CHICAGOCarotid intima-media tHICkness in Atherosclerosis using pioGlitazOne trial

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

T2DM = type 2 diabetes mellitus

Mazzone T et al. JAMA. 2006.

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 demographics

ITT population CIMT population

Pioglitazone(n = 230)

Glimepiride(n = 228)

Pioglitazone(n = 175)

Glimepiride(n = 186)

Age (years) 59.3 59.9 58.9 59.8

Men (%) 63.5 62.7 63.4 64.0

White (%) 59.6 65.4 57.7 64.0

Black (%) 30.9 26.8 33.7 28.0

Asian (%) 9.1 7.9 8.6 8.1

Hispanic (%) 9.1 9.6 8.0 8.1

Mazzone T et al. JAMA. 2006.

CHICAGO: Medical history

ITT population CIMT population

Pioglitazone(n = 230)

Glimepiride(n = 228)

Pioglitazone(n = 175)

Glimepiride(n = 186)

Diabetes duration (years) 8.0 7.5 7.8 7.5

Hypertension (%) 67.8 72.8 66.3 73.7

MI (%) 7.8 13.6 6.9 15.1

Stroke/TIA (%) 3.9 3.5 4.6 3.8

Angina (%) 6.1 8.8 6.9 6.5

Arrhythmia (%) 6.5 5.7 6.3 5.4

HF (%) 0.9 1.8 1.1 1.6

PAD (%) 1.3 1.8 1.7 1.1

Mazzone T et al. JAMA. 2006.

CHICAGO: Baseline CV medications

ITT population CIMT population

Pioglitazone(n = 230)

Glimepiride(n = 228)

Pioglitazone(n = 175)

Glimepiride(n = 186)

Antihypertensive (%)

ACEIs/ARBs 53.9 60.1 53.7 60.2

β-blockers 21.7 21.1 18.9 22.0

CCBs 20.0 19.3 22.3 19.9

Diuretics 22.6 34.2 22.9 36.0

Other 4.8 6.6 4.6 7.5

Antithrombotic (%)

Aspirin 38.3 53.1 38.9 53.2

Other 3.5 2.6 2.9 2.7

Lipid lowering (%) 61.7 61.4 60.6 60.8

Statins 54.3 56.1 52.0 55.4

Mazzone T et al. JAMA. 2006.

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

Mazzone T et al. JAMA. 2006.NR = not reported

CHICAGO: Treatment effect on posterior wall CIMT

Mazzone T et al. JAMA. 2006.

P = 0.02

Week 72Week 48Week 24Baseline-0.012

-0.008

-0.004

0

0.004

0.008

0.012

0.016

Change from

baseline (least-square means,

mm)

Glimepiride Pioglitazone

CHICAGO: Treatment effect on posterior wall CIMT in prespecified subgroups

Mazzone T et al. JAMA. 2006.

Number of patients

Parameter Pioglitazone Glimepiride

N 175 186Age (years) ≤64 >64

13441

13650

Gender Male Female

11164

11967

Systolic BP (mm Hg) <130 ≥130

8788

10878

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

8491

9789

BMI (kg/m2) ≤31.3 >31.3

8689

9096

A1C (%) <7 ≥7

71104

70116

Statins Yes* No

9184

10185

-0.04 -0.03 -0.02 -0.01 0 0.01 0.02

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

Favorspioglitazone

Favorsglimepiride

*Within 7 days of 1st study drug dose

CHICAGO: Treatment effect on glucose control

Mazzone T et al. JAMA. 2006.*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

* †

‡

HDL-C change

from baseline

(least square means, mg/dL)

CHICAGO: Treatment effect on HDL-C

Glimepiride (n = 206) Pioglitazone (n = 201)

Mazzone T et al. JAMA. 2006. Courtesy of SM Haffner, MD.

*P < 0.001 (treatment-group difference)†HDL-C mg/dL (SE): Glimepiride 47.6 (0.91), Pioglitazone 47.1 (0.90)

24 48 72

**

*

-2

0

2

4

6

8

Week

6.45 mg/dL(95% CI 4.97–7.93)

Baseline†

CHICAGO: Adverse events

AE (%)Pioglitazone

(n = 230)Glimepiride

(n = 228)

Hypoglycemia 19.6 23.2

Peripheral edema 13.0 7.0

Headache 8.7 10.1

Fatigue 7.0 7.9

Extremity pain 7.0 5.7

Dizziness 6.5 9.6

Weight gain 6.5 4.4

Nausea 6.1 3.9

Hypertension 5.2 6.1

Back pain 4.8 7.5

Mazzone T et al. JAMA. 2006.

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, A1C, 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*

• 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.

*PROspective pioglitAzone Clinical Trial In macroVascular Events