dual events contributing to the primary composite endpoint is shown in Table 6.
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 Eventsn (%)
Total Eventsn
First Eventsn (%)
Total Eventsn
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
CABG=coronary artery bypass grafting; PCI=percutaneous intervention
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 events of hypoglycemia were reported based on clinical judgment of the investigators and did not require confirmation with fingerstick 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 sulf
