Summary

Commonly reported side effects of pioglitazone include: upper respiratory tract infection, edema, and hypoglycemia. Other side effects include: cardiac failure, exacerbation of congestive heart failure, bone fracture, headache, and pharyngitis. Continue reading for a comprehensive list of adverse effects.

Applies to pioglitazone: oral tablets.

Side effects include:

Upper respiratory tract infection, headache, sinusitis, myalgia, pharyngitis, edema.

For Healthcare Professionals

Applies to pioglitazone: oral tablet.

Cardiovascular

Very common (greater than 10%): Edema

Common (1% to 10%): Congestive heart failure (including nonfatal and fatal cases), cardiac failure, chest pain^[Ref]

In the PROactive trial, a study in 5238 patients with type 2 diabetes and a history of macrovascular disease who were force-uptitrated to pioglitazone 45 mg once a day or given placebo in addition to standard of care, edema occurred in 27.3% of patients treated with pioglitazone (n=2605) compared with 15.9% of placebo (n=2633) patients. Treatment-emergent adverse events leading to at least 1 hospitalized congestive heart failure event occurred in 5.7% of patients receiving pioglitazone and 4.1% of patients receiving placebo.

The primary objective of the 3-year PROactive trial was to examine the effect of pioglitazone on mortality and macrovascular morbidity in high-risk patients. No statistically significant difference between pioglitazone and placebo/standard care were observed for time to the first occurrence of their first event (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 patients receiving pioglitazone experienced at least 1 event compared with 572 patients receiving placebo/standard care.

Pioglitazone is associated with edema (peripheral, generalized, and pitting edema and fluid retention) when used alone or when used in combination therapy. In pioglitazone monotherapy trials, edema occurred in 2.5% (n=81), 4.7% (n=275), and 6.5% (n=169) of patients receiving 15 mg, 30 mg, and 45 mg of pioglitazone daily for 16 to 26 weeks. Pioglitazone in combination with a sulfonylurea for 16 to 24 weeks resulted in edema in 1.6% (n=184), 11.3% (n=540), and 23.1% (n=351) of patients receiving 15 mg, 30 mg, and 45 mg of pioglitazone daily, respectively. In a study in patients with NYHA class II or III heart failure the percentage of patients experiencing CHF progression during the study was 13.4% and 8.2% in patients receiving pioglitazone (n=262) and glyburide (n=256), respectively.

Postmarketing reports of congestive heart failure have been received in patients treated with pioglitazone. Reports have been received from patients both with and without a history of a known history of heart disease and both with and without concomitant insulin use.^[Ref]

Hypersensitivity

Frequency not reported: Hypersensitivity and allergic reactions^[Ref]

Metabolic

Very common (10% or more): Hypoglycemia (up to 27.3%), increased weight (up to 26.2%)^[Ref]

General

The most commonly reported side effects were hypoglycemia, increased weight, edema, and upper respiratory tract infection.^[Ref]

Hematologic

Frequency not reported: Small reduction in mean hemoglobin and hematocrit^[Ref]

Ocular

Visual disturbances have been reported early in treatment and may be related to changes in blood glucose due to temporary alteration in the turgidity and refractive index of the lens. Macular edema has been reported postmarketing in patients taking pioglitazone or another thiazolidinedione. Some patients presented with blurred vision or decreased visual acuity, although some were diagnosed on routine ophthalmologic examination. Most patients had peripheral edema at time of diagnosis. Some patients improved with drug discontinuation.^[Ref]

Common (1% to 10%): Visual disturbance, abnormal vision

Frequency not reported: Macular edema^[Ref]

Hepatic

Postmarketing reports of fatal and nonfatal hepatic failure have been received in patients treated with this drug; these reports have been insufficient to establish causality. During clinical trials, there was no evidence of drug-induced hepatotoxicity.^[Ref]

Uncommon (0.1% to 1%): Increased alanine aminotransferase

Frequency not reported: Decreased mean values of bilirubin, AST, alkaline phosphatase, and GGT

Postmarketing reports: Fatal and nonfatal hepatic failure, hepatocellular dysfunction^[Ref]

Other

Common (1% to 10%): Fatigue, accidental injury, peripheral edema, asthenia, malaise^[Ref]

Gastrointestinal

Common (1% to 10%): Tooth disorder, tooth abscess, gastroenteritis, diarrhea, upper abdominal pain^[Ref]

Genitourinary

Common (1% to 10%): Urinary tract infection^[Ref]

Musculoskeletal

Common (1% to 10%): Fractures, myalgia, pain in extremity, back pain, cramped legs, arthralgia^[Ref]

In the prospective pioglitazone clinical trial in macrovascular events (PROactive), the incidence of bone fractures in female patients with this drug was 5.1% (44/870) compared to 2.5% (23/905) for placebo treated patients. The majority of fractures were nonvertebral including lower limb and distal upper limb. The incidence in men was 1.7% and no different than placebo (2.1%).^[Ref]

Nervous system

Common (1% to 10%): Headache, Hypoesthesia^[Ref]

Psychiatric

Uncommon (0.1% to 1%): Insomnia^[Ref]

Respiratory

Very common (10% or more): Upper respiratory tract infection (up to 13.2%)

Common (1% to 10%): Sinusitis, pharyngitis, bronchitis, influenza^[Ref]

Oncologic

Uncommon (0.1% to 1%): Bladder cancer^[Ref]

The US FDA has released results of its review of pioglitazone and bladder cancer and concluded that the data suggests use of this drug may be linked to an increase risk of bladder cancer. A 10-year prospective cohort study in diabetic patients performed by the manufacturer (n=158,918 never users; n=34,181 ever users) identified 1075 newly diagnosed cases of bladder cancer in never users and 186 cases in ever users. The fully adjusted hazard ratio (HR) showed pioglitazone use was not associated with an increased risk (HR 1.06 (95% confidence interval 0.89 to 1.26). And while a modest trend towards higher risk with increasing duration was observed, this trend was not statistically significant. Compared to the interim 5-year results, the 10-year results found weaker associations that were not statistically significant. However, there are studies that have shown a statistically significant association between exposure to this drug and bladder cancer and an association between cumulative dose or cumulative duration of exposure and bladder cancer. Overall, this drug may be associated with an increase in the risk of urinary bladder tumors, however there is insufficient data to determine whether this drug is a tumor promoter for urinary bladder tumors.^[Ref]