Benefits and harms of antidiabetic agents in patients with diabetes and heart failure: systematic review

Objective To review the literature on the association between antidiabetic agents and morbidity and mortality in people with heart failure and diabetes. Design Systematic review and meta-analysis of controlled studies (randomised trials or cohort studies) evaluating antidiabetic agents and outcomes (death and admission to hospital) in patients with heart failure and diabetes. Data sources Electronic databases, manual reference search, and contact with investigators. Review methods Two reviewers independently extracted data. Risk estimates for specific treatments were abstracted and pooled estimates derived by meta-analysis where appropriate. Results Eight studies were included. Three of four studies found that insulin use was associated with increased risk for ail cause mortality (odds ratio 1.25, 95% confidence interval 1.03 to 1.51; 3.42, 1.40 to 8.37 in studies that did not adjust for diet and antidiabetic drugs; hazard ratio 1.66, 1.20 to 2.31; 0.96, 0.88 to 1.05 in the studies that did). Metformin was associated with significantly reduced all cause mortality in two studies (hazard ratio 0.86, 0.78 to 0.97) compared with other antidiabetic drugs and insulin; 0.70, 0.54 to 0.91 compared with sulfonylureas); a similar trend was seen in a third. Metformin was not associated with increased hospital admission for any cause or for heart failure specifically. In four studies, use of thiazolidinediones was associated with reduced all cause mortality (pooled odds ratio 0.83, 0.71 to 0.97, I-2=52%, P=0.02). Thiazolidinediones were associated with increased risk of hospital admission for heart failure (pooled odds ratio 1.13, 1.04 to 1.22, I-2=0%, P=0.004). The two studies of sulfonylureas had conflicting results, probably because of differences in comparator treatments. Important limitations were noted in all studies. Conclusion Metformin was the only antidiabetic agent not associated with harm in patients with heart failure and diabetes. It was associated with reduced all cause mortality in two of the three studies. The role of antidiabetic agents in managing diabetes in patients with heart failure is uncertain,(1) and considerable controversy exists about their overall effect on outcomes in people with comorbid diabetes and heart failure.(w1 w2) Some evidence also suggests that tight glycaemic control (glycated haemoglobin <= 7%) may be associated with worse survival than less tight control in patients with heart failure, irrespective of the agent used.(2) We conducted a systematic review to examine the relation between antidiabetic treatment and outcomes in people with heart failure and diabetes.