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Metformin offers moderate protection against cardiovascular outcomes, meta-analysis suggests

Wednesday, November 19 2008 | Comments

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What's This? Patients with type 2 diabetes who take metformin hydrochloride may receive moderate protection against adverse cardiovascular outcomes, while rosiglitazone maleate may increase the risk of such events, suggests a new meta-analysis. But researchers caution that large, long-term studies are required to draw firm conclusions about the major clinical benefits and risks related to oral diabetes agents.

The study, conducted by the Johns Hopkins Evidence-Based Practice Center under contract from the Agency for Healthcare Research and Quality, examined the peer-reviewed literature pertaining to the cardiovascular risk associated with oral agents used to treat adults with type 2 diabetes (second-generation sulfonylureas, biguanides, thiazolidinediones, and meglitinides).

The researchers identified 40 controlled trials that reported information about cardiovascular events (primarily myocardial infarction and stroke) and that met other inclusion criteria. Most of the trials were conducted in the United States or the United Kingdom. The mean age of participants ranged from 52 to 69 years.

Of the 40 trials considered, 8 tracked cardiovascular outcomes as a primary or secondary endpoint, and the remaining 32 considered cardiovascular outcomes as serious adverse events. The researchers noted the quality of serious adverse event reporting among these trials was fair, with an average quality score of 3 (maximum possible score, 4). Twelve trials scored a perfect 4, indicating that all serious adverse events, withdrawals, and dropouts were reported and that clear definitions of serious adverse events were provided in the manuscripts.

The odds of death from a cardiovascular event were reduced by 26% with metformin compared with any other oral diabetes agent or placebo (pooled odds ratio [OR], 0.74; 95% CI, 0.62-0.89). The results for cardiovascular morbidity and all-cause mortality were similar but not statistically significant.

The researchers noted that rosiglitazone was the only diabetes agent associated with an increased risk of cardiovascular morbidity, cardiovascular mortality, and/or all-cause mortality (ie, pooled ORs >1.0), although none of these associations was statistically significant. Specifically, use of rosiglitazone (vs use of other agents or placebo) was associated with an OR of 1.68 (95% CI, 0.92-3.06) for cardiovascular morbidity, an OR of 1.03 (95% CI, 0.30-3.53) for cardiovascular mortality, and an OR of 1.21 (95% CI, 0.39-3.77) for all-cause mortality.

The authors explained that this lack of statistical significance could have been influenced by small sample sizes and a limited number of included studies (n=5).

"No other differences in cardiovascular risk between other commonly used oral diabetes medications were evident in this literature," the authors concluded. "Nonetheless, the poor quality and inconsistent reporting of adverse events and the profound lack of long-term studies make it difficult to draw firm conclusions." (Selvin E, et al. Arch Intern Med 2008;168:2070-2080.)

"The current approach to assessing the relatively rare but clinically important adverse effects of diabetes management is unsatisfactory," wrote Dr. David Nathan of the Diabetes Center at Massachusetts General Hospital, adding that the "vagaries of meta-analyses make them unreliable."

Dr. Nathan called for innovation in ensuring the safety of drugs without slowing their development, suggesting the phased introduction of new drugs with standardized collection of adverse outcome data "to identify relatively rare complications before the drugs are used by millions" as well as the use of clinical databases to provide an early alert regarding adverse outcomes. (Arch Intern Med 2008;168:2064-2066.)

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