IN JULY 2010, TAKEDA LAUNCHED AN AGGRESSIVE AD campaign proclaiming that its leading diabetes medication, pioglitazone, was far safer than its rival, rosiglitazone. The ad stated, “Actos lower[s] blood sugar without increasing your risk of having a heart attack or stroke.” This may be true, but just because pioglitazone might be safer than rosiglitazone does not mean it is the safest and most effective treatment choice. For many patients currently taking rosiglitazone, simply switching to another thiazolidinedione (TZD) such as pioglitazone is not necessarily the best option. When making treatment decisions, physicians and patients must weigh the benefits and risks of therapy. Treatment for diabetes with glucose-lowering agents is focused on preventing complications of diabetes without causing adverse effects. The balance of these risks and benefits depends on the safety and effectiveness of individual medications in the context of clinical factors (such as comorbidities and life expectancy) and patient values. At present, there is insufficient evidence from clinical trials to support the choice of one specific class of glucoselowering agents over another with respect to long-term outcomes. The prevailing assumption has been that the degree to which these agents reduce glucose levels will determine how well they reduce the risk of complications, including major cardiovascular events, regardless of the medication strategy chosen. Recent experience with rosiglitazone suggests otherwise. As a result, the US Food and Drug Administration (FDA) recently began to require data on cardiovascular outcomes for approval of diabetes agents. Because long-term clinical outcomes data for most glucose-lowering agents are still lacking, the current consensus statement of the American Diabetes Association and European Association for the Study of Diabetes makes therapeutic recommendations based on surrogate outcomes, such as effectiveness of glucose lowering, safety, tolerability, and expense. These comparisons tend to favor metformin; therefore, metformin is recommended as the first-line agent for treatment of diabetes along with lifestyle modification. Metformin is safe and well tolerated and reduces blood glucose levels effectively without causing hypoglycemia or weight gain. Moreover, in a small subgroup of the UK Prospective Diabetes Study, metformin reduced the risk of cardiovascular events. The consensus statement recommends either insulin or sulfonylureas (depending on glucose level) as preferred second-line medications with the strongest supportive evidence if metformin is contraindicated or does not achieve desired glucose control. Sulfonylureas are as effective as metformin for glucose lowering and insulin can be used to manage glucose to achieve a more tightly controlled target level. However, both sulfonylureas and insulin have potential adverse effects, including weight gain and hypoglycemia. Thiazolidinediones are not recommended as part of the well-validated core therapy for diabetes because of their adverse effect profile. Both rosiglitazone and pioglitazone increase the risk of significant weight gain and lowerextremity edema and have been associated with accelerated bone loss and fractures among women. Moreover, both medications now carry an FDA black box warning after multiple studies have confirmed that they increase the risk of heart failure and related adverse events. Although the magnitude of the risk associated with each agent varies by degree among different studies, the most recent FDA metaanalysis confirmed that the risk was elevated for both agents—nearly 1.5 greater odds for pioglitazone and double for rosiglitazone. The risk of heart failure is particularly concerning. Heart failure prognosis in patients with diabetes is known to be poor. Although some supporters of TZD therapy argue that the medications result in benign fluid overload, the evidence suggests that these heart failure events represent significant adverse outcomes, including hospitalization for heart failure or prolongation of a hospitalization stay, fatal or lifethreatening events, and events resulting in persistent significant disability or incapacity. These serious adverse events have been estimated to occur once among every 62 patients treated for approximately 3 years. Despite these concerns, physicians rapidly adopted TZDs for the treatment of diabetes. Although these medications were first introduced to the market in 1997, by
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Sep 28, 2023
Valentina Guarnotta + 6
Open Access
