ppar activation impact on pathways of clinical care

PPAR activation Impact on pathways of

clinical care

New paradigm of multiple risk factormanagement

The future of drug therapy belongs to prevention,

which is just now being addressed,

and to intensive management of all cardiovascular

risk factors

Kaplan NM. Hypertension. 2005;46:257-8.

TRIPOD: Treating insulin resistance reduces incidence of type 2 diabetes

TRoglitazone In Prevention Of Diabetes(n = 236 Hispanic women with gestational diabetes)

60

40

20

0

New-onset diabetes (%)

Follow-up (months)

0 12 24 36 48 60

Buchanan TA et al. Diabetes. 2002;51:2796-803.

Placebo

Troglitazone 400 mg

12.1%

5.4%

Annual incidence

55% RRRHR 0.45 (0.25–0.83)*

P = 0.009

* Unadjusted

TRIPOD & PIPOD: Evidence that insulin resistance causes -cell failure

• PPAR activation: 55% relative risk reduction for new-onset diabetes (HR 0.45; 0.25–0.83)

• 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

• PPAR activation associated with preserved -cell function

• TRIPOD and PIPOD studies demonstrate that prevention of type 2 diabetes is possible through ß-cell rest

Buchanan TA et al. Diabetes. 2002;51:2796-803

TRIPOD = Troglitazone in Prevention of DiabetesPIPOD = Pioglitazone in Prevention of Diabetes

Anticipated results from large multicenter trials in (pre)diabetes

2005 2006 2007 2008 2009

PROactive

DREAMCHICAGOADOPT

APPROACHACCORDBARI-2DORIGIN

Clinical outcomes Surrogate outcomes

NAVIGATOR

VADT

RECORD

ACT-NOW

PERISCOPE

DREAMBackground and study objective

• Previous studies have shown evidence for new-onset diabetes with RAAS and PPAR agonists

• Does treatment with ramipril and/or rosiglitazone prevent or delay the development of diabetes in persons with IGT or IFG and no diabetes?

DREAM Trial Investigators. Diabetologia. 2004;47:1519-27.

Diabetes REduction Assessment with ramipril and rosiglitazone Medication

DREAMStudy design

Primary outcome:Diabetes or death from any cause

Secondary outcomes I: CV events

Combined MI, stroke, CV death, revascularization, HF,

angina, ventricular arrhythmia

Secondary outcomes II: Renal events

Progression to micro- or macroalbuminuria,

or 30% CrCl

Ramipril 15 mg/d vs placeboAND

Rosiglitazone 8 mg/d vs placebo

Randomized, double-blind 2 × 2 factorial designN = 5269 with IFG and/or IGT, free from CV disease

Follow-up: 3–5 years

Secondary outcomes III: Glycemic

Glucose levels,regression to

normoglycemia

DREAM Trial Investigators. Lancet. 2006;368:1096-1105.

DREAM: Rosiglitazone prolongs time to occurrence of new-onset diabetes or death

DREAM Trial Investigators. Lancet. 2006;368:1096-1105.

No. at riskPlaceboRosiglitazone

26342635

24702538

21502414

11481310

177217

0.6

0.5

0 1 2 3 4

Follow-up (years)

0.4

0.3

0.2

0.1

0.0

Rosiglitazone

Placebo60% RRR HR 0.40 (0.35–0.46) P < 0.0001

Cumulative hazard rate

DREAM results: Summary

Rosiglitazone

• 60% RRR in new-onset diabetes or death (P < 0.001) NNT = 7

• Benefit observed regardless of ethnicity, gender, age, weight, and fat distribution

• Increased regression to normoglycemia* vs placebo (50.5% vs 30.3%)(HR 1.71, P < 0.0001)

Ramipril

• 9% RRR in new-onset diabetes or death (non significant)

• Increased regression to normoglycemia* vs placebo (42.5% vs 38.2%)(HR 1.16, P = 0.001)

DREAM Trial Investigators. Lancet. 2006;368:1096-1105

*FPG < 110 mg/dL and 2-h glucose < 141 mg/dL

0

TZDs blunt diabetes progression

Knowler WC et al. DPP Research Group. Diabetes 2005;54:1150-6.

* Withdrawn from study after 1.5 yr

Diabetes Prevention Program

10

15

5

1.5

Cumulativeincidence

of diabetes(%)

Years

1.00.50

Placebo

Metformin850 mg bid

Lifestyle

Troglitazone400 mg/d*

23773915682343n =

75% vs placebo

P < 0.001

Anticipated results from large multicenter trials in (pre)diabetes

2005 2006 2007 2008 2009

PROactive

DREAMCHICAGOADOPT

APPROACHACCORDBARI-2DORIGIN

Clinical outcomes Surrogate outcomes

NAVIGATOR

VADT

RECORD

ACT-NOW

PERISCOPE

CHICAGO: Background and rationale

• Even in the presence of optimal cardiovascular (CV) risk factor control (LDL-C and BP), individuals with T2DM remain at high risk for CV events

• Thiazolidinediones have shown favorable effects on systemic inflammation, coagulation, lipids, and endothelial function

• Carotid intima-media thickness (CIMT) is a highly validated surrogate endpoint to detect future CV disease risk

Mazzone T et al. JAMA. 2006.

CHICAGO compared the long-term effects of pioglitazone vs glimepiride on CIMT progression in ethnically and racially diverse, urban patients with T2DM


CHICAGO: Study design

Pioglitazone 15–45 mg*(n = 232)

N = 462 with T2DM

Glimepiride 1–4 mg*(n = 230)

Primary endpoint:Change in mean posterior-wall CIMT in right and left common carotid arteries

Follow-up: 18 months

*Initial dose based on sulfonylurea use and titrated to achieve fasting plasma glucose (FPG) ≤140 mg/dL†Baseline + 1 qualifying CIMT image

Primary CIMT analysis†: n = 175Intention-to-treat (ITT) analysis: n = 230

Primary CIMT analysis†: n = 186ITT analysis: n = 228

Double-blindComparator-controlled

CHICAGO: Baseline risk factors

ITT population CIMT population

Pioglitazone(n = 230)

Glimepiride(n = 228)

Pioglitazone(n = 175)

Glimepiride(n = 186)

A1C (%) 7.43 7.40 7.44 7.36

FPG (mg/dL) 151.7 149.6 149.2 148.2

BMI (kg/m2) 32.0 31.9 32.2 32.0

BP (mm Hg) 130.1/78.3 128.7/77.1 130.0/78.5 128.3/77.0

LDL-C (mg/dL) 113.8 111.3 NR NR

HDL-C (mg/dL) 47.1 47.6 NR NR

TG (mg/dL) 178.6 170.4 NR NR


NR = not reported

CHICAGO: Treatment effect on glucose control


*P = 0.04; †P = 0.01; ‡P = 0.002 (treatment-group difference)

Glimepiride Pioglitazone

724824Baseline-0.6

-0.4

-0.2

0

0.2

A1C change

from baseline

(least square

means, %)

60403216Week

* †

‡

CHICAGO: Treatment effect on posterior wall mean CIMT


P = 0.02

Week 72Week 48Week 24Baseline-0.012

-0.008

-0.004

0

0.004

0.008

0.012

0.016

Mean change from baseline

(least squares, mm)

Glimepiride Pioglitazone

CIMT = carotid intima-media thickness

CHICAGO: Treatment effect on posterior wall mean CIMT in prespecified subgroups


10185

9184

Statins Yes* No

70116

71104

A1C (%) <7 ≥7

9096

8689

BMI (kg/m2) ≤31.3 >31.3

9789

8491

Duration of type 2 diabetes (months) ≤67 >67

10878

8788

Systolic BP (mm Hg) <130 ≥130

11967

11164

Gender Male Female

13650

13441

Age (years) ≤64 >64

186175NGlimepiridePioglitazoneParameter

Number of patients

Treatment-group difference in posterior wall CIMT(mean change, mm)

-0.04 -0.03 -0.02 -0.01 0 0.01 0.02

Favorspioglitazone

Favorsglimepiride

*Within 7 days of 1st study drug dose

CHICAGO: Summary

• In an ethnically and racially diverse patient population with T2DM, treatment with pioglitazone demonstrated clinical benefits:

–Progression of carotid atherosclerosis was retarded vs sulfonylurea (P = 0.02)

–Benefits observed across all prespecified subgroups: age, gender, SBP, diabetes duration, BMI, HbA1C, statin use

• Edema and weight gain were higher in TZD group

• CIMT may be preferred for assessing treatment-related changes in carotid atherosclerosis

Mazzone T et al. JAMA. 2006.Bernard S et al. Diabetes Care. 2005;28:1158-62.

CHICAGO: Implications

• Compared with previous trial cohorts, patients in CHICAGO were well-treated at baseline and had near-optimal risk factor control:– Mean LDL-C 113.8 mg/dL (pioglitazone) and 111.3 mg/dL (glimepiride)

– 130.1/78.3 mm Hg (pioglitazone) and 128.7/77.1 mm Hg (glimepiride)

• Slowed atherosclerosis progression is consistent with clinical endpoint data reported in PROactive

• Results are similar to those by Langenfeld et al., who also showed pioglitazone was associated with a greater reduction in carotid IMT at 24 weeks compared with glimepiride in diabetic patients

• Additional data will contribute to the overall understanding and clinical significance of CHICAGO results

Mazzone T et al. JAMA. 2006.Dormandy JA et al. Lancet. 2005;366:1279-89.

Langenfeld et al. Circulation 2005;111:2525-31.

Aggressive medical therapy in diabetes

Adapted from Beckman JA et al. JAMA. 2002;287:2570-81.

Atherosclerosis

Platelet activationand aggregation

Dyslipidemia

HyperglycemiaInsulin resistance

Hypertension

MetforminTZDs

SulfonylureasNonsulfonylureas

SecretagoguesInsulin

StatinsFibric acid derivatives

ACE inhibitorsARBs

β-blockersCCBs

Diuretics

ASAClopidogrelTiclopidine

Summary: Optimizing outcomes inpatients with multiple CVD risks

Improved clinical outcome

Multifactorial risk reduction

Traditional risk factors

Emergingbiomarkers

Clinicaltrials

ppar activation impact on pathways of clinical care

Documents