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

Abstract

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 metaanalysis where appropriate. Results Eight studies were included. Three of four studies found that insulin use was associated with increased risk for all 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. INTRODUCTIONWorldwide, more than 171 million people have diabetes, and its prevalence is expected to double by 2030.1 People with diabetes are at increased risk of developing heart failure, 2 3 with the relative risk increasing by 10-15% per unit increase in glycated haemoglobin. [4][5][6][7] Conversely, heart failure is present in 25-40% of all adults with diabetes.2 8-12 Moreover, people with heart failure have worse outcomes if they also have diabetes, [13][14][15] and it has been suggested that any level of hyperglycaemia is associated with increased rates of hospital admission, even in patients without manifest diabetes. 16How best to achieve glycaemic control in patients with diabetes and heart failure is therefore an important clinical question. Many antidiabetic drugs are now available to control hyperglycaemia. However, their role in managing diabetes in patients with heart failure is uncertain, 17 and considerable controversy exists about the overall effect of antidiabetic agents on ou...

The influence of glucose-lowering therapies on cancer risk in type 2 diabetes

“…It remains an open question as to whether, or to what extent, differences in circulating levels of insulin influence cancer progression in patients receiving treatment for diabetes, but answers to this question are urgently needed. The use of exogenous insulin is also associated with an increase in all-cause mortality in type 2 diabetes [18,19]. The association between diabetes and cancer has hitherto attracted relatively little attention from diabetes specialists, mainly because it was considered to be unavoidable.…”

Metformin reverses hexokinase and phosphofructokinase downregulation and intracellular distribution in the heart of diabetic mice

“…Our results here show that the treatment of diabetic mice with metformin ameliorates the downregulation of HK and PFK observed on nontreated diabetic animals. Among oral hypoglycemic agents, metformin has proved to be the only effective agent not associated with harm in patients with heart failures and diabetes (6,31). Moreover, this drug was also associated with the reduction of mortality of diabetic patients owing to the complications of diabetes cardiomyopathy, among other causes (6,31).…”

ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD – Summary

“…This drug has, however, been associated with lower mortality, lower all-cause hospital admission, and fewer adverse events. 305,306 When studied, accumulation of lactic acidosis was not verified. 307 In a nested case-control study including newly diagnosed heart failure and DM, the use of metformin [adjusted OR 0.65 (0.48-0.87)] or metformin with or without other agents [0.72 (0.59-0.90)] was associated with lower mortality, while other oral glucose-lowering agents or insulin were neutral in this respect.…”