A systematic review pooled 29 randomised trials and 67,873 adults with type 2 diabetes, with and without existing cardiovascular disease, to test whether dipeptidyl peptidase-4 (DPP-4) inhibitors raise heart failure events. Only randomised trials were included; cohort and case-control studies were excluded. Subgroups were analysed by individual drug, follow-up duration and comparator.
Across the class there was no association: risk ratio 1.06, 95% CI 0.94 to 1.12. In subgroup analysis, saxagliptin alone showed a significant increase in heart failure risk. The authors flag several limitations and ask that the result be read cautiously.
This matters most where gliptins are used most. In India they are a mainstay second-line agent, chosen for tolerability, weight neutrality, safety in kidney impairment and cost relative to newer classes. A class-wide heart failure warning would have unsettled a very large number of prescriptions. It does not appear to be warranted — but the drug-specific finding is consistent with the regulatory warnings issued years ago for saxagliptin and alogliptin, and those warnings still stand.
So: sitagliptin, linagliptin and vildagliptin can continue as before in patients without heart failure. In a patient who has heart failure, or is at high risk of it, the question is not really which gliptin — it is whether a sodium-glucose cotransporter-2 (SGLT2) inhibitor should be in the regimen instead, since that class actively reduces heart failure hospitalisation rather than merely not causing it.
- Do not stop a gliptin for heart failure risk alone in a patient without heart failure
- Avoid saxagliptin in anyone with heart failure or reduced ejection fraction; switch rather than monitor
- In a patient with type 2 diabetes and heart failure, ask whether an SGLT2 inhibitor is being used before debating the gliptin
- Record ejection fraction or a heart failure diagnosis in the notes when choosing between agents in this class
- Review any patient still on saxagliptin who has developed breathlessness or oedema since starting
The statistics, in plain English
A risk ratio of 1.06 with an interval spanning 1.0 means the trials cannot distinguish this from no effect, and the upper bound of 1.12 rules out a large class-wide hazard. Note what a subgroup finding is worth: with subgroups by drug, by duration and by comparator, several comparisons were made, and one turning positive by chance is expected. The saxagliptin result carries weight not because of this analysis but because it agrees with a dedicated cardiovascular outcome trial and the regulatory warning that followed it.
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