Patients with type 2 diabetes and NYHA class II or early class III congestive heart failure were randomized to receive 24 weeks of double-blind treatment with either pioglitazone at daily doses of 30 mg to 45 mg (N=262) or glyburide at daily doses of 10 mg to 15 mg (N=256). A summary of the incidence of adverse reactions related to congestive heart failure reported in this study is provided in Table 4.

Table 4. Treatment-Emergent Adverse Reactions of Congestive Heart Failure (CHF) in Patients with NYHA Class II or III Congestive Heart Failure Treated with Pioglitazone or Glyburide
Number (%) of Subjects
Pioglitazone
N=262 Glyburide
N=256
Death due to cardiovascular causes (adjudicated) 5 (1.9%) 6 (2.3%)
Overnight hospitalization for worsening CHF (adjudicated) 26 (9.9%) 12 (4.7%)
Emergency room visit for CHF (adjudicated) 4 (1.5%) 3 (1.2%)
Patients experiencing CHF progression during study 35 (13.4%) 21 (8.2%)
Congestive heart failure events leading to hospitalization that occurred during the PROactive trial are summarized in Table 5.

Table 5. Treatment-Emergent Adverse Reactions of Congestive Heart Failure (CHF) in PROactive Trial
Number (%) of Patients
Placebo
N=2633 Pioglitazone
N=2605
At least one hospitalized congestive heart failure event 108 (4.1%) 149 (5.7%)
Fatal 22 (0.8%) 25 (1%)
Hospitalized, nonfatal 86 (3.3%) 124 (4.7%)
Cardiovascular Safety

In the PROactive trial, 5238 patients with type 2 diabetes and a history of macrovascular disease were randomized to pioglitazone (N=2605), force-titrated up to 45 mg daily or placebo (N=2633) in addition to standard of care. Almost all patients (95%) were receiving cardiovascular medications (beta blockers, ACE inhibitors, angiotensin II receptor blockers, calcium channel blockers, nitrates, diuretics, aspirin, statins and fibrates). At baseline, patients had a mean age of 62 years, mean duration of diabetes of 9.5 years and mean A1C of 8.1%. Mean duration of follow-up was 34.5 months.

The primary objective of this trial was to examine the effect of pioglitazone on mortality and macrovascular morbidity in patients with type 2 diabetes mellitus who were at high risk for macrovascular events. The primary efficacy variable was the time to the first occurrence of any event in a cardiovascular composite endpoint that included all-cause mortality, nonfatal myocardial infarction (MI) including silent MI, stroke, acute coronary syndrome, cardiac intervention including coronary artery bypass grafting or percutaneous intervention, major leg amputation above the ankle and bypass surgery or revascularization in the leg. A total of 514 (19.7%) patients treated with pioglitazone and 572 (21.7%) placebo-treated patients experienced at least one event from the primary composite endpoint (hazard ratio 0.90; 95% Confidence Interval: 0.80, 1.02; p=0.10).

Although there was no statistically significant difference between pioglitazone and placebo for the three-year incidence of a first event within this composite, there was no increase in mortality or in total macrovascular events with pioglitazone. The number of first occurrences and total individual events contributing to the primary co