There have been few rigorous systematic reviews of hard clinical outcomes comparing oral diabetes agents. Recent meta-analyses have focused on possible cardiovascular effects of single drugs, particularly the newer thiazolidinediones, rosiglitazone and pioglitazone(6
). We included the most common oral diabetes medications currently in use in the U.S. to provide a comprehensive picture of possible cardiovascular risk. When compared to any other treatment or placebo, we found that metformin was associated with a statistically significant decrease in cardiovascular mortality(OR=0.74, 95%CI 0.62-0.89). The point estimates for metformin with cardiovascular morbidity and all-cause mortality were similar, but not statistically significant. When compared to any other diabetes agent or placebo, rosiglitazone was the only therapy which was associated with a possible increase in risk of cardiovascular morbidity or mortality, but these results were not statistically significant. No other differences in cardiovascular risk between other commonly used oral diabetes medications were evident in this literature. Nonetheless, the poor quality and inconsistent reporting of adverse events and profound lack of long-term studies makes it difficult to draw firm conclusions.
The UKPDS was designed principally to examine the effect of absolute reductions in glucose on long-term outcomes. In UKPDS, the lack of difference in cardiovascular risk reduction when indirect comparisons were made across treatments but significant reduction observed when intensive control was compared to the conventional treatment group suggests that it is glycemic control per se
which may be partially driving cardiovascular risk reduction. This is consistent with several other large, epidemiologic studies(2
). Furthermore, in the PROactive study, the pioglitazone group had a 0.8 absolute percentage point decrease in HbA1c
compared to a 0.3 absolute percentage point decrease in the control arm; this trial showed a corresponding moderate reduction in the secondary endpoint (all-cause mortality, non-fatal myocardial infarction, and stroke) in the pioglitazone-treated group compared to control.
Questions have recently been raised regarding possible “cardiotoxic” side-effects of rosiglitazone, a newer thiazolidinedione. The Diabetes Reduction Assessment with Ramipril and Rosiglitazone Medication (DREAM), a large study in individuals with pre-diabetes published in 2006, showed that rosiglitazone was associated with a reduced risk of the composite outcome of incident diabetes (based on glucose levels) and death(36
). The interpretation of this trial has been controversial because of a borderline statistically significant increase in cardiovascular events(RR=1.37, p-value=0.08) and a statistically significant increase in congestive heart failure cases in the treatment arm(RR=7.03, p-value = 0.01)(37
). A second study in persons with type 2 diabetes, the A Diabetes Outcome Prevention Trial(ADOPT), was published after the completion of our literature search and so was not included in our analyses(38
). The ADOPT trial showed a non-significant increase in fatal and non-fatal myocardial infarction in the rosiglitazone group compared with metformin or glyburide. A recent meta-analysis by Nissen et al(6
) suggested a statistically significant excess of cardiovascular morbidity due to treatment with rosiglitazone in a pooled analysis that included a diverse population of published and unpublished studies of individuals with and without type 2 diabetes (including ADOPT and DREAM). An interim analysis of the Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycaemia in Diabetes (RECORD) trial showed no statistically significant elevation in cardiovascular risk (besides congestive heart failure) related to rosiglitazone treatment compared with metformin and sulfonlyureas (39
). Some data relevant to the question of cardiovascular risk among persons taking oral diabetes medications exists outside the peer-reviewed literature and have been included in previous reviews including that by Nissen et al(6
). In a sensitivity analysis in which we pooled data from the ADOPT, RECORD, and eligible unpublished trials analyzed by Nissen et al with our included studies resulted in a pooled ORs of 1.28(95%CI 0.95-1.76) for cardiovascular morbidity and 1.24(95%CI 0.87-1.79) for cardiovascular mortality when comparing rosiglitazone with any other comparator. Our main results, based exclusively on published data in persons with type 2 diabetes, are not inconsistent with an increase in cardiovascular risk with rosiglitazone treatment, but we had an insufficient number of studies to draw firm conclusions. The interpretation of the data on rosiglitazone remains controversial.
The limitations of this meta-analysis largely reflect the limitations of the published literature on oral diabetes medications. A major weakness is there have been few trials undertaken to examine the comparative effectiveness of oral diabetes medications on cardiovascular outcomes. Indeed, there were only two studies included in our quantitative analyses that had participant follow-up greater than 2 years. Importantly, despite combining multiple comparator groups together, the total number of events in each of our comparisons of interest was small and we only included studies which had at least one cardiovascular event in one arm. Studies which did not report collecting information on cardiovascular events were excluded from the review. Furthermore, while we attempted to exclude congestive heart failure cases from all analyses, we relied on the definitions in the individual studies and there were instances in which the reporting of cardiovascular events was ambiguous.
The current evidence of comparing specific oral diabetes medications for risk of cardiovascular morbidity and mortality is inconclusive. Our study demonstrates that there are few trials of oral diabetes therapies that last longer than 6 months, and adverse event reporting for cardiovascular disease is poor. As most medications have similar short-term efficacy(10
) selecting appropriate oral therapy is largely based on patient and provider preferences, side effect profile, and cost. There is a critical need for studies of oral diabetes medications with long-term outcomes. The relatively modest differences in blood pressure, cholesterol, and weight observed with treatment of oral diabetes medications in short term trials may not translate to changes in long term cardiovascular risk. Only long-term trials can provide definitive conclusions regarding the comparative efficacy of oral diabetes medications and long term risks. Because individuals with diabetes are at a dramatically elevated risk of cardiovascular disease, trials of even one to two years duration with rigorous and standardized adverse event reporting can provide important information, especially when the results of separate studies can be pooled. One clear conclusion from the literature is that all clinical trials comparing oral diabetes medications, regardless of duration, should endeavor to rigorously collect and report adverse events including cardiovascular and all-cause mortality. This includes clear protocols for reporting adverse events and determining reasons for withdrawal of study participants. The development of the CONSORT standards for reporting of randomized clinical trials(14
)—which requires that “all important adverse events or side effects in each intervention group” be reported—should help ameliorate this problem, but such standards need to be rigorously and consistently applied.
In conclusion, our meta-analysis suggested that compared to other oral diabetes agents and placebo, metformin appeared moderately protective and rosiglitazone possibly harmful, but lack of power prohibited firmer conclusions. Larger, long-term studies taken to hard endpoints 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.