Metformin moderately protective against CV risk in type 2 diabetics

Compared with biguanides, thiazolidinediones, meglitinides, and second-generation sulfonylureas, metformin is the sole oral therapy associated with a decreased risk of cardiovascular (CV) mortality in patients with type 2 diabetes, according to a meta-analysis published in the Archives of Internal Medicine.

With regard to oral medications targeting glycemic control, effects upon the long-term risk of fatal and nonfatal CV disease and all-cause mortality are not yet well understood. In the absence of large, tightly controlled studies focused specifically on CV end points, authors of this meta-analysis sought to systematically review data from published, peer-reviewed, randomized, controlled clinical trials drawn from Medline, EMBASE, and the Cochrane Central Register of Controlled Trials through January 19, 2006. Inclusion criteria called for studies of commonly used single or combination therapies that had collected data on CV events and mortality. Studies of treatments rarely prescribed in the United States (eg, combinations of 3 agents, first-generation sulfonylureas, and alpha-glucosidase inhibitors) were excluded. The investigators also sought to exclude, to the extent possible, congestive heart failure events from CV outcomes. Minimum sample size was set at 40 patients, and the minimum trial duration was set at 3 months.

The 40 trials that met study criteria included both large undertakings, such as the United Kingdom Prospective Diabetes Study (UKPDS) and the Prospective Pioglitazone Clinical Trial in Macrovascular Events (PROactive), and other trials that were smaller and more limited. Patients had a mean age of 52 to 69 years, with a mean baseline hemoglobin (Hb) A1c ranging from 6.2% to 10.2%. Data were abstracted and analyzed by 2 independent reviewers according to standardized protocols for qualitative summary and quantitative synthesis. Consensus was used to reach agreement when necessary. Oral agents under examination were metformin, second-generation sulfonylureas, rosiglitazone, pioglitazone, and the meglitinides, taken alone or in combination and compared with other agents or with placebo and diet.

By any comparison, only metformin use demonstrated a statistically significant decrease in CV mortality (OR=0.74; 95% CI, 0.62–0.89). Metformin also appeared be the sole treatment to affect CV morbidity (OR=0.85; 95% CI, 0.69–1.05) and all-cause mortality (OR=0.81; 95% CI, 0.60–1.08), albeit slightly. Rosiglitazone was the only oral agent associated with an increased risk of CV mortality and morbidity and all-cause mortality (OR>1.0 for each outcome), although these increased risks were not statistically significant; the authors suggested that the statistical insignificance was likely because of small sample sizes and the scant number of studies considered.

In an accompanying editorial, David M. Nathan, MD, stated that “although carefully constructed,” this meta-analysis “cannot be better than the quality of the studies that it includes,” adding that “it is not clear whether we come closer to the truth by bundling together the results of large, well-constructed clinical trials, which specifically measure the outcomes of interest, with those of smaller studies, in which outcomes are collected more informally.” The authors of the meta-analysis appeared to agree, stating that “larger, long-term studies taken to hard end points and better reporting of cardiovascular events in short-term studies will be required to draw firm conclusions about major clinical benefits and risks related to oral diabetes agents.”

For the time being, said Dr Nathan, “we should continue to emphasize a goal of HbA1c levels of less than 7% for patients likely to benefit and the aggressive application of other interventions that reduce [CV] risk as demonstrated in clinical trials.”

Sources
Selvin E, Bolen S, Yeh H-C, et al. Cardiovascular outcomes in trials of oral diabetes medications. Arch Intern Med. 2008;168;2070–2080.

Nathan D. Glycemic management of type 2 diabetes: How tight is right and how to get there [editorial]. Arch Intern Med. 2008;168;2064–2066.