New Antihyperglycemic Drugs and Heart Failure: Synopsis of Basic and Clinical Data

The assessment of the cardiovascular safety profile of any newly developed antihyperglycemic drug is mandatory before registration, as a meta-analysis raised alarm describing a significant increase in myocardial infarction with the thiazolidinedione rosiglitazone. The first results from completed cardiovascular outcome trials are already available: TECOS, SAVOR-TIMI, and EXAMINE investigated dipeptidyl peptidase 4 (DPP-4) inhibitors, ELIXA, LEADER, and SUSTAIN-6 investigated glucagon-like peptide 1 (GLP-1) receptor agonists, and EMPA-REG OUTCOME and CANVAS investigated sodium-dependent glucose transporter 2 (SGLT-2) inhibitors. LEADER, SUSTAIN-6, EMPA-REG OUTCOME, and CANVAS showed potential beneficial results, while the SAVOR-TIMI trial had an increased rate of hospitalization for heart failure. Meanwhile, the same drugs are investigated in preclinical experiments mainly using various animal models, which aim to find interactions and elucidate the underlying downstream mechanisms between the antihyperglycemic drugs and the cardiovascular system. Yet the direct link for observed effects, especially for DPP-4 and SGLT-2 inhibitors, is still unknown. Further inquiry into these mechanisms is crucial for the interpretation of the clinical trials' outcome and, vice versa, the clinical trials provide hints for an involvement of the cardiovascular system. The synopsis of preclinical and clinical data is essential for a detailed understanding of benefits and risks of new antihyperglycemic drugs.