Over 8500 patients with type 2 diabetes have been treated with pioglitazone in randomized, double-blind, controlled clinical trials. This includes 2605 high-risk patients with type 2 diabetes treated with pioglitazone from the PROactive clinical trial. Over 6000 patients have been treated for 6 months or longer, and over 4500 patients for one year or longer. Over 3000 patients have received pioglitazone for at least 2 years.
The most common adverse events reported in at least 5% of patients in the controlled 16-week clinical trial between placebo plus metformin and pioglitazone 30 mg plus metformin were upper respiratory tract infection (15.6% and 15.5%), diarrhea (6.3% and 4.8%), combined edema/peripheral edema (2.5% and 6.0%) and headache (1.9% and 6.0%), respectively.
The incidence and type of adverse events reported in at least 5% of patients in any combined treatment group from the 24-week study comparing pioglitazone 30 mg plus metformin and pioglitazone 45 mg plus metformin are shown in Table 4; the rate of adverse events resulting in study discontinuation between the two treatment groups was 7.8% and 7.7%, respectively.
Table 4. Adverse Events That Occurred in ≥ 5% of Patients in Any Treatment Group During the 24-Week Study
| Adverse Event|
| Pioglitazone 30 mg |
| Pioglitazone 45 mg |
|Upper Respiratory Tract Infection ||51 (12.4)||56 (13.5)|
|Diarrhea ||24 (5.8)||20 (4.8)|
|Nausea||24 (5.8)||15 (3.6)|
|Headache||19 (4.6)||22 (5.3)|
|Urinary Tract Infection|| 24 (5.8)|| 22 (5.3)|
|Sinusitis|| 18 (4.4)|| 21 (5.0)|
|Dizziness|| 22 (5.4)|| 20 (4.8)|
|Edema Lower Limb||12 (2.9)||47 (11.3)|
|Weight Increased||12 (2.9)||28 (6.7)|
Most clinical adverse events were similar between groups treated with pioglitazone in combination with metformin and those treated with pioglitazone monotherapy. Other adverse events reported in at least 5% of patients in controlled clinical trials between placebo and pioglitazone monotherapy included myalgia (2.7% and 5.4%), tooth disorder (2.3% and 5.3%), diabetes mellitus aggravated (8.1% and 5.1%) and pharyngitis (0.8% and 5.1%), respectively.
In U.S. double-blind studies, anemia was reported in ≤ 2% of patients treated with pioglitazone plus metformin (see PRECAUTIONS, General: Pioglitazone hydrochloride ).
In monotherapy studies, edema was reported for 4.8% (with doses from 7.5 mg to 45 mg) of patients treated with pioglitazone versus 1.2% of placebo-treated patients. Most of these events were considered mild or moderate in intensity (see PRECAUTIONS, General: Pioglitazone hydrochloride ).
Prospective Pioglitazone Clinical Trial In Macrovascular Events (PROactive)
In PROactive, 5238 patients with type 2 diabetes and a prior history of macrovascular disease were treated with ACTOS (n=2605), force-titrated up to 45 mg daily, or placebo (n=2633), in addition to standard of care. Almost all subjects (95%) were receiving cardiovascular medications (beta blockers, ACE inhibitors, ARBs, calcium channel blockers, nitrates, diuretics, aspirin, statins, fibrates). Patients had a mean age of 61.8 years, mean duration of diabetes 9.5 years, and mean A1C 8.1%. Average duration of follow-up was 34.5 months. The primary objective of this trial was to examine the effect of ACTOS 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 the cardiovascular composite endpoint (see table 5 below). Although there was no statistically significant difference between ACTOS and placebo for the 3-year incidence of a first event within this composite, there was no increase in mortality or in total macrovascular events with ACTOS.
Table 5 Number of First and Total Events for Each Component within the Cardiovascular Composite Endpoint
| Placebo |
| ACTOS |
| Cardiovascular Events ||First Events|
|Cardiac intervention (CABG/PCI)||101||240||101||195|
|Major leg amputation||15||28||9||28|
Postmarketing reports of new onset or worsening diabetic macular edema with decreased visual acuity have also been received (see PRECAUTIONS, General: Pioglitazone hydrochloride ).