Table 6. PROactive: Number of First and Total Events for Each Component Within the Cardiovascular Composite Endpoint
Cardiovascular Events Placebo
N=2633 Pioglitazone
N=2605
First Events
n (%) Total Events
n First Events
n (%) Total Events
n
CABG=coronary artery bypass grafting; PCI=percutaneous intervention
Any Event 572 (21.7) 900 514 (19.7) 803
  All-Cause Mortality 122 (4.6) 186 110 (4.2) 177
  Nonfatal Myocardial Infarction (MI) 118 (4.5) 157 105 (4) 131
  Stroke 96 (3.6) 119 76 (2.9) 92
  Acute Coronary Syndrome 63 (2.4) 78 42 (1.6) 65
  Cardiac Intervention (CABG/PCI) 101 (3.8) 240 101 (3.9) 195
  Major Leg Amputation 15 (0.6) 28 9 (0.3) 28
  Leg Revascularization 57 (2.2) 92 71 (2.7) 115
Weight Gain

Dose-related weight gain occurs when pioglitazone is used alone or in combination with other antidiabetic medications. The mechanism of weight gain is unclear but probably involves a combination of fluid retention and fat accumulation.

Edema

Edema induced from taking pioglitazone is reversible when pioglitazone is discontinued. The edema usually does not require hospitalization unless there is coexisting congestive heart failure.

Hepatic Effects

There has been no evidence of pioglitazone-induced hepatotoxicity in the pioglitazone controlled clinical trial database to date. One randomized, double-blind, three-year trial comparing pioglitazone to glyburide as add-on to metformin and insulin therapy was specifically designed to eva luate the incidence of serum ALT elevation to greater than three times the upper limit of the reference range, measured every eight weeks for the first 48 weeks of the trial then every 12 weeks thereafter. A total of 3/1051 (0.3%) patients treated with pioglitazone and 9/1046 (0.9%) patients treated with glyburide developed ALT values greater than three times the upper limit of the reference range. None of the patients treated with pioglitazone in the pioglitazone controlled clinical trial database to date have had a serum ALT greater than three times the upper limit of the reference range and a corresponding total bilirubin greater than two times the upper limit of the reference range, a combination predictive of the potential for severe drug-induced liver injury.

Hypoglycemia

In the pioglitazone clinical trials, adverse reactions of hypoglycemia were reported based on clinical judgment of the investigators and did not require confirmation with finger stick glucose testing. In the 16 week add-on to sulfonylurea trial, the incidence of reported hypoglycemia was 3.7% with pioglitazone 30 mg and 0.5% with placebo. In the 16 week add-on to insulin trial, the incidence of reported hypoglycemia was 7.9% with pioglitazone 15 mg, 15.4% with pioglitazone 30 mg and 4.8% with placebo. The incidence of reported hypoglycemia was higher with pioglitazone 45 mg compared to pioglitazone 30 mg in both the 24 week add-on to sulfonylurea trial (15.7% versus 13.4%) and in the 24 week add-on to insulin trial (47.8% versus 43.5%). Three patients in these four trials were hospitalized due to hypoglycemia. All three patients were receivi