. There were graded increases in both all-cause 

mortality and CVD mortality across the range from normal glucose tolerance (NGT) to 

known diabetes mellitus (KDM). Of note is the fact that both impaired fasting glucose 

(IFG) and impaired glucose tolerance (IGT) — two conditions that could be termed 

“prediabetes” — demonstrated intermediate mortality rates between normal glucose 

tolerance and diabetes mellitus. This would indicate that conditions associated with a 

Source: Lipids Online Slide Library (www.lipidsonline.org) Page 1 of 36 

© 2009 Baylor College of Medicine, Houston, Texas

high risk for future diabetes could be considered targets for intervention in order to 

reduce mortality. The exact factors that govern risk within prediabetes are under 

evaluation and are still being debated. These factors could include “traditional factors,” 

such as dyslipidemia, hypertension, dysglycemia, and the proinflammatory and 

prothrombotic factors associated with insulin resistance. 

Reference: 

Barr EL, Zimmet PZ, Welborn TA, et al. Risk of cardiovascular and all-cause mortality 

in individuals with diabetes mellitus, impaired fasting glucose, and impaired glucose 

tolerance: the Australian Diabetes, Obesity, and Lifestyle Study (AusDiab). Circulation. 

2007;116:151-157. 

TNT Study: Substantial Risk of Cardiovascular 

Events Persists in Patients With CHD Despite 

Treatment With a Maximal Dose Statin 

Patients With Major 

Cardiovascular Event (%) 

20 

All Metabolic Syndrome 

18 

Atorvastatin 10 mg (n = 2820) 

16 


P < 0.0001 

14 

All Metabolic Syndrome, No Diabetes 

12 


10 


8 

P = 0.0002 

6 

4 

2 

Residual Risk 

0 

0 1 2 3 4 5 6 

Time to First Major Cardiovascular Event (Years) 

CHD = coronary heart disease; TNT = Treating to New Targets study 

Reprinted from Deedwania P, et al. Lancet 2006; 

368:919–928, with permission from Elsevier. 

Slide Source 



TNT Study: Substantial Risk of Cardiovascular Events Persists in Patients With 

CHD Despite Treatment With a Maximal Dose Statin 

In the subgroup of patients with metabolic syndrome and diabetes in the Treating to New 

Targets study, 80 mg of atorvastatin was more effective than 10 mg of atorvastatin at 

reducing the risk of major cardiovascular events. Although there was a robust reduction 

in risk among the patients who received the maximal dose of atorvastatin, a substantial 

residual risk remained despite maximal lowering of low-density lipoprotein. Furthermore, 

the residual risk of patients with metabolic syndrome and diabetes was nearly double that 

in patients without these metabolic disturbances. 

Reference: 

Deedwania P, Barter P, Carmena R, et al, for the Treating to New Targets Investigators. 

Reduction of low-density lipoprotein cholesterol in patients with coronary heart disease 

and metabolic syndrome: analysis of the Treating to New Targets study. Lancet. 

2006;368:919-928. 



TNT Study: Impact of Glucometabolic 

Characteristics on Risk of Major 

Cardiovascular Events Among All Patients 

Patients with Major 

Cardiovascular Event (%) 

16 

12 

8 

4 

0 

Low 

High-Density 

Lipoprotein 

Characteristic Absent 

Characteristic Present 

HR = 1.33 

HR = 1.30 

Fasting 

Glucose 

100 mg/dL 

HR = 1.24 HR = 1.18 HR = 1.48 

Body-Mass 

Index 

28 kg/m 2 

Triglycerides 

250 mg/dL 

Hypertension 

TNT = Treating to New Targets study 

Reprinted from Deedwania P, et al. Lancet. 2006; 


Slide Source 



TNT Study: Impact of Glucometabolic Characteristics on Risk of Major 

Cardiovascular Events Among All Patients 

The factors associated with residual risk are the criteria commonly used to make a 

diagnosis of metabolic syndrome. According to the Treating to New Targets study, 

patients who have low levels of high-density lipoprotein, a fasting glucose >100 mg/dL, 

obesity, hypertriglyceridemia, and hypertension are placed at risk despite the lowering of 

low-density lipoprotein with high-dose atorvastatin. These 5 factors could then represent 

additional targets for intervention with the hope that some of the residual risk could be 

reduced. At present, attention has been directed to the possibility that an intervention that 

lowers fasting glucose could remove some of this residual risk. 

Reference: 

Deedwania P, Barter P, Carmena R, et al, for the Treating to New Targets Investigators. 

Reduction of low-density lipoprotein cholesterol in patients with coronary heart disease 

and metabolic syndrome: analysis of the Treating to New Targets study. Lancet. 

2006;368:919-928. 



UKPDS: Hemoglobin A 1c and Rates for Myocardial 

Infarction and Microvascular Complications 

Adjusted Incidence per 

1,000 Person Years (%) 

80 

60 

40 

20 

Myocardial infarction 

Microvascular endpoints 

0 

5 6 7 8 9 10 11 

Updated Mean HbA 1c Concentration 

HbA 1c = hemoglobin A 1c (glycosylated) 

UKPDS = United Kingdom Prospective Diabetes Study 

Stratton IM, et al. BMJ. 2000;321:405–412; reproduced 

with permission from the BMJ Publishing Group. 

Slide Source 



UKPDS: Hemoglobin A 1c and Rates for Myocardial Infarction and Microvascular 

Complications 

In United Kingdom Prospective Diabetes Study, which examined the updated mean 

hemoglobin A 1c (HbA 1c ) on treatment and the incidence of both myocardial infarction 

(MI) and microvascular endpoints, there were graded increases across glycemia for the 

risk of these end-organ complications. The risk of microvascular disease was much 

greater than the risk for MI at the same HbA 1c concentration. These data support 

observations, over the years, that reductions in HbA 1c with treatment could produce 

robust decreases in microvascular endpoints. The slope of the curve of glycemic control 

related to MI risk is not as steep, indicating that if intervention is to be successful in 

reducing MI risk, then larger decreases in HbA 1c may be required. Of note is the fact that 

across the range of HbA 1c concentrations from 5.5% to 9.5%, the absolute risk for MI 

was greater than the risk for the development of microvascular disease. The mechanism 

by which glycemia increases risk for vascular disease has been the subject of intense 

scrutiny. 

Reference: 

Stratton IM, Adler AI, Neil HA, et al. Association of glycaemia with macrovascular and 

microvascular complications of type 2 diabetes (UKPDS 35): prospective observational 

study. BMJ. 2000;321:405-412. 



The Proinflammatory Milieu in Atheromata 

Is Mediated by RAGEs in Diabetes Mellitus 

RAGE = receptor for advanced glycosylated end-products 

Reprinted from Cipollone F, et al. Circulation. 2003;108:1070–1077, 


Slide Source 



The Proinflammatory Milieu in Atheromata Is Mediated by RAGEs in Diabetes 

Mellitus 

In this study by Cipollone et al., carotid endarterectomy specimens from diabetic patients 

were found to be distinctly different from those of nondiabetic patients. This study also 

provided in-vivo data demonstrating that atheromata in diabetic patients may have a 

different pathobiology. The diabetic carotid atheroma specimens contained localized 

dense infiltrates of mononuclear cells expressing surface markers consistent with active 

inflammation. The specimens from the nondiabetic patients did not show this degree of 

inflammatory infiltrate. Monocytes, macrophages, and lymphocytes reside in this region 

of the plaque because the receptors for advanced glycosylated end-products (RAGEs) are 

located in these areas, and the attachment of the RAGEs to the receptor induces a 

chemotactic response accounting for the inflammatory appearance of atheroma 

specimens from diabetic patients. Furthermore, the density of the RAGEs was related to 

the level of glycemia in these particular patients, thus providing a link between glycemia 

and vascular inflammation. The specimens from the diabetic patients expressed high 

concentrations of matrix metallinoproteinases in the area of inflammatory cells, but those 

of the nondiabetic patients did not. 

Let us now examine the possibility that the pharmacologic strategies used to lower 

glucose in both prediabetes and diabetes can reduce the risk of cardiovascular disease. 

Reference: 

Cipollone F, Iezzi A, Fazia M, et al. The receptor RAGE as a progression factor 

amplifying arachidonate-dependent inflammatory and proteolytic response in human 

atherosclerotic plaques: role of glycemic control. Circulation. 2003;108:1070-1077. 



Effect of Acarbose on the Probability of 

Remaining Free of Cardiovascular Disease 

Probability of Any 

Cardiovascular Event 

0.06 

0.05 

0.04 

0.03 

0.02 

0.01 

P = 0.04 (Log-Rank Test) 

P = 0.03 (Cox Proportional Model) 

Placebo 

Acarbose 

0.00 

0 

No. at Risk 

Placebo 686 

Acarbose 682 

100 200 300 400 500 600 700 800 900 1000 1100 1200 1300 1400 

675 

659 

667 

635 

658 

622 

643 

608 

Days After Randomization 

638 

601 

633 

596 

627 

590 

615 

577 

611 

567 

604 

558 

519 

473 

424 

376 

332 232 

286 203 

Chiasson JL, et al. JAMA. 2003;290;486–494. Copyright 

© 2003 American Medical Association. All rights reserved. 

Slide Source 



Effect of Acarbose on the Probability of Remaining Free of Cardiovascular Disease 

In the STOP-NIDDIM trial, Chiasson et al. (2002) showed that patients with an impaired 

glucose tolerance who were randomized to receive acarbose had a lower rate of 

conversion to type 2 diabetes over 3 years. In addition, the authors examined the effect of 

acarbose on the development of major cardiovascular events, including coronary heart 

disease (myocardial infarction, new angina, revascularization procedures), cardiovascular 

death, congestive heart failure, cerebrovascular events, and peripheral vascular disease. 

These subjects also showed, with a significant P value, a lower risk for any 

cardiovascular event. 

References: 

Chiasson JL, Josse RG, Gomis R, Hanefeld M, Karasik A, Laakso M, for the STOP- 

NIDDM Trial Research Group. Acarbose treatment and the risk of cardiovascular disease 

and hypertension in patients with impaired glucose tolerance: the STOP-NIDDM trial. 

JAMA. 2003;290:486-494. 


NIDDM Trial Research Group. Acarbose for prevention of type 2 diabetes mellitus: the 

STOP-NIDDM randomised trial. Lancet. 2002;359:2072-2077. 



STOP-NIDDM Trial: Acarbose Prevents Type 2 

Diabetes Mellitus and Cardiovascular Events in 

Subjects With Impaired Glucose Tolerance 

Study Population 

Acarbose 

n=662 

Placebo 

n=888 

Hazard Ratio 

(95% CI) 

P 

Value 

Favors 

Acarbose 

Favors 

Placebo 


1 

12 

0.09 (0.01–0.72) 

0.02 

Angina 

5 

12 

0.45 (0.16–1.28) 

0.13 

Revascularization 

procedures 

11 

20 

0.61 (0.29–1.26) 

0.18 

Cardiovascular death 

1 

2 

0.55 (0.05–6.11) 

0.63 

Congestive heart failure 

0 

2 

Cerebrovascular stroke 

2 

4 

0.56 (0.10–3.07) 

0.51 

Any cardiovascular 

event 

15 

32 

0.51 (0.28–0.95) 

0.03 

CI = confidence interval 

0 0.5 1.0 1.5 

Hazard Ratio 

Chiasson JL, et al. JAMA. 2003;290;486–494. Copyright © 2003 

American Medical Association. All rights reserved. 

Slide Source 



STOP-NIDDM Trial: Acarbose Prevents Type 2 Diabetes Mellitus and 

Cardiovascular Events in Subjects With Impaired Glucose Tolerance 

Examining the different events between the acarbose and placebo populations in the 

STOP-NIDDM trial showed that there were 15 events in the acarbose group and 32 

events in the placebo groups, suggesting that a treatment focused on postprandial 

hyperglycemia could reduce the risk for cardiovascular events. These intriguing data 

await further confirmation and additional studies. 

Reference: 


NIDDM Trial Research Group. Acarbose treatment and the risk of cardiovascular disease 

and hypertension in patients with impaired glucose tolerance: the STOP-NIDDM trial. 

JAMA. 2003;290:486-494. 



Controlling Postprandial Hyperglycemia Leads to Regression of 

Carotid Atherosclerosis in Patients With Type 2 Diabetes Mellitus 

Repaglinide Glyburide 

1.4 

*P = 0.01 

Postprandial Postprandial 1.3 

260 

Peak 

Peak 

1.2 

P 0.001 P 0.01 

220 

1.1 

* 

180 

1.0 

* 

140 

0.9 

100 

Before After Before After 

0.8 

260 

0.7 

220 

0.6 

180 

0.5 

140 

0.4 

100 

P 0.001 P 0.01 

0 

Before After Before After 

0 60 120 0 60 120 

Minutes 

Repaglinide Glyburide 

Glucose (mg/dL) 

Carotid Intima-Media Thickness 

(mm) 

C-IMT Regression Associated With PPG, IL-6, and CRP 

C-IMT = carotid intima-media thickness; PPG = postprandial glucose; IL-6 = interleukin 6; 

CRP = C-reactive protein 

Reprinted from Esposito K, et al. Circulation. 2004;110:214–219, 


Slide Source 



Controlling Postprandial Hyperglycemia Leads to Regression of Atherosclerosis in 

Patients With Type 2 Diabetes Mellitus 

Esposito et al. (2004) investigated repaglinide, a prandial secretagogue, as a strategy for 

reducing postprandial hyperglycemia in patients with type 2 diabetes mellitus. Patients 

enrolled in the study were randomized to receive either repaglinide or glyburide. Those 

who received repaglinide had a reduction in the progression of carotid intima-media 

thickness when compared to those who received glyburide. The data from this study 

would support the findings of the STOP-NIDDM trial (previous slide). 

Reference: 

Esposito K, Giugliano D, Nappo F, Marfella R, for the Campanian Postprandial 

Hyperglycemia Study Group. Regression of carotid atherosclerosis by control of 

postprandial hyperglycemia in type 2 diabetes mellitus. Circulation. 2004;110:214-219. 



Controlling Postprandial Hyperglycemia Leads to 

Regression of Atherosclerosis in Patients With 

Type 2 Diabetes Mellitus (Continued) 

• 78 drug-naïve type 2 diabetes mellitus patients with hemoglobin A 1c

Glycemic Control and Macrovascular 

Disease in Patients With Type 1 or Type 2 

Diabetes: Meta-analysis analysis of Clinical Trials 

Trials 

Holman 

Verrillo 

Lauritzen 

Feldt- 

Rasmussen 

DCCT PP 

DCCT SI 

SDIS 

MCSG 

Overall 

Trials in Type 1 Diabetes 

Favors 

Intensified 

Glycemic 

Control 

Favors 

Conventional 

Glycemic 

Control 

0.01 0.1 .5 1 2 10 100 

Incidence Rate Ratio 

% 

Weight 

1.5 

6.6 

1.5 

1.7 

35.4 

44.0 

7.8 

1.5 

100.0 

Reprinted from Stettler C, et al. Am Heart J. 2006; 


Trials in Type 2 Diabetes 

Favors Favors 

Intensified Conventional 

Glycemic Glycemic 

Trials 

Control Control 

Veterans 

Affairs 

UKPDS 1 

UKPDS 2 

UKPDS 3 

Kumamoto PP 

Kumamoto SI 

Overall 

0.01 0.1 0.5 1 2 10 100 

Incidence Rate Ratio 

% 

Weight 

4.3 

53.6 

27.2 

14.3 

0.1 

0.5 

100.0 

Slide Source 



Glycemic Control and Macrovascular Disease in Patients With Type 1 or Type 2 

Diabetes: Meta-analysis of Clinical Trials 

Stettler et al. (2006) evaluated those trials in which pharmacologic treatment of 

hyperglycemia in patients with type 2 diabetes was evaluated with respect to 

macrovascular disease. They found that, at best, intensified glycemic control was 

associated with only a modest reduction in macrovascular disease. Although these data 

are promising, none of the trials that were evaluated showed the degree of dramatic 

reduction that one might expect based on the epidemiological correlation between the 

level of glycemia and cardiovascular risk. 

Reference: 

Stettler C, Allemann S, Jüni P, et al. Glycemic control and macrovascular disease in types 

1 and 2 diabetes mellitus: meta-analysis of randomized trials. Am Heart J. 2006;152:27- 

38. 



DCCT-EDIC: 

Long-term Risk of 

Macrovascular Complications 

Hemoglobin A 1C 

12% 

10% 

8% 

6% 

Conventional 

Intensive 

P < 0.001 P < 0.001 P = 0.61 

Cumulative Incidence 

0.12 

0.10 

0.08 

0.06 

0.04 

0.02 

Any Cardiovascular Outcome 

42% risk reduction 

P = 0.02 

Conventional 

Intensive 

DCCT 

End of 

Randomized 

Treatment 

EDIC 

Year 1 

EDIC 

Year 7 

0.00 

0 2 4 6 8 10 12 14 16 18 20 

Years Since Entry* 

*Diabetes Control and Complications Trial (DCCT) ended and Epidemiology of Diabetes 

Interventions and Complications (EDIC) began in year 10 (1993). Mean follow-up: 17 years. 

DCCT/EDIC Research Group. JAMA. 2002;287:2563-2569. Copyright © 2002 

American Medical Association. All rights reserved. | Nathan DM, et al. N Engl J 

Med. 2005;353:2643-2653. Copyright © 2005 Massachusetts Medical Society. 

All rights reserved. 

Slide Source 



DCCT-EDIC: Long-term Risk of Macrovascular Complications 

At the end of the randomized treatment phase in the Diabetes Control and Complications 

Trial, the research group found a difference in the concentration of hemoglobin A 1c 

between the patients with type 1 diabetes in the intensive treatment group and those in the 

conventional treatment group. At the end of the trial, there was a nonsignificant reduction 

in cardiovascular outcome in the intensively treated group. The trial ended at 

approximately 9 years; afterward, there was convergence of treatments and similar levels 

of glycemic control were achieved. There was persistent benefit, however, among the 

intensively treated group such that there was a statistically significant reduction in 

cardiovascular disease when compared to the conventionally treated group in the followup 

phase (up to 20 years) of the study. These data would indicate that 10 years of 

intensive treatment yielded a cardiovascular benefit during the first 10 years that was 

sustained and became greater in the follow-up phase. 

References: 

Diabetes Control and Complications Trial/Epidemiology of Diabetes Interventions and 

Complications Research Group. Effect of intensive therapy on the microvascular 

complications of type 1 diabetes mellitus. JAMA. 2002;287:2563-2569. 

Nathan DM, Cleary PA, Backlund JY, et al, for the Diabetes Control and Complications 

Trial/Epidemiology of Diabetes Interventions and Complications (DCCT/EDIC) Study 

Research Group. Intensive diabetes treatment and cardiovascular disease in patients with 

type 1 diabetes. N Engl J Med. 2005;353:2643-2653. 



UKPDS: Metformin Is Associated With a 

Reduction in Cardiovascular Events 

9 

Glibenclamide Insulin 

Metformin 

Sulfonylurea/ 

Insulin 

Hemoglobin A 1c 

8 

7 

6 

Conventional 

Chlorpropamide 

Metformin 

5 

0 2 4 6 8 10 

Years 

UKPDS = United Kingdom Prospective 

Diabetes Study 

Reprinted in an adapted form from UKPDS Group. Lancet 

1998;352:854–865, with permission from Elsevier. 

Diabetes-related 

death 

All-cause 

mortality 

Any diabetesrelated 

endpoint 

Myocardial 

infarction 

Stroke 

Mean 

Change 

in Risk* 

42% 

36% 

32% 

39% 

41% 

P Value 

0.017 

0.011 

0.002 

0.010 

0.13 

Mean 

Change 

in Risk* 

20% 

8% 

7% 

21% 

14% 

P Value 

0.19 

0.49 

0.46 

0.11 

0.6 

*Compared with conventional therapy based on 

diet/exercise in overweight patients 

Slide Source 



UKPDS: Metformin Is Associated With a Reduction in Cardiovascular Events 

In the United Kingdom Prospective Diabetes Study, metformin emerged as one treatment 

for diabetes that was associated with a decrease in both myocardial infarction and stroke. 

Despite the similar concentrations of hemoglobin A 1c achieved with insulin, various 

sulfonylureas and metformin, the use of metformin in the small subgroup of patients with 

obesity did show this cardiovascular benefit. These data helped to solidify the belief that 

the use of metformin as an initial therapy in the treatment of type 2 diabetes may be 

preferable from a cardiovascular point of view. 

Reference: 

UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose 

control with metformin on complications in overweight patients with type 2 diabetes 

(UKPDS 34). Lancet. 1998;352:854-865. 



Non–UKPDS Trials: 

Metformin vs. Other Interventions 

RR (Fixed) 95% CI 

Study 

All-cause mortality 

DeFronzo 1995 

Horton 2000 

Subtotal (95% CI) 

MET 

n/N 

1/210 

1/178 

388 

Favours 

Comparison Metformin 

0/209 

0/172 

381 

Favours Weight 

Comparison (%) 

49.6 

50.4 

100.0 

RR (fixed) 

95% CI 

2.99 [0.12, 72.88] 

2.90 [0.12, 70.69] 

2.94 [0.31, 28.16] 

Ischemic heart disease 

DeFronzo 1995 

1/210 

0/209 

25.2 

2.99 [0.12, 72.88] 

Hallsten 2002 

1/13 

0/14 

24.2 

3.21 [0.14, 72.55] 

Horton 2000 

1/178 

0/172 

25.5 

2.90 [0.12, 70.69] 

Teupe 1991 

1/50 

0/50 

25.1 

3.00 [0.13, 71.92] 

Subtotal (95% CI) 

451 

445 

100.0 

3.02 [0.62, 14.75] 

0.01 0.1 1 10 100 

CI = confidence interval; MET = metformin; RR = relative risk; 


Reprinted from Saenz A, et al. Cochrane Database Syst Rev. 

2005;(3):CD002966, with permission from Wiley. 

Slide Source 



Non–UKPDS Trials: Metformin vs. Other Interventions 

When one looks at metformin data in studies outside of the United Kingdom Prospective 

Diabetes Study, however, there apparently is no evidence of cardiovascular benefit, as in 

this meta-analysis conducted by Saenz et al. (2005). Furthermore, these other studies tend 

to have small numbers of patients. 

Reference: 

Saenz A, Fernandez-Esteban I, Mataix A, Ausejo M, Roque M, Moher D. Metformin 

monotherapy for type 2 diabetes mellitus. Cochrane Database Syst Rev. 

2005;(3):CD002966. 

Non–UKPDS Trials: 

Metformin vs. Conventional Treatment 

RR (Fixed) 95% CI 

UKPDS 

Any diabetes-related 

outcomes 

MET 

n/N 

98/342 

Conventional Favours 

n/N metformin 

160/411 

Favours Weight 

comparison (%) 

100.0 

RR (fixed) 

95% CI 

0.74 [0.60, 0.90] 

Diabetes-related 

death 

28/342 

55/411 

100.0 

0.61 [0.40, 0.94] 

All-cause mortality 

50/342 

89/411 

100.0 

0.68 [0.49, 0.93] 


39/342 

73/411 

100.0 

0.64 [0.45, 0.92] 

Stroke 

12/342 

23/411 

100.0 

0.63 [0.32, 1.24] 

Peripheral vascular 

disease 

6/342 

9/411 

100.0 

0.80 [0.29, 2.23] 

Microvascular 

24/342 

38/411 

100.0 

0.76 [0.46, 1.24] 

0.2 0.5 1 2 5 

CI = confidence interval; MET = metformin; RR = relative risk; 


Reprinted from Saenz A, et al. Cochrane Database Syst Rev. 

2005;(3):CD002966, with permission from Wiley. 

Slide Source 





Non-UKPDS Trials: Metformin vs. Conventional Treatment 

When one looks at metformin data in studies outside of the United Kingdom Prospective 

Diabetes Study, however, there apparently is no evidence of cardiovascular benefit, as in 

this meta-analysis conducted by Saenz et al. (2005). Furthermore, these other studies tend 

to have small numbers of patients. 

Reference: 

Saenz A, Fernandez-Esteban I, Mataix A, Ausejo M, Roque M, Moher D. Metformin 

monotherapy for type 2 diabetes mellitus. Cochrane Database Syst Rev. 

2005;(3):CD002966. 

Nissen and Wolski Meta-analysis: 

analysis: 

Rates of Myocardial Infarction and 

Death from Cardiovascular Causes 

UKPDS 

Rosiglitazone 

Control 

Odds Ratio 

(95% CI) 

p 

value 

Myocardial Infarction 

Small trials 

44/10,285 (0.43%) 

22/6105 (0.36%) 

1.45 (0.88–2.39) 

0.15 

DREAM 

15/2,635 (0.57%) 

9/2634 (0.34%) 

1.65 (0.74–3.68) 

0.22 

ADOPT 

27/1,456 (1.85%) 

41/2895 (1.44%) 

1.33 (0.80–2.21) 

0.27 

Total 

86/14371 (0.60%) 

72/11634 (0.62%) 1.43 (1.03–1.98) 

0.03 

Death from Cardiovascular Causes 

Small trials 

25/6,845 (0.36%) 

7/3,980 (0.18%) 

2.40 (1.17–4.91) 

0.02 

DREAM 

12/2,635 (0.46%) 

10/2,634 (0.38%) 

1.20 (0.52–2.78) 

0.67 

ADOPT 

2/1,456 (0.14%) 

5/2,895 (0.17%) 

0.80 (0.17–3.86) 

0.78 

Total 

39/10648 (0.37%) 

22/9188 (0.24%) 

1.64 (0.98–2.74) 

0.06 

CI = confidence interval; UKPDS = United Kingdom Prospective Diabetes Study 

Nissen SE, Wolski K. N Engl J Med. 2007; 356. 2457–2471. Copyright 

© 2007 Massachusetts Medical Society. All rights reserved. 

Slide Source 



Nissen and Wolski Meta-analysis: Rates of Myocardial Infarction and Death from 

Cardiovascular Causes 

Based on their meta-analysis of the cardiovascular safety of rosiglitazone, Nissen and 

Wolski (2007) raised the question of whether there is a risk for myocardial infarction 

among diabetic patients treated with rosiglitazone versus other treatments. In the studies 

they evaluated, cardiovascular endpoints were neither adjudicated nor were they primary 

endpoints; the mean follow-up period for most of the evaluated studies was only 6 

months. These observations raised concern about whether the preclinical studies of 

rosiglitazone, which had shown the drug to have antiatherosclerotic affects, were relevant 

to patients with type 2 diabetes. Since then, there have been numerous studies whose 

findings conflict with those of this meta-analysis. 

Reference: 

Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and 

death from cardiovascular causes. N Engl J Med. 2007;356:2457-2471. 



Balance of Evidence: Is Rosiglitazone 

Associated With Cardiovascular Risk? 

MI = myocardial infarction 

MET = metformin 

SU = sulfonylurea 

PIO = pioglitazone 

FDA Analysis 

MI signal with 

insulin and nitrates 

GSK ICT analysis 

MI signal 

Nissen et al. 

MI signal 

ACCORD 

Mortality not linked to to any 

specific diabetes drug 

ADOPT 

No significant risk 

Comparable to to MET, SU 

Lago et et al. Lancet. 


Comparable to to PIO 

RECORD 


Comparable to to MET, SU 

McAfee et et al. 


Comparable to to MET/SU 

Rosen et al. 


Comparable to to PIO 

“…[W]e believe that only prospective clinical trials designed for the specific 

purpose of establishing the cardiovascular benefit or risk of rosiglitazone 

will resolve the controversy about its safety.” — Diamond et al., 2007 

Diamond GA, et al. Ann Intern Med. 2007;147:578–581 | Home PD. N Engl J Med. 

2007;357:28–38 | Krall RL. Lancet. 2007;369:1995–1996. | Lago RM, et al. Lancet. 

2007;370:1129–1136 | McAfee AT, et al. Pharmacoepidemiol Drug Saf. 2007; 

16:711–725 | Nissen SE, et al. N Engl J Med. 2007;356:2457–2471 | Rosen CJ. 

N Engl J Med. 2007;357:844–846. 

Slide Source 



Balance of Evidence: Is Rosiglitazone Associated With Cardiovascular Risk? 

Recently published data from the ACCORD and ADVANCE studies — both of which 

evaluated whether lowering the hemoglobin A 1c concentration (below its current 

recommended target of 7%) is associated with cardiovascular benefit — did not show any 

link between rosiglitazone and an excess risk for myocardial infarction. Furthermore, a 

meta-analysis conducted by Lago et al. (2007) did not show any significant risk for 

cardiovascular death when they compared rosiglitazone to other treatments, particularly 

pioglitazone. The interim analysis of the RECORD trial also showed that rosiglitazone 

carries a risk for cardiovascular disease that is comparable to metformin and 

sulfonylureas. 

ACCORD = Action to Control Cardiovascular Risk in Diabetes 

ADVANCE = Action in Diabetes and Vascular Disease: Preterax and Diamicron MR 

Controlled Evaluation 

RECORD = Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycemia 

in Diabetes 

References: 

Diamond GA, Bax L, Kaul S. Uncertain effects of rosiglitazone on the risk for 

myocardial infarction and cardiovascular death. Ann Intern Med. 2007;147:578-581. 

Home PD, Pocock SJ, Beck-Nielsen H, et al, for the RECORD Study Group. 

Rosiglitazone evaluated for cardiovascular outcomes—an interim analysis. N Engl J Med. 

2007;357:28-38. 

Krall RL. Cardiovascular safety of rosiglitazone. Lancet. 2007;369:1995-1996. 



Lago RM, Singh PP, Nesto RW. Congestive heart failure and cardiovascular death in 

patients with prediabetes and type 2 diabetes given thiazolidinediones: a meta-analysis of 

randomised clinical trials. Lancet. 2007;370:1129-1136. 

McAfee AT, Koro C, Landon J, Ziyadeh N, Walker AM. Coronary heart disease 

outcomes in patients receiving antidiabetic agents. Pharmacoepidemiol Drug Saf. 

2007;16:711-725. 

Nissen SE, Wolski K. Effect of rosiglitazone on the risk of myocardial infarction and 

death from cardiovascular causes. N Engl J Med. 2007;356:2457-2471. 

Rosen CJ. The rosiglitazone story—lessons from an FDA Advisory Committee meeting. 

N Engl J Med. 2007;357:844-846. 

PROactive: Time to Primary Composite 

Endpoint: Pioglitazone vs. Placebo 

Kaplan-Meier Event Rate 

0.25 

0.20 

N events: 

Placebo 572 / 2633 

Pioglitazone 514 / 2605 

0.15 What if this was a 

3-Year Estimate: 

6-month trial ? 

23.5% 

0.10 

21.0% 

HR 95% CI p value 

0.05 

Pioglitazone 

0.80 

0.90 

vs. placebo 

1.02 

0.095 

0.0 

0 6 12 18 24 30 36 

No. at Risk: 5238 5018 4786 4619 4433 4268 693 

Time from Randomization (Months) 

CI = confidence interval; HR = hazard ratio 

Reprinted from Dormandy JA, et al. Lancet. 2005;366: 

1279–1289, with permission from Elsevier. 

Slide Source 



PROactive: Time to Primary Composite Endpoint: Pioglitazone vs. Placebo 

The Prospective Pioglitazone Clinical Trial in Macrovascular Events (PROactive) 

evaluated patients with type 2 diabetes and a history of cardiovascular disease and 

randomized them to receive either pioglitazone or placebo. The primary endpoint showed 

a nonstatistical benefit in favor of pioglitazone. 

Reference: 

Dormandy JA, Charbonnel B, Eckland DJ, et al, for the PROactive investigators. 

Secondary prevention of macrovascular events in patients with type 2 diabetes in the 

PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a 

randomised controlled trial. Lancet. 2005;366:1279-1289. 



PROactive: Difference in Number of First Events 

Comprising the Primary Composite Endpoint: 

Pioglitazone vs. Placebo 

Difference in Number of 

First Events 

20 

10 

0 

-10 

-20 

-12 

Pioglitazone: n = 2605 

Placebo: n = 2633 

-10 

Death Nonfatal Silent Stroke MLA ACS Revascularization 

MI* MI coronary leg 

ACS = acute coronary syndrome; MI = myocardial infarction; MLA = major leg 

amputation 

Dormandy JA, et al. Lancet. 2005;366:1279–1289. 

-3 

*Excluding silent myocardial infarction 

-6 

-20 -21 

0 

+14 

Slide Source 



PROactive: Difference in Number of First Events Comprising the Primary 

Composite Endpoint: Pioglitazone vs. Placebo 

The primary endpoint shown on this slide contained a variety of cardiovascular 

outcomes, including death, myocardial infarction, stroke, acute coronary syndromes, and 

revascularization of either the coronary arteries or the peripheral arteries. Overall, the 

more “traditional” cardiovascular endpoints occurred less often in the pioglitazone group; 

however, this group had more coronary leg revascularizations than did the placebo group. 

Reference: 







PROactive: Pioglitazone Reduces “Hard” 

Coronary Heart Disease Endpoints 


Time to Fatal/Nonfatal MI 

Time to Acute Coronary 

(Excluding Silent MI) 

Syndrome 

0.10 

HR 95% CI P value 

0.06 

HR 95% CI P value 

PIO vs. 

0.52 

PIO vs. 

0.41 

0.72 

.045 

0.63 

.035 

placebo 

0.99 

placebo 

0.97 

0.08 

0.05 

0.04 

0.06 

-28% -37% 

0.03 

0.04 

0.02 

0.02 

PIO (65/1230) 

PIO (35/1230) 

0.01 

Placebo (88/1215) 

Placebo (54/1215) 

0.00 

0.00 

0 6 12 18 24 30 36 

0 6 12 18 24 30 36 




Prespecified 

Post-Hoc Exploratory Analysis 

CHD = coronary heart disease; CI = confidence interval; HR = hazard ratio; MI = 

myocardial infarction; PIO = pioglitazone 

Reprinted from Erdmann E, et al. J Am Coll Cardiol. 2007;49:1772-1780, 

with permission from Elsevier | Erdmann E. PROactiveresults.com. Available 

at: http://www.proactive-results.com/html/analysis.htm 

results.com/html/analysis.htm. © On Screen 

Productions Ltd. All rights reserved. 

Slide Source 



PROactive: Pioglitazone Reduces “Hard” Coronary Heart Disease Endpoints 

In a prespecified secondary endpoint study in the PROactive trial, which examined time 

to fatal or nonfatal myocardial infarction (MI), patients who were treated with 

pioglitazone had a 28% reduction in MIs when compared to those who were treated with 

placebo. In a post-hoc exploratory analysis, the pioglitazone group also benefited, with a 

reduction in the time to occurrence of acute coronary syndromes. These data would 

indicate that pioglitazone is not associated with an excess risk for MI, although the drug 

did increase the risk for congestive heart failure (CHF) in this trial. The increase in CHF 

risk is not surprising, since these patients had cardiovascular disease; many of them were 

also on insulin therapy and were randomized to receive pioglitazone at the highest dosage 

range. 

References: 

Erdmann E, for the PROactive Investigators. The effect of pioglitazone on recurrent 

myocardial infarction in 2445 patients with type 2 diabetes and previous myocardial 

infarction: results from the PROactive study. PROactiveresults.com. 

http://www.proactive-results.com/html/analysis.htm. Accessed November 2008. 

Erdmann E, Dormandy JA, Charbonnel B, Massi-Benedetti M, Moules IK, Skene AM, 

for the PROactive Investigators. The effect of pioglitazone on recurrent myocardial 

infarction in 2,445 patients with type 2 diabetes and previous myocardial infarction: 

results from the PROactive (PROactive 05) Study. J Am Coll Cardiol. 2007;49:1772- 

1780. 



Factors Possibly Contributing to the 

Beneficial Effect of Pioglitazone 

Hemoglobin A 1c 

−0.5% 

HDL cholesterol +8.9% 

Blood pressure 

−3 mm Hg 

LDL/HDL 5.3% 

Triglycerides 

−13.2% 

vs. placebo 

C-reactive protein 

Insulin sensitivity 

Not measured 

Not measured 

HDL = high-density lipoprotein; LDL = low-density lipoprotein 

Reprinted from Dormandy JA, et al. Lancet 2005;366: 

1279–1289, with permission from Elsevier. 

Slide Source 



Factors Possibly Contributing to the Beneficial Effect of Pioglitazone 

The factors possibly contributing to the beneficial effect of pioglitazone include: a 

modest reduction of 0.5% in the concentration of hemoglobin A 1c , an increase of 

approximately 9% in the concentration of high-density lipoprotein (HDL), a drop of 3 

mm Hg in blood pressure, an improvement in the low-density lipoprotein (LDL):HDL 

ratio, and a drop in the concentration of triglycerides. The aggregate directional change in 

these factors may have accounted for the benefit of pioglitazone when compared to 

placebo in the PROactive trial, as mentioned earlier. 

Reference: 







Risk of Congestive Heart Failure and Cardiovascular 

Death With Thiazolidinediones 

Risk of CHF 

ADOPT (RSG) 

Dargie et al. (RSG) 

Mazzone et al. (Pio) 

DREAM (RSG) 

PPAR (RSG) 

PROactive (Pio) 

RECORD (RSG) 

TOTAL 

Risk of CHF 

ADOPT (RSG) 

Dargie et al. (RSG) 

Mazzone et al. (Pio) 

DREAM (RSG) 

PPAR (RSG) 

PROactive (Pio) 

RECORD (RSG) 

TOTAL 

Risk Ratio (95% Confidence Interval) 

Decreased Risk Increased Risk 

0.1 0.2 0.5 1 2 5 10 

Risk Ratio (95% Confidence Interval) 

Decreased Risk Increased Risk 

0.1 0.2 0.5 1 2 5 10 

Weight 

12.0% 

7.3% 

1.1% 

5.0% 

1.2% 

49.0% 

23.5% 

100.0% 

Weight 

9.8% 

6.4% 

1.4% 

15.2% 

1.9% 

20.9% 

44.5% 

100.0% 

Risk Ratio (95% CI) 

1.49 (0.62, 3.53) 

1.81 (0.55, 6.02) 

2.97 (0.12, 72.63) 

7.00 (1.59, 30.76) 

2.88 (0.12, 69.94) 

1.31 (1.03, 1.67) 

2.24 (1.27, 3.96) 

1.72 (1.21, 2.42) 

Test for overall effect: p = 0.002 

Risk Ratio (95% CI) 

0.83 (0.29, 2.35) 

1.30 (0.36, 4.07) 

0.99 (0.06, 15.75) 

1.20 (0.52, 2.77) 

0.48 (0.04, 5.21) 

1.01 (0.50, 2.06) 

0.83 (0.51, 1.35) 

0.93 (0.67, 1.29) 

Test for overall effect: p = 0.068 

Reprinted from Lago RM, et al. Lancet. 2007; 


Slide Source 



Risk of Congestive Heart Failure and Cardiovascular Death With 

Thiazolidinediones 

A meta-analysis by Lago et al. (2007) examined randomized clinical trials in which 

cardiovascular (CV) events were either endpoints or were adjudicated by an expert panel. 

These investigators found that there was no excess risk of CV-related death when 

thiazolidinediones were compared to other treatments and when rosiglitazone was 

compared to pioglitazone. 

Reference: 

Lago RM, Singh PP, Nesto RW. Congestive heart failure and cardiovascular death in 

patients with prediabetes and type 2 diabetes given thiazolidinediones: a meta-analysis of 

randomised clinical trials. Lancet. 2007;370:1129-1136. 

Annual Incidence of Congestive Heart Failure in 

Randomized Clinical Trials of PPAR- Agonists 

Trial 

Disease 

N 

Diagnosed CHF 

TZD 

Comparator 

DREAM 

IFG /IGT 

5269 

Adjudicated 

RSG 0.18% 

Placebo 0.03% 

ADOPT 

T2DM 

4351 

Adverse events 

RSG 0.21% 

SU 0.5% 

Metformin 0.21% 

RECORD 

T2DM 

4447 

Hospital CHF, 

adjudicated, and 

pending 

RSG 0.56% 

Metformin / SU 

0.26% 

CHICAGO 

T2DM 

462 

Adjudicated CHF 

Pio 0.62% 

SU (0) 

PPAR 

Metabolic Syndrome 

CAD + PCI 

200 


RSG 1.2% 

Placebo (0) 

PROactive 

T2DM / CVD 

5238 

Hospitalized 

Pio 2.0% 

Placebo 1.4% 

PROactive 

T2DM / CVD Status 

Post MI 

2445 

Hospitalized 

Pio 2.6% 

Placebo 1.8% 

Dargie et al. 

T2DM / NYHA I/II CHF 

224 


RSG 6.3% 

Placebo 3.5% 

CAD = coronary artery disease; CHF= congestive heart failure; CVD = cardiovascular disease; IFG = 

impaired fasting glucose; IGT = impaired glucose tolerance; MI = myocardial infarction; NYHA = New 

York Heart Association; PCI = percutaneous coronary intervention; Pio = pioglitazone; PPAR = 

peroxisome proliferator-activated receptor; RSG = rosiglitazone; SU = sulfonylurea; T2DM = type 2 

diabetes mellitus; TZD = thiazolidinedione 

Slide Source 





Annual Incidence of Congestive Heart Failure in Randomized Clinical Trials of 

PPAR- Agonists 

The major problem associated with the use of thiazolidinediones, in general, has been the 

risk of congestive heart failure (CHF). This risk varies, depending on whether the patient 

has pre-existing cardiovascular disease. As one can see in this slide, which summarizes a 

large number of randomized clinical trials, the annual incidence of CHF varies greatly. 

For example, the annual risk of CHF was 0.21% per year in the ADOPT trial, and CHFrelated 

hospitalization occurred annually in 2.00% of the patients in the PROactive trial. 

PROactive: Risk Factors for Serious 

Congestive Heart Failure 

Creatinine 130 µmol/L 

Diuretic use 

LDL cholesterol >4 mmol/L 

(versus

Clinical Trials Will (or Should) Answer 

Important Questions About Type 2 Diabetes 

Mellitus and Cardiovascular Risk 

Question 1: 

Does treatment-directed 

lowering of HbA 1c 1c 

reduce 

the risk of cardiovascular 

disease? 

• ACCORD 

• ADVANCE 

• VADT 

• ORIGIN 

Question 2: 

Does it matter which 

diabetes treatment is used 

to achieve a lower HbA 1c 1c 

concentration? 

• PERISCOPE 

• APPROACH 

• BARI-2D 

• RECORD 

• VICTORY 

HbA 1c = hemoglobin A 1c 

Slide Source 



Clinical Trials Will (or Should) Answer Important Questions About Type 2 

Diabetes Mellitus and Cardiovascular Risk 

There are two major questions regarding type 2 diabetes and cardiovascular risk. First, 

does treatment-directed lowering of the hemoglobin A 1c concentration reduce the risk of 

cardiovascular disease? We have received some answers to this question from the 

findings of the recent ACCORD, ADVANCE, and VADT studies. The ORIGIN trial is 

underway and is evaluating whether giving insulin to patients with prediabetes or newonset 

diabetes can reduce cardiovascular disease. 

Second, does it matter which diabetes treatment is used to achieve a lower concentration 

of hemoglobin A 1c ? The PERIOSCOPE and APPROACH trials each looked at the 

progression of atherosclerosis by using intracoronary ultrasound to compare the effects of 

treatment with thiazolidinediones or sulfonylureas. The BARI-2D trial is evaluating 

whether an insulin-sensitizing approach is better than an insulin-providing approach in 

reducing cardiovascular events in patients with type 2 diabetes and coronary artery 

disease. The RECORD trial is comparing rosiglitazone to sulfonylureas and metformin 

with regard to cardiovascular endpoints, and the VICTORY trial is examining the 

progression of disease in saphenous vein grafts in diabetic patients who were randomized 

to receive rosiglitazone or placebo. 

ACCORD = Action to Control Cardiovascular Risk in Diabetes 

ADVANCE = Action in Diabetes and Vascular Disease: Preterax and Diamicron MR 


APPROACH = Assessment on the Prevention of Progression by Rosiglitazone on 

Atherosclerosis in diabetes patients with Cardiovascular History 

BARI-2D = Bypass Angioplasty Revascularization Investigations 2 Diabetes 



ORIGIN = Outcome Reduction with Initial Glargine Intervention 

PERISCOPE = Pioglitazone Effect on Regression of Intravascular Sonographic Coronary 

Obstruction Prospective Evaluation 

RECORD = Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycemia 

in Diabetes 

VADT = Veterans Affairs Diabetes Trial 

VICTORY = Vein-Coronary Atherosclerosis and Rosiglitazone After Bypass Surgery 

ACCORD: Deaths in Intensive vs. Standard 

Glycemic Control Groups: Preliminary Results 

Deaths, n 

Rate per 1,000 

patients/year 

Standard Glycemic Control 

(Hemoglobin A 1c 7.0–7.9%) 

203 

11 

Intensive Glycemic 

Control 

(Hemoglobin A 1c ,

http://www.nhlbi.nih.gov/health/prof/heart/other/accord/remarks.pdf. Dated February 6, 

2008. Accessed November 2008. 

National Heart Lung and Blood Institute. For safety, NHLBI changes intensive blood 

sugar treatment strategy in clinical trial of diabetes and cardiovascular disease. National 

Heart Lung and Blood Institute Web site. http://www.nih.gov/news/health/feb2008/nhlbi- 

06.htm. Dated February 6, 2008. Accessed November 2008. 

ADVANCE: Action in Diabetes and Vascular Disease: 

Preterax and Diamicron MR Controlled Evaluation 

Primary objective: 

To determine the effect of blood pressure treatment (ACE-inhibitor 

+ diuretic vs. placebo) and glycemic intervention (intensive vs. 

standard) on microvascular and macrovascular complications in 

patients with type 2 diabetes mellitus (2 2 factorial design) 

Patient population: Type 2 diabetes (hypertensive + nonhypertensive) (N = 11,140) 

Glycemic Control 

Blood Pressure Intervention 

Intensive* (HbA 1c ≤6.5%) Perindopril + Indapamide 

Placebo 

Standard 

Perindopril + Indapamide 

Placebo 

*Gliclazide plus oral agents/insulin to achieve hemoglobin A 1c (HbA 1c ) target 

Based on standard guidelines 

Primary endpoint: 

Macrovascular: composite of nonfatal stroke, nonfatal 

myocardial infarction, cardiovascular death 

Microvascular: composite of new or worsening nephropathy 

or retinopathy 

Secondary endpoints: Cerebrovascular disease, cardiovascular disease, peripheral 

vascular disease, microalbuminuria, visual deterioration, 

neuropathy, heart failure, cognitive function and dementia, 

all-cause mortality 

Treatment duration: 

4.5 years 

ADVANCE Management Committee. Diabetologia. 2001;44:1118–1120. 

Slide Source 



ADVANCE: Action in Diabetes and Vascular Disease: Preterax and Diamicron MR 


The ADVANCE trial showed that lowering glucose with a target of

PERISCOPE: Study Design 

IVUS at 

Screening 

Visit 

IVUS = intravascular 

ultrasound 

Randomization 

Pioglitazone 

18 Months 

Glimepiride 

IVUS at 

Final 

Visit 

• Pioglitazone HCl (15 mg titrated to 30 mg titrated to 45 mg or 30 mg titrated 

to 45 mg, depending on the dose of sulfonylurea) 

• Glimepiride (1 mg titrated to 2 mg titrated to 4 mg or 2 mg titrated to 4 mg, 

depending on the dose of sulfonylurea) 

• Allowance to increase the standard of therapy once on maximum dose of 

study medication, if required to maintain glycemic control 

• Allowance to decrease the standard of therapy in order to maintain adequate 

glycemic control 

Adapted from Nissen SE, et al. JAMA. 2008;299:1561–1573. 

Slide Source 



PERISCOPE: Study Design 

The recent findings of the PERISCOPE study showed that, among diabetic patients 

undergoing coronary angiography, those treated with pioglitazone had less progression of 

atherosclerosis as measured by intravascular (intracoronary) ultrasound when compared 

to patients who were treated with glimepiride. 



Reference: 

Nissen SE, Nicholls SJ, Wolski K, et al, for the PERISCOPE Investigators. Comparison 

of pioglitazone vs. glimepiride on progression of coronary atherosclerosis in patients with 

type 2 diabetes: the PERISCOPE randomized controlled trial. JAMA. 2008;299:1561- 

1573. 



PERISCOPE: Primary Efficacy Parameter: 

Change in Percent Atheroma Volume 

Change in Percent 

Atheroma Volume (%) 

0.9 

0.7 

0.5 

0.3 

0.1 

-0.1 

-0.3 

p < 0.001 

0.73 

Glimepiride 

Glimepiride (n = 181) 

Pioglitazone (n = 179) 

P = 0.002 

−0.16 

p = 0.44 

Pioglitazone 

Nissen SE, et al. JAMA. 2008;299:1561–1573. 

Slide Source 



PERISCOPE: Primary Efficacy Parameter: Change in Percent Atheroma Volume 

The primary efficacy parameter in the PERISCOPE trial was the change in percent 

atheroma volume. Patients treated with glimepiride had an increase in percent atheroma 

volume over the 18 months between coronary assessments, whereas those treated with 

pioglitazone had no such increase. 



Reference: 




1573. 



PERISCOPE: Intravascular 

Ultrasound: Secondary Endpoints 

0.015 

Atheroma 

Thickness (mm) 

0.0 

Atheroma 

Volume (mm 3 ) 

0.0 

Most-Diseased 

10 mm (mm 3 ) 

0.010 

0.011 

-1.0 

-1.5 

0.005 

P = 0.006 

-2.0 

-1.0 

P = 0.06 P = 0.93 

0.000 

-3.0 

-0.005 

-4.0 

-2.0 

-2.1 

-2.0 

-0.010 

-0.011 

-5.0 

-5.5 

-0.015 

-6.0 

Glimepiride 

-3.0 

Pioglitazone 

Nissen SE, et al. JAMA. 2008;299:1561–1573. 

Slide Source 



PERISCOPE: Intravascular Ultrasound: Secondary Endpoints 

Furthermore, atheroma thickness, atheroma volume, and the severity of the most diseased 

10-mm segment – in addition to percent atheroma volume – were examined in the 

PERISCOPE trial. All of these secondary endpoints showed trends toward benefit in the 

group treated with pioglitazone. 



Reference: 




1573. 



IVUS as a Tool to Evaluate Coronary 

Atherosclerosis: Change from Baseline 

in Percent Atheroma Volume 

APO = apolipoprotein; IVUS = intravascular ultrasound; 

NS = not significant; PAV = percent atheroma volume 

Slide Source 



IVUS as a Tool to Evaluate Coronary Atherosclerosis: Change from Baseline in 

Percent Atheroma Volume 

When one places the results of the PERISCOPE trial in the context of several other trials 

using this methodology (i.e., intravascular ultrasound) to evaluate atherosclerosis in 

response to various interventions, the benefit of pioglitazone (when compared to 

glimepiride) was of approximately the same magnitude as other interventions in reducing 

atheroma progression. 

ASTEROID = A Study to Evaluate the Effect of Rosuvastatin on Intravascular 

Ultrasound 

CAMELOT = Comparison of Amlodipine vs. Enalapril to Limit Occurrences of 

Thrombosis 

IVUS = intravascular ultrasound 



REVERSAL = REVERSing Atherosclerosis with Aggressive Lipid Lowering 



APPROACH: Using Intravascular Ultrasound to Assess 

Progression of Coronary Artery Disease With Rosiglitazone 

• Population: 

– 600 patients with type 2 diabetes and coronary artery disease admitted for 

angiography or percutaneous coronary intervention 

• Intervention: 

– Rosiglitazone vs. control with comparable glycemic control (Glipizide) 

– Adherence to cardiovascular risk factor guidelines 

• Endpoints: 

– 1% change in percent atheroma volume within a 40-mm segment of 

nonintervened coronary artery based on intravascular ultrasound 

Patients with T2DM 

and CAD to Have PCI 

or Angiography 

n = 300, Active Arm - Rosiglitazone 

n = 300, Control Arm - Glipizide 

Randomization 

Screen 

IVUS and Angiography 

18-Month Treatment 

 

Week 

- 1 0 1 2 3 6 9 12 15 18 

CAD = coronary artery disease; IVUS = intravascular ultrasound; 

PCI = percutaneous coronary intervention; T2DM = type 2 diabetes mellitus 

Ratner RE, et al. Am Heart J 2008;156:1074−1079. 

Slide Source 



APPROACH: Using Intravascular Ultrasound to Assess Progression of Coronary 

Artery Disease With Rosiglitazone 

The APPROACH trial, which was reported at the annual scientific sessions of American 

Heart Association in November 2008, has a study method similar to that of the 

PERISCOPE trial. Patients with diabetes and coronary artery disease undergoing 

coronary angiography were randomized to receive either rosiglitazone or glipizide. 

Patients had assessments of percent atheroma volume at baseline and at the end of the 18- 

month treatment phase. 



Reference: 

Ratner RE, Cannon CP, Gerstein HC, et al, for the APPROACH Study Group. 

Assessment on the Prevention of Progression by Rosiglitazone on Atherosclerosis in 

diabetes patients with Cardiovascular History (APPROACH): study design and baseline 

characteristics. Am Heart J. 2008;156:1074-1079. 



APPROACH: Primary Endpoint: 

Change in Percent Atheroma Volume 

Change in Percent 

Atheroma Volume (%) 

0.5 

0.4 

0.3 

0.2 

0.1 

0.0 

-0.1 

-0.2 

-0.3 

0.43 (−0.22,( 

1.08) P = 0.19 

Glipizide 

N = 462 

Treatment Difference 

−0.64 (−1.46,( 

0.17) 

P = 0.12 

Rosiglitazone 

−0.21 (−0.86,( 

0.44) P = 0.53 

Nesto RW, et al, for the APPROACH Study Group. 

Circulation. 2008;118:2313. Abstract #5221. 

Slide Source 



APPROACH: Primary Endpoint: Change in Percent Atheroma Volume 

The primary endpoint, change in percent atheroma volume, was −0.21% in the 

rosiglitazone group versus 0.43% in the glipizide group (p = 0.12 between groups). 

By looking at the results of the PERISCOPE trial and the APPROACH trial together, and 

evaluating the relative benefits of thiazolidinediones against sulfonylureas with regard to 

progression of atherosclerosis, a virtual “head-to-head” comparison of these two agents 

was made. The resulting data were interesting in view of the debate over the past year of 

whether rosiglitazone and pioglitazone have different properties that might either increase 

or reduce the risk of cardiovascular events. 



Reference: 

Nesto RW, Cannon CP, Gerstein HC, et al, for the APPROACH Study Group. Results of 

the APPROACH trial: assessment on the prevention of progression by rosiglitazone on 

atherosclerosis in type 2 diabetes patients with cardiovascular history. Circulation. 

2008;118:2313. Abstract #5221. 



STENO-2: 

Reduction in Cardiovascular Disease 

Through a Multifactorial Intervention in Patients 

Who Have Type 2 Diabetes and Microalbuminuria 

Primary Composite 

Endpoint (%) 

60 

50 

40 

30 

20 

10 

Steno Diabetes Center 

P = 0.007 

Conventional therapy 

Intensive therapy 

n = 80 

n = 80 

0 

0 

12 24 36 48 60 72 

Months of Follow-up 

84 96 

Intensive Treatment Goals: hemoglobin A 1c ,

STENO-2: 

No Other Clinical Trial of Patients With Type 2 

Diabetes Has Shown Such a Dramatic Reduction in 

Cardiovascular Events With a Pharmacologic Intervention 

Number of 

Cardiovascular Events 

40 Intensive Therapy 

35 

Conventional Therapy 

30 

25 

20 

15 

10 

5 

0 

Stroke 


Death from 

Cardiovascular 

Causes 

Myocardial 

Infarction 

Coronary 

Artery 

Bypass 

Graft 

Surgery 

Percutaneus 

Coronary 

Intervention 

Amputation 

Reprinted from Gaede P, et al. N Engl J Med. 2003;358:580−591. 

Copyright © 2003 Massachusetts Medical Society. All rights reserved. 

Slide Source 



STENO-2: No Other Clinical Trial of Patients With Type 2 Diabetes Has Shown 

Such a Dramatic Reduction in Cardiovascular Events With a Pharmacologic 

Intervention 

The patients in the STENO-2 study had fewer deaths from cardiovascular disease, had 

fewer strokes and myocardial infarctions, and had less need for bypass surgery or 

angioplasty and revascularization or amputations when compared to the patients 

randomized to the conventional-therapy group. 

Reference: 

Gaede P, Lund-Andersen H, Parving HH, Pedersen O. Effect of a multifactorial 

intervention on mortality in type 2 diabetes. N Engl J Med. 2008;358:580-591. 

STENO-2: 

Risk-Factor Targets Attained at 7.8 

Years With an Intensive Treatment Program 

Patients (%) 

80 p < .001 

Intensive Therapy 

Conventional Therapy 

p = 0.19 

60 

p = 0.001 

A Message 

40 

to 

ACCORD? 

p = 0.06 

20 

p = 0.21 

0 

Hemoglobin 

A 1c 

STENO-2: Risk-Factor Targets Attained at 7.8 Years With an Intensive Treatment 

Program 

Among the group that was randomized to receive intensive therapy in the STENO-2 

study, more patients had a total cholesterol of

Slide Source 

STENO-2: 

Lipid-Lowering Lowering Therapy 

Accounted for More Than 70% of 


Percent of Total Calculated Risk 

Reduction in Cardiovascular 

Disease-Related Events 

80 

60 

40 

20 

0 

Lipids 

Analysis of STENO-2 data based on the risk 

engine from the United Kingdom Prospective 

Diabetes Study (UKPDS) 

Hemoglobin 

A 1c 

Systolic 

Blood 

Pressure 

Reprinted with permission from Gaede P, Pederson O. Diabetes. 

2004;53(Suppl 3):S39−S47. Copyright © 2004 American Diabetes Association. 



STENO-2: Lipid-Lowering Therapy Accounted for More Than 70% of 


A subsequent analysis of those factors that could be responsible for the dramatic 

reduction in cardiovascular events in the STENO-2 study showed that reduction in total 

cholesterol accounted for approximately 70% of the overall benefit, with less of the 

overall benefit attributable to either improvement in glycemic control or reduction of 

systolic blood pressure. 

Reference: 

Gaede P, Pedersen O. Intensive integrated therapy of type 2 diabetes: implications for 

long-term prognosis. Diabetes. 2004;53(Suppl 3):S39-S47. 

SANDS Randomized Trial: Effects of Lower LDL- 

Cholesterol and Blood-Pressure Targets on C-IMT C 

and Left Ventricular Mass in Patients With Diabetes 

• Standard group treated to target LDL = 100 mg/dL and SBP = 130 mm Hg 

• Intensive group treated to target LDL = 70 mg/dL and SBP = 115 mm Hg 

• Carotid intima-media thickness (C-IMT) and left ventricular mass (LVM) 

measured at baseline and at 18 and 36 months 

Patients (%) 

80 

60 

40 

20 

Decrease (Improved) No Change Increase (Worsened) 

Intima-Media Thickness 

Patients (%) 

80 

60 

40 

20 

Left Ventricular Mass Index 

0 

Standard 

Treatment 

(n = 230) 

Aggressive 

Treatment 

(n = 224) 

Reprinted from Howard BV, et al. JAMA 2008;299:1678−1689. 

Copyright © 2008 American Medical Association. All rights reserved. 

0 

Standard 

Treatment 

(n = 200) 

Aggressive 

Treatment 

(n = 202) 

Slide Source 





SANDS Randomized Trial: Effects of Lower LDL-Cholesterol and Blood-Pressure 

Targets on C-IMT and Left Ventricular Mass in Diabetes 

In the SANDS trial, Native Americans with type 2 diabetes underwent measurements of 

carotid intima-media thickness (C-IMT) and left ventricular mass (LVM) at baseline, at 

18 months, and again at 36 months. One group, called the “standard” group, had their 

low-density lipoprotein (LDL) targeted to 100 mg/dL and their systolic blood pressure 

(SBP) targeted to 130 mm Hg. The second group, called the “intensive” group, had 

targets of 70 mg/dL and 115 mm Hg for LDL and SBP, respectively. Among the patients 

randomized to the intensive targets, fewer patients had a progression of C-IMT, and 

fewer patients had an increase in LVM. This study is interesting because it suggests that 

lowering LDL and SBP to targets beyond that which are currently recommended for 

these patients could yield additional cardiovascular benefit. 

Reference: 

Howard BV, Roman MJ, Devereux RB, et al. Effect of lower targets for blood pressure 

and LDL cholesterol on atherosclerosis in diabetes: the SANDS randomized trial. JAMA. 

2008;299:1678-1689. 

BARI-2D: 

Evaluating Treatment Options for 

Patients With Type 2 Diabetes Mellitus and 

Coronary Artery Disease 

Inclusion Criteria 

Type 2 DM 

Stable CAD 

Exclusion Criteria 

Mandatory CABG 

–Unstable CAD 

–CAD extent 

–Left ventricular 

function 

Insulin 

Providing 

Insulin 

Sensitizing 

2 x 2 Factorial Design (n = 2600) 

Medical Rx 

Medical Rx 

CATH 


of Choice 

and 

Medical Rx 


of Choice 

and 

Medical Rx 

CABG = coronary artery bypass graft; CAD = coronary artery disease; DM = diabetes mellitus 

Brooks MM, et al. Am J Cardiol. 2006;97:9G-19G. 

Slide Source 



BARI-2D: Evaluating Treatment Options for Patients With Type 2 Diabetes 

Mellitus and Coronary Artery Disease 

In the trial design of the BARI-2D study, patients with diabetes and stable coronary 

artery disease are randomized to receive either an insulin-providing regimen with 

sulfonylurea and insulin or an insulin-sensitizing regimen with metformin and 

rosiglitazone. Patients are also randomized to revascularization of choice with either 

percutaneous coronary intervention or coronary artery bypass graft surgery, depending on 

the extent of coronary artery disease, or intensive medical treatment for angina. The 

results of this study will be reported at meetings of the American Diabetes Association in 



2009. This study should help to resolve the question about whether the manner in which 

diabetes is treated has an impact on cardiovascular outcomes. 

Reference: 

Brooks MM, Frye RL, Genuth S, et al, for the Bypass Angioplasty Revascularization 

Investigation 2 Diabetes (BARI 2D) Trial Investigators. Hypotheses, design, and methods 

for the Bypass Angioplasty Revascularization Investigation 2 Diabetes (BARI 2D) Trial. 

Am J Cardiol. 2006;97:9G-19G. 

Conclusion 

• Treatment of traditional risk factors, such as 

blood pressure and lipids, reduces 

cardiovascular disease events in patients with 

diabetes. 

• However, even after treatment of traditional 

risk factors, there remains an increased risk of 

events in diabetic patients. 

• Ongoing trials will determine whether a 

treatment that is directed at lowering 

hemoglobin A 1c reduces the risk of 

cardiovascular disease. 

• Ongoing trials will determine whether certain 

antidiabetic drugs can reduce the risk of 

cardiovascular disease. 

Slide Source 



Conclusion

Relationship of Glycemia to Cardiovascular Disease ... - Lipids Online

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