Analysis Clarifies Drug Choices for People With Type 2 Diabetes

Norra MacReady

March 14, 2011

March 14, 2011 — Drug combinations used in the management of type 2 diabetes have similar hypoglycemic effects but show marked differences in adverse events, according to a new analysis.

The evidence supports the choice of metformin as first-line therapy but also finds that the long-term benefits and harms of diabetes medications remain unclear, the study's authors say.

Of the 11 unique medication classes approved to treat hyperglycemia in type 2 diabetes mellitus, 9 have been available since 1995, the researchers explain. This review of the literature was performed at the request of the Agency for Healthcare Research and Quality as an update of the agency's 2007 systemic review of the comparative safety and efficacy of oral hypoglycemic agents. The review includes drug classes newly approved by the US Food and Drug Administration. The goal of the review was to help clinicians and patients make well-informed choices regarding glucose control and the risk for adverse effects.

"This systematic review is the first to address the comparative effectiveness of newer diabetes medication classes as monotherapy and in combination therapies for a wide range of clinical outcomes in patients with type 2 diabetes," write Wendy L. Bennett, MD, MPH, of the Johns Hopkins University School of Medicine in Baltimore, Maryland, and colleagues in the Annals of Internal Medicine, published online March 14.

The review authors searched the MEDLINE, EMBASE, and Cochrane Central Register of Controlled Trials for original studies on nonpregnant participants 18 years or older with type 2 diabetes that assessed the harms and benefits of medications in a head-to-head comparison. Included in the analysis were metformin, second-generation sulfonylureas, thiazolidinediones, meglitinides, dipeptidyl peptidase-4 (DPP-4) inhibitors, and glucagon-like peptide-1 receptor agonists, both as monotherapy and in combination.

They chose studies that included intermediate outcomes (eg, changes in levels of hemoglobin A1c [HbA1c]); long-term clinical outcomes (eg, mortality); and effects on body weight, lipid levels, liver damage, congestive heart failure, cancer, allergic reactions, and other serious adverse events. Studies that had fewer than 40 patients, had followed up on the participants for less than 3 months, or had not had a drug comparison of interest were excluded. Three or more investigators graded each study on the quantity, quality, and consistency of the results; the directness of the measures used for each outcome; the precision of the results; and the magnitude of the effect observed. A total of 140 randomized clinical trials and 26 observational studies met the inclusion criteria.

Most of the medications reduced HbA1c levels by approximately 1 percentage point, but metformin was more effective than the DPP-4 inhibitors. All of the drugs also were associated with weight gain, with the notable exception of metformin, which "was consistently associated with weight reduction or neutrality," the study authors found.

Sulfonylureas were associated with a 4-fold increased risk for hypoglycemia vs metformin alone. In combination with metformin, the sulfonylureas increased hypoglycemia risk more than 5-fold vs metformin plus thiazolidinediones. The thiazolidinediones also increased the risk for congestive heart failure vs sulfonylureas, and the risk for bone fractures relative to metformin. Metformin, in turn, carried a risk for gastrointestinal tract adverse effects, particularly diarrhea, vs the thiazolidinediones. The effects of 2-drug combinations were additive vs monotherapy, both in glucose control and in the risk for adverse effects and weight gain.

The review excluded placebo-controlled trials, and many of the studies were of relatively short duration or had enrolled small numbers of patients. Also, the search was limited to English-language studies, the review authors said. Still, they concluded that "the evidence supports the use of metformin as a first-line agent." Although there was limited difference among the 2-drug combinations in impact on HbA1c levels, "some combinations increased risk for hypoglycemia and other adverse events." These data can help clinicians and patients make better decisions about their treatment options.

The Agency for Healthcare Research and Quality was the primary funding source for this study. A complete description of relevant financial relationships can be viewed at the Annals of Internal MedicineWeb site .

Ann Intern Med. Published online March 14, 2011. Full text

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