Diabetes Metab J.  2015 Oct;39(5):373-383. 10.4093/dmj.2015.39.5.373.

Dipeptidyl Peptidase 4 Inhibitors and the Risk of Cardiovascular Disease in Patients with Type 2 Diabetes: A Tale of Three Studies

• Son JW
• Kim S

• KMID: 2174010
• DOI: http://doi.org/10.4093/dmj.2015.39.5.373

Abstract

Dipeptidyl peptidase 4 (DPP4) inhibitors have been touted as promising antihyperglycemic agents due to their beneficial effects on glycemia without inducing hypoglycemia or body weight gain and their good tolerability. Beyond their glucose-lowering effects, numerous clinical trials and experimental studies have suggested that DPP4 inhibitors may exert cardioprotective effects through their pleiotropic actions via glucagon-like peptide 1-dependent mechanisms or involving other substrates. Since 2008, regulatory agencies have required an assessment of cardiovascular disease (CVD) safety for the approval of all new anti-hyperglycemic agents, including incretin-based therapies. Three large prospective DPP4 inhibitor trials with cardiovascular (CV) outcomes have recently been published. According to the Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus (SAVOR-TIMI 53) and EXamination of cArdiovascular outcoMes with alogliptIN versus standard of carE in patients with type 2 diabetes mellitus and acute coronary syndrome (EXAMINE) trials, DPP4 inhibitors, including saxagliptin and alogliptin, did not appear to increase the risk of CV events in patients with type 2 diabetes and established CVD or high risk factors. Unexpectedly, saxagliptin significantly increased the risk of hospitalization for heart failure by 27%, a finding that has not been explained and that requires further exploration. More recently, the Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS) trial demonstrated the CV safety of sitagliptin, including assessments of the primary composite CV endpoint and hospitalization for heart failure in patients with type 2 diabetes and established CVD. The CV outcomes of an ongoing linagliptin trial are expected to provide new evidence about the CV effects of a DPP4-inhibitor in patients with type 2 diabetes.

Keyword

Cardiovascular diseases; Diabetes mellitus, type 2; Dipeptidyl peptidase 4

MeSH Terms

Acute Coronary Syndrome
Body Weight
Cardiovascular Diseases*
Diabetes Mellitus
Diabetes Mellitus, Type 2
Dipeptidyl Peptidase 4*
Dipeptidyl-Peptidase IV Inhibitors*
Heart Failure
Hospitalization
Humans
Hypoglycemia
Hypoglycemic Agents
Prospective Studies
Risk Factors
Standard of Care
Linagliptin
Sitagliptin Phosphate
Dipeptidyl Peptidase 4
Dipeptidyl-Peptidase IV Inhibitors
Hypoglycemic Agents

Figure

• 

  Fig. 1 Dipeptidyl peptidase 4 inhibitor cardiovascular outcome trials. TECOS, The trial to Evaluate Cardiovascular Outcomes after treatment with Sitagliptin; EXAMINE, EXamination of cArdiovascular outcoMes with alogliptIN versus standard of carE in patients with type 2 diabetes mellitus and acute coronary syndrome; SAVOR-TIMI 53, Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus; CAROLINA, CARdiovascular Outcome Trial of LINAgliptin Versus Glimepiride in Type 2 Diabetes; CV, cardiovascular; MACE, major cardiac adverse events; 4P-MACE, cardiovascular (CV) death, non-fatal myocardial infarction (MI), non-fatal stroke or hospitalization for unstable angina; MI, myocardial infarction; 3P-MACE, CV death, non-fatal MI or non-fatal stroke.

• 

  Fig. 2 Risk of hospitalization for heart failure in SAVOR-TIMI 53, EXAMINE, and TECOS. CI, confidence interval; SAVOR-TIMI 53, Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus; EXAMINE, EXamination of cArdiovascular outcoMes with alogliptIN versus standard of carE in patients with type 2 diabetes mellitus and acute coronary syndrome; TECOS, The trial to Evaluate Cardiovascular Outcomes after treatment with Sitagliptin.

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