How Does Pioglitazone Compare With Rosiglitazone?

William C. Gong, PharmD


March 24, 2011

A critical care nurse recently submitted the following inquiry:

I am concerned since the antidiabetic drug Avandia has been withdrawn from the market due to markedly increased incidences of cardiac complications. Can you tell me if these complications have been seen with the closely related drug Actos?

The adverse cardiovascular effects of Avandia (rosiglitazone) were first brought to prominence by a meta-analysis conducted by Nissen and coworkers,[1] who found that rosiglitazone was associated with a 43% higher risk for myocardial infarction (P = .03) and a 64% higher risk for cardiovascular death (P = .06). Because of these adverse cardiovascular effects, the European Medicine Agency Committee for Medicinal Products for Human Use suspended the use of rosiglitazone in the European Union. Rosiglitazone has not been suspended in the United States, but the US Food and Drug Administration (FDA) is requiring Avandia maker GlaxoSmithKline to create a risk evaluation and mitigation strategy (REMS) for rosiglitazone and other rosiglitazone-containing products to address safety concerns for patients who use the drug.

Under REMS guidelines for rosiglitazone, the drug will be available only for patients who are not able to achieve glycemic control on other oral antidiabetic drugs, as well as for those who in consultation with their health professional decide not to take pioglitazone for medical reasons. Patients who currently take rosiglitazone may continue to do so under the REMS only if they appear to benefit from the drug and if they understand the risks.

The REMS requires prescribers to provide documentation of their patient's eligibility to take the drug. In addition, the patient will need to review information about concerns over the drug's cardiovascular safety in order to receive the drug. This process will effectively reduce the use of rosiglitazone in the United States, requiring the enrollment of patients, physicians, and pharmacists.

So the question comes up, can pioglitazone be used safely in patients with diabetes? The important thing to keep in mind is that all drugs administered to patients are foreign chemicals introduced into the body. The question is really whether the benefits of introducing a foreign chemical to the body outweigh the risks.

Both rosiglitazone and pioglitazone are associated with some adverse cardiovascular effects, but there are some differences. On the basis of a single meta-analysis of randomized trials comparing it with placebo or an active comparator, pioglitazone was associated with an 18% relative risk reduction for death, myocardial infarction, or stroke (P < .005) and a 41% increase in relative risk for heart failure (P < .002).[2] A separate meta-analysis of rosiglitazone trials showed a 42% increased relative risk for myocardial infarction (P = .2) and a 109% increased relative risk for heart failure (P < .001).[3] In addition, a study of national observational, retrospective, inception cohort of 227,571 patients 65 years or older found that patients taking rosiglitazone were more likely than patients taking pioglitazone to experience cardiovascular events, including heart failure and death.[4]

Clearly, the level of side effects differs for rosiglitazone and pioglitazone. Effects on lipid levels also differ. These disparities suggest key differences between the 2 drugs. In a study comparing the effects of pioglitazone and rosiglitazone, Goldberg and associates found that triglyceride levels of patients who were treated with pioglitazone decreased by 51.9 ± 7.8 mg/dL, whereas the triglyceride levels of patients on rosiglitazone increased by 13.1 ± 7.8 mg/dL (P < .001). Both drugs increased high-density lipoprotein cholesterol (HDL-C), but the benefits were greater in the pioglitazone group than in the rosiglitazone group (respectively, 5.2 ± 0.95 vs 2.4 ± 0.5 mg/dL; P < .0001). The increase in low-density lipoprotein cholesterol (LDL-C) was less with pioglitazone than with rosiglitazone (respectively, 12.3 ± 1.6 vs 21.3 ± 1.6 mg/dL; P < .0001).[5]

Compared with pioglitazone, rosiglitazone produces unfavorable changes in plasma LDL-C, lipoprotein particles, and triglycerides. The 2 drugs are structurally different and may have different affinities for the nuclear receptors PPAR-gamma and PPAR-alpha. Activation of the PPAR-alpha receptor is associated with "fibrate-like" effects of lowering triglycerides levels and raising HDL-C, whereas activation of the PPAR-gamma is associated with glucose-lowering and insulin-sensitizing effects. Pioglitazone seems to act like a partial PPAR-alpha agonist in vitro, whereas rosiglitazone seems to be a pure PPAR-gamma agonist.[6]

Whether to use pioglitazone in light of the cardiovascular adverse effects demonstrated with rosiglitazone should be a decision made by the provider and the patient. Factors in making the decision include whether the patient is willing to use insulin to improve glycemic control. Generally, pioglitazone is added to therapy when other oral agents do not sufficiently reach the patient's glycemic goals. One of the main advantages of pioglitazone is that it targets the pathophysiology of type 2 diabetes by addressing insulin resistance. By decreasing insulin resistance, pioglitazone may have some beta-cell preservation effects on the pancreas and perhaps reduce the rate of pancreatic exhaustion.

However, if a patient is at a point where insulin therapy is necessary to achieve glycemic control, pioglitazone may not be needed, because insulin can more effectively fine tune the patient's glycemic control. Once on insulin therapy, I would normally recommend taking patients off pioglitazone because there is really no need for oral agents, other than perhaps metformin, which is weight neutral and may help reduce the weight gain commonly associated with type 2 diabetes. In these situations, avoiding pioglitazone will preclude any cardiovascular adverse effects that may result, and will simplify drug therapy and avoid the costs of having another drug on board.


Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.
Post as: