It is possible some anti-diabetic drugs may increase or decrease the risk of adverse cardiovascular events. The risk arrhythmia seems to be higher with exenatide, but the risk of all-cause mortality appears to be low with sitagliptin.


Diabetes is considered an important risk factor for cardiovascular disease. Alone or in a combination, anti-diabetic medications have been shown to be efficient to achieve short- and long-term goals regarding glycemic control. Glucagon-like peptide 1 receptor agonists (GLP-1 RAs) and dipeptidylpeptidase-4 inhibitors (DPP-4i) are drug classes constituting the incretin-based therapies (IBTs). These medications can be used as a monotherapy or along with other anti-diabetic drugs such as metformin, sulfonylureas, thiazolidinediones, or basal insulin. However, it is possible that not only diabetes, but also some anti-diabetic medications such as IBTs, may also be associated with an elevated risk for cardiovascular disease.

To test this hypothesis, researchers from China and USA performed a meta-analysis to evaluate major adverse cardiovascular events (MACE) along with arrhythmia and heart failure caused by IBTs in individuals with type 2 diabetes mellitus (T2DM). Authors included randomized controlled trials published after November 2014 with strict criteria regarding sample size [>100 participants for each group (intervention group receiving IBTs) and control group)] and follow-up (>24 weeks). One or more MACE was considered for analysis along with other endpoints such as arrhythmia and heart failure. One hundred randomized trials resulted in a total of 54,758 IBTs users and 48,175 controls.

The risk of arrhythmia using exenatide was almost three times higher versus controls. The mechanisms are not well understood, but it is possible that a hypoglycemic effect induced by anti-diabetic drugs may be a factor. An increased heart rate possibly caused by GLP-1 receptors located in the sinoatrial node is a common finding in literature. Saxagliptin seemed to be associated with heart failure, but the effect disappeared after adjusting for confounding factors. Sitagliptin use had a decreased risk of all-cause mortality in comparison with patients in the control group. Strengths of this meta-analysis include the use of studies that analyze MACE with IBT, rigorous inclusion criteria, follow-ups, large sample sizes and isolated endpoints rather than a composite of MACE outcomes. Studies that were not designed to address cardiovascular outcomes, low MACE incidence and a limited number of trials regarding the drugs albiglutide and dulaglutide are limitations of this meta-analysis.

Therefore, the increased risk of arrhythmia with exenatide and reduced risk of all-cause mortality with sitagliptin require further confirmation.




Written By: Vagner Raso

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