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Metformin Reduces CardioVascular Mortality Risk by 26%

The widely prescribed metformin was alone among oral antidiabetic agents to show a significant effect on cardiovascular (CV) risk in a meta-analysis of 40 select controlled trials. It reduced CV mortality by 26% relative to any other antidiabetic agent or placebo, but there was no effect on all-cause mortality.

Rosiglitazone was the only such drug to show a possible risk increase, and it did so for all evaluated end points, none significantly, however.

"Our meta-analysis suggested that . . . metformin appeared moderately protective against cardiovascular effects and that rosiglitazone was possibly harmful, but a lack of power prohibited firmer conclusions," write the authors, led by Dr Elizabeth Selvin (Johns Hopkins Bloomberg School of Public Health, Baltimore, MD).

The group is up-front about the limitations of available data on the subject; in particular, the trials generally had glycemia-based end points and were too short to sufficiently evaluate CV risks. Few were longer than six months.

Dr David M Nathan  (Massachusetts General Hospital, Boston) said that,  "I think that the study was well done and that they did the best they could with the available data. Meta-analyses can’t be better than the data that underlie them. The included studies had been culled from 142 published randomized, controlled trials of oral drug therapy in type 2 diabetes. They were limited to those looking at second-generation sulfonylureas, biguanides, thiazolidinediones, and meglitinides that reported CV outcomes. Only two of the studies, however, included CV outcomes as prospectively defined end points.

Odds ratios (95% CI) for the effect of metformin vs any oral-antidiabetic comparator regimen or placebo in meta-analysis

End point

OR (95% CI)

Studies, n

Total participants, n

CV morbidity*

0.85 (0.69 – 1.05)

7

11,986

CV mortality

0.74 (0.62 – 0.89)

6

11,385

All-cause mortality

0.81 (0.60 – 1.08)

9

13,046

*Fatal and nonfatal myocardial infarction (MI) or stroke.

The meta-analysis had excluded heart-failure (HF) outcomes except when they couldn’t be distinguished from other events in combined end points. That was done, Selvin explained, "to isolate the possible risk related to fatal and nonfatal myocardial infarction or stroke," events that defined the third main end point of the meta-analysis, "cardiovascular morbidity."

Without consideration of HF end points, the analysis could not show whether the oral drugs might promote heart failure. However, Nathan observed, the thiazolidinedione effect on fluid retention and possible heart failure and the lack of such an effect with the other antidiabetic agents are well defined.

Given the limitations of the current meta-analysis and others that have recently looked at the CV safety of antidiabetic agents, according to Nathan’s editorial, "the conclusions drawn will be disappointing for healthcare practitioners who want a clear answer to the question ‘Is it safe?’ "

Practice Pearls:

  • Among the oral antidiabetic agents, reduction in CV morbidity and mortality rates has not been clearly demonstrated except for metformin.
  • Use of rosiglitazone for type 2 diabetes may be associated with increased CV mortality and morbidity rates.
  • Selvin E, Bolen S, Hsin-Chieh Yeh HC, et al. Cardiovascular outcomes in trials of oral diabetes medications: A systematic review. Arch Intern Med. 2008;168:2070-2080.
  • Nathan DM. Glycemic management of type 2 diabetes: How tight is right and how to get there. Arch Intern Med. 2008;168:2064-2066.