Cardiovascular Effects of New Oral Glucose-Lowering Agents: DPP-4 and SGLT-2 Inhibitors.

Abstract

Cardiovascular disease (CVD) is a major challenge in the management of type 2 diabetes mellitus. Glucose-lowering agents that reduce the risk of major cardiovascular events would be considered a major advance, as recently reported with liraglutide and semaglutide, 2 glucagon-like peptide-1 receptor agonists, and with empagliflozin and canagliflozin, 2 SGLT-2 (sodium-glucose cotransporter type 2) inhibitors, but not with DPP-4 (dipeptidyl peptidase-4) inhibitors. The present review is devoted to CV effects of new oral glucose-lowering agents. DPP-4 inhibitors (gliptins) showed some positive cardiac and vascular effects in preliminary studies, and initial data from phase 2 to 3 clinical trials suggested a reduction in major cardiovascular events. However, subsequent CV outcome trials with alogliptin, saxagliptin, and sitagliptin showed noninferiority but failed to demonstrate any superiority compared with placebo in patients with type 2 diabetes mellitus and high CV risk. An unexpected higher risk of hospitalization for heart failure was reported with saxagliptin. SGLT-2 inhibitors (gliflozins) promote glucosuria, thus reducing glucose toxicity and body weight, and enhance natriuresis, thus lowering blood pressure. Two CV outcome trials in type 2 diabetes mellitus patients mainly in secondary prevention showed remarkable positive results. Empagliflozin in EMPA-REG-OUTCOME (EMPAgliflozin Cardiovascular OUTCOME Events in Type 2 Diabetes Mellitus Patients) reduced major cardiovascular events, CV mortality, all-cause mortality, and hospitalization for heart failure. In CANVAS (Canagliflozin Cardiovascular Assessment Study), the reduction in CV mortality with canagliflozin failed to reach statistical significance despite a similar reduction in major cardiovascular events. The underlying protective mechanisms of SGLT-2 inhibitors remain unknown and both hemodynamic and metabolic explanations have been proposed. CVD-REAL studies (Comparative Effectiveness of Cardiovascular Outcomes in New Users of Sodium-Glucose Cotransporter-2 Inhibitors; with the limitation of an observational approach) suggested that these favorable results may be considered as a class effect shared by all SGLT-2 inhibitors (including dapagliflozin) and be extrapolated to a larger population of patients with type 2 diabetes mellitus in primary prevention. Ongoing CV outcome trials with other DPP-4 (linagliptin) and SGLT-2 (dapagliflozin, ertugliflozin) inhibitors should provide additional information about CV effects of both pharmacological classes.

• Authors: André J Scheen
• Journal: Circulation research (Circ Res) Vol. 122 Issue 10 Pg. 1439-1459 (05 11 2018) ISSN: 1524-4571 [Electronic] United States
• PMID: 29748368 (Publication Type: Journal Article, Review)
• Copyright: © 2018 The Authors.

Chemical References

• Dipeptidyl-Peptidase IV Inhibitors
• Glucagon-Like Peptide-1 Receptor
• Hypoglycemic Agents
• Incretins
• Sodium-Glucose Transporter 2 Inhibitors

Topics

• Cardiovascular Diseases (etiology, mortality, prevention & control)
• Cardiovascular System (drug effects)
• Clinical Trials as Topic
• Diabetes Mellitus, Type 2 (complications, drug therapy)
• Diabetic Cardiomyopathies (prevention & control)
• Diabetic Nephropathies (prevention & control)
• Dipeptidyl-Peptidase IV Inhibitors (adverse effects, pharmacology, therapeutic use)
• Glucagon-Like Peptide-1 Receptor (agonists)
• Hospitalization
• Humans
• Hypoglycemic Agents (adverse effects, pharmacology, therapeutic use)
• Incretins (metabolism)
• Meta-Analysis as Topic
• Multicenter Studies as Topic
• Observational Studies as Topic
• Risk
• Sodium-Glucose Transporter 2 Inhibitors (pharmacology, therapeutic use)
• Treatment Outcome