A 42-year-old woman with type 2 diabetes has not achieved glycemic control with lifestyle modifications after three months.
Should pioglitazone (Actos) be used, alone or in combination with other oral antihyperglycemic medications, in patients with type 2 diabetes?
Pioglitazone produces a reduction in A1C levels similar to that produced by other drugs. One trial found that although pioglitazone, used as an adjunct to other antihyperglycemic medications, may lead to a statistically significant reduction in morbidity and mortality in patients with established macrovascular disease, it also increases the likelihood of hospitalization for heart failure. There is no evidence on the effectiveness of pioglitazone monotherapy for reducing morbidity and mortality. Patients taking pioglitazone, alone or in combination, are more likely to experience edema, weight gain, or congestive heart failure compared with patients taking other antihyperglycemic medications.1
Oral treatment options for type 2 diabetes include medications from several drug classes, each with a unique mechanism for reducing blood glucose levels. Pioglitazone, a thiazolidinedione, lowers blood glucose levels by increasing cellular glucose uptake and hepatic sensitivity to insulin. The U.S. Food and Drug Administration has approved pioglitazone for use alone or in combination with other oral medications or insulin. This Cochrane review found that pioglitazone, alone or in combination, lowered A1C levels by 0.8 percent compared with 0.3 percent in the placebo group, and increased high-density lipoprotein levels by 19 percent compared with 10 percent in the placebo group.
Although there is clear evidence that pioglitazone modestly improves clinical surrogates of disease, only one of the 22 studies included in this review investigated the effect of pioglitazone on patient-oriented outcomes such as death, myocardial infarction, and stroke. The large study included more than 6,200 patients with type 2 diabetes and established macrovascular disease.2 Patients taking pioglitazone in combination with other oral antihyperglycemic medications had a statistically significant lower risk of the combined end point of all-cause mortality, non-fatal myocardial infarction, or stroke when compared with placebo (11.6 versus 13.6 percent; number needed to treat [NNT] = 49). Patients taking combination pioglitazone also had a higher risk of hospitalization for heart failure (number needed to harm = 62). This study did not include patients taking pioglitazone monotherapy, and the scientific rigor of the interpretation of the results has been called into question.
In contrast, metformin (Glucophage) monotherapy has been shown to improve patient-oriented outcomes such as all-cause mortality, diabetes-related mortality, and myocardial infarction in overweight patients compared with all other classes of oral medications and insulin.3,4 Pioglitazone costs more than metformin ($326 versus $33 per month)5,6 and significantly increases the risk of edema compared with other oral hypoglycemic medications.
To help patients with type 2 diabetes reach an A1C level of less than 7 percent, the American Diabetes Association (ADA) recommends oral medications that decrease insulin resistance and suppress hepatic glucose production over medications that increase insulin secretion.7 The ADA recommends metformin or thiazolidinediones, alone or in combination, over sulfonylureas as first-line treatments; however, this is not entirely an evidence-based recommendation.7 Because of recent concerns about the cardiovascular risks of the thiazolidinedione rosiglitazone (Avandia), it is likely that the ADA will revisit this recommendation in the near future.8
Background: Diabetes has long been recognized as a strong, independent risk factor for cardiovascular disease, a problem that accounts for approximately 70 percent of all-cause mortality in persons with diabetes. Prospective studies show that compared with their nondiabetic counterparts, the relative risk of cardiovascular mortality is 2 to 3 for men with diabetes and 3 to 4 for women with diabetes. The two largest trials of type 2 diabetes, the United Kingdom Prospective Diabetes Study (UKPDS) and the University Group Diabetes Program (UGDP) study, did not reveal a reduction in cardiovascular end points with improved metabolic control. Theoretical benefits of the newer peroxisome proliferator activated receptor gamma activators (e.g., pioglitazone) on endothelial function and cardiovascular risk factors might result in fewer macrovascular disease events in persons with type 2 diabetes.
Objectives: To assess the effects of pioglitazone in the treatment of type 2 diabetes.
Search Strategy: Studies were obtained from searches of Medline, Embase, and the Cochrane Library. The last search was conducted in August 2006.
Selection Criteria: Studies were included if they were randomized controlled trials of adults with type 2 diabetes and if they had a trial duration of at least 24 weeks.
Data Collection and Analysis: Two authors independently assessed trial quality and extracted data. Pooling of studies by means of random-effects meta-analysis could be performed for adverse events only.
Main Results: A total of 22 trials, which randomized approximately 6,200 persons to pioglitazone treatment, were identified. The longest duration of therapy was 34.5 months. Published studies of at least 24 weeks of pioglitazone treatment in persons with type 2 diabetes did not provide convincing evidence that patient-oriented outcomes such as mortality, morbidity, adverse effects, costs, and health-related quality of life are positively influenced by this treatment. Metabolic control measured by A1C level as a surrogate end point did not demonstrate clinically relevant differences to other oral antidiabetes drugs. Occurrence of edema was significantly increased. The results of the single trial with relevant clinical end points (i.e., PROspective pioglit- Azone Clinical Trial In macroVascular Events [PROactive study]) have to be regarded as hypothesis-generating and need to be confirmed.
Authors' Conclusions: Until new evidence becomes available, the risk-benefit ratio of pioglitazone remains unclear. Different therapeutic indications for pioglitazone from the two large U.S. and European drug agencies should be clarified to reduce uncertainties among patients and physicians.
These summaries have been derived from Cochrane reviews published in the Cochrane Database of Systematic Reviews in the Cochrane Library. Their content has, as far as possible, been checked with the authors of the original reviews, but the summaries should not be regarded as an official product of the Cochrane Collaboration; minorediting changes have been made to the text (http://www.cochrane.org).