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Metformin linked with decreased CV risk, rosiglitazone linked with increased risk
However, meta-analysis lacks power and establishes need for long-term studies.
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Findings from a new meta-analysis demonstrate a moderately protective effect of metformin against cardiovascular events.
Elizabeth Selvin, PhD, MPH, and colleagues at Johns Hopkins and Washington University analyzed data from 40 clinical trials published on or before Jan. 19, 2006. Each trial assessed the benefits or risks of oral diabetes medications approved for use in the United States — biguanides, meglitinides, sulfonylureas, thiazolidinediones — and the effects on myocardial infarction, stroke and other CV events.
“With the addition of newer oral therapies to the market in the late 1990s, such as TZDs and meglitinides, it is critical to evaluate how these agents compare with older medications,” the researchers wrote in Archives of Internal Medicine.
The analysis revealed that metformin was associated with a decreased risk for CV mortality (OR=0.74; 95% CI, 0.62-0.89) when compared with other diabetes therapies or placebo. No association was reported between other oral diabetes medications and CV effects.
Rosiglitazone was the only diabetes agent associated with an increased risk for CV morbidity and mortality (OR=1.68; 95% CI, 0.92-3.06).
However, the meta-analysis lacked power and prohibited firmer conclusions, according to the researchers. They cited poor quality and inconsistent reporting of CV data and lack of long-term studies (68% were less than one year in duration).
“The relatively modest differences in blood pressure, cholesterol levels and weight observed after treatment with oral diabetes medications in short-term trials may not translate to changes in long-term CV risk,” the researchers wrote.
Problematic quality of data
David M. Nathan, MD, echoed the researchers’ recommendation for long-term studies.
“Selvin et al noted that, when it comes to choosing the safest oral agents, the quality of the data is problematic,” he wrote in an accompanying editorial. “The current approach to assessing the relatively rare but clinically important adverse effects of diabetes management is unsatisfactory. The vagaries of meta-analyses make them unreliable.”
Nathan recommended several new approaches, such as phased introduction of new medications, standardized collection of adverse event data and use of clinical databases. – Katie Kalvaitis
Arch Intern Med. 2008;168:2070-2080.
The systematic review by Selvin et al is a comprehensive look at oral diabetes medications and their effects on CV outcomes in the context of glycemic control. The results are not that surprising, but one has to look at such results in the context of a systematic review not being better than an outcome trial. Specifically, a careful look at the studies used in this analysis method shows that UKPDS clearly leads the way in terms of numbers of patients studied and duration of follow-up. Bundling more studies together with more diverse inclusion criteria does not necessarily bring one closer to the ‘truth.’ Nevertheless, the study confirms that in patients without significant kidney disease, metformin is beneficial in lowering CV events and that rosiglitazone and pioglitazone don’t seem to offer as much benefit yet are not harmful, even though mechanistically they showed great promise. Until ACCORD is finished we really won’t know the exact benefit of glycemic control with the cocktail used to achieve HbA1c <7%. We do know that too aggressive glycemic control increases CV events. In short, this review confirms that metformin is useful for CV risk reduction in patients with early diabetes and normal kidney function. Is that really news? The problem is that the prevalence and incidence of diabetes is increasing and record numbers of patients are reaching dialysis. Metformin has no role in such patients or those with a glomerular filtration rate <60 mL per minute, the highest CV risk group with diabetes. So the conclusions from this analysis only apply to early treatment of patients with diabetes and not advanced disease.
– George Bakris, MD
Endocrine Today Editorial Board member
Director, Hypertensive Diseases Unit, University of Chicago – Pritzker School of Medicine