Cardiovascular outcomes in trials of oral diabetes medications: a systematic review

Abstract

Background: A wide variety of oral diabetes medications are currently available for the treatment of type 2 diabetes mellitus, but it is unclear how these agents compare with respect to long-term cardiovascular risk. Our objective was to systematically examine the peer-reviewed literature on the cardiovascular risk associated with oral agents (second-generation sulfonylureas, biguanides, thiazolidinediones, and meglitinides) for treating adults with type 2 diabetes.

Methods: We searched MEDLINE, EMBASE, and the Cochrane Central Register of Controlled Trials, from inception through January 19, 2006. Forty publications of controlled trials that reported information on cardiovascular events (primarily myocardial infarction and stroke) met our inclusion criteria. Using standardized protocols, 2 reviewers serially abstracted data from each article. Trials were first described qualitatively. For comparisons with 4 or more independent trials, results were pooled quantitatively using the Mantel-Haenszel method. Results are presented as odds ratios (ORs) and corresponding 95% confidence intervals (CIs).

Results: Treatment with metformin hydrochloride was associated with a decreased risk of cardiovascular mortality (pooled OR, 0.74; 95% CI, 0.62-0.89) compared with any other oral diabetes agent or placebo; the results for cardiovascular morbidity and all-cause mortality were similar but not statistically significant. No other significant associations of oral diabetes agents with fatal or nonfatal cardiovascular disease or all-cause mortality were observed. When compared with any other agent or placebo, rosiglitazone was the only diabetes agent associated with an increased risk of cardiovascular morbidity or mortality, but this result was not statistically significant (OR, 1.68; 95% CI, 0.92-3.06).

Conclusions: Meta-analysis suggested that, compared with other oral diabetes agents and placebo, metformin was moderately protective and rosiglitazone possibly harmful, but lack of power prohibited firmer conclusions. 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.

Figure 1. Summary of Literature Search (number of articles)

Figure 2. Forrest Plots of Odds Ratios of Cardiovascular Morbidity for Major Comparisons of Interest

Panel A. Metformin vs Placebo or Other Oral Agent Panel B. Any Sulfonlyurea vs Placebo or Other Oral Agent Panel C. Rosiglitazone vs Placebo or Other Oral Agent Panel D. Pioglitazone vs Placebo or Oral Agent Boxes are the odds ratios estimated from each study; the horizontal bars are 95% confidence intervals. The size of the box is proportional to the weight of the study in the pooled analysis. The pooled Mantel- Haenszel odds ratios are represented by the diamonds; the width of the diamond represents the pooled 95% confidence interval. The vertical line at 1.0 indicates no effect.

Figure 2. Forrest Plots of Odds Ratios of Cardiovascular Morbidity for Major Comparisons of Interest

Panel A. Metformin vs Placebo or Other Oral Agent Panel B. Any Sulfonlyurea vs Placebo or Other Oral Agent Panel C. Rosiglitazone vs Placebo or Other Oral Agent Panel D. Pioglitazone vs Placebo or Oral Agent Boxes are the odds ratios estimated from each study; the horizontal bars are 95% confidence intervals. The size of the box is proportional to the weight of the study in the pooled analysis. The pooled Mantel- Haenszel odds ratios are represented by the diamonds; the width of the diamond represents the pooled 95% confidence interval. The vertical line at 1.0 indicates no effect.

Figure 2. Forrest Plots of Odds Ratios of Cardiovascular Morbidity for Major Comparisons of Interest

Panel A. Metformin vs Placebo or Other Oral Agent Panel B. Any Sulfonlyurea vs Placebo or Other Oral Agent Panel C. Rosiglitazone vs Placebo or Other Oral Agent Panel D. Pioglitazone vs Placebo or Oral Agent Boxes are the odds ratios estimated from each study; the horizontal bars are 95% confidence intervals. The size of the box is proportional to the weight of the study in the pooled analysis. The pooled Mantel- Haenszel odds ratios are represented by the diamonds; the width of the diamond represents the pooled 95% confidence interval. The vertical line at 1.0 indicates no effect.

Figure 2. Forrest Plots of Odds Ratios of Cardiovascular Morbidity for Major Comparisons of Interest

Panel A. Metformin vs Placebo or Other Oral Agent Panel B. Any Sulfonlyurea vs Placebo or Other Oral Agent Panel C. Rosiglitazone vs Placebo or Other Oral Agent Panel D. Pioglitazone vs Placebo or Oral Agent Boxes are the odds ratios estimated from each study; the horizontal bars are 95% confidence intervals. The size of the box is proportional to the weight of the study in the pooled analysis. The pooled Mantel- Haenszel odds ratios are represented by the diamonds; the width of the diamond represents the pooled 95% confidence interval. The vertical line at 1.0 indicates no effect.