Dipeptidyl Peptidase 4 (DPP-4) Inhibitors

DPP-4 inhibitors inhibit the degradation of a variety of peptides involved with glucose-dependent stimulation of insulin secretion, such as glucagon-like peptide 1 (GLP-1) and gastric inhibitory peptide (GIP).1 DPP-4 contributes to myocardial damage through a variety of mechanisms, including cleaving and inactivating cardioactive peptides. By interfering with cleavage of these peptides, DPP-4 inhibitors may interfere with sodium reabsorption and increase the natriuretic response and may be effective in the setting of myocardial infarction (MI) and HF by potentiating the vascular and renal effects of natriuretic peptides.

A major trial, the Saxagliptin and Cardiovascular Outcomes in Patients with Type 2 Diabetes Mellitus (SAVOR-TIMI 53) evaluated the safety and efficacy of the DPP-4 inhibitor saxagliptin in patients with a history of or at risk for cardiovascular events. Saxagliptin was associated with an increased risk of HF hospitalization (3.5% vs 2.8%, P=0.007)6 and a post hoc analysis7 found that at 12 months, 1.9% of patients treated with saxagliptin were hospitalized for HF, compared to 1.3% in the placebo group (P=0.002). However, there was no significant difference in hospitalization between the saxagliptin and the placebo groups in rates beyond one year, and patients at greatest risk for hospitalization for HF had more severe disease.

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The Alogliptin after Acute Coronary Syndrome in patients with type 2 DM and acute coronary syndrome (EXAMINE)8 trial found that the rates of adverse cardiovascular events in the alogliptin group were not increased, as compared to placebo; and a post hoc analysis9 revealed that alogliptin had no effect on the composite of cardiovascular death and hospital admission for HF. However, there appeared to be a significantly increased risk of hospitalization in those without HF at baseline.9

The Trial Evaluating Cardiovascular Outcomes with Sitagliptin (TECOS)10,11 found no significant difference in all-cause mortality and HF hospitalization between the sitagliptin and the placebo groups.9 Vildagliptin, another DPP-4 inhibitor, may exert differential myocardial effects, as compared to the other agents in the same class.1 The Vildagliptin in Ventricular Dysfunction Diabetes (VIVIDD) study evaluated the effect of DPP-4 inhibition on left ventricular ejection fraction (LVEF) in patients with type 2 DM and NYHA class I-III HF.11-13 After 52 weeks, there were no significant differences in LVEF or HF hospitalization, but there were increases in LV systolic and end-diastolic volume in the vildagliptin group.11

The authors suggested that there may be in-class differences between the DPP-4 inhibitors, or that the difference in patient populations may be responsible for the divergent results.1