The Effects of DPP-4 Inhibitors, GLP-1RAs, and SGLT-2/1 Inhibitors on Heart Failure Outcomes in Diabetic Patients With and Without Heart Failure History: Insights From CVOTs and Drug Mechanism

Abstract

Patients with type 2 diabetes (T2D) have a higher risk of heart failure (HF) than healthy people, and the prognosis of patients with diabetes and current or previous HF is worse than that of patients with only diabetes. We reviewed the HF outcomes in recently published cardiovascular outcome trials (CVOTs) of three new classes of anti-diabetic agents, namely, dipeptidyl peptidase-4 inhibitors (DPP-4is), glucagon-like-peptide 1 receptor agonists (GLP-1RAs), and sodium glucose cotransporter-2 inhibitors (SGLT-2is) or SGLT-2 and SGLT-1 dual inhibitors and divided the patients into two groups based on the history of HF (with or without) and analyzed their risks of HHF based on the receipt of the aforementioned anti-diabetes drug types. Since the follow-up period differed among the trials, we expressed the rate of HHF as events/1,000 person-years to describe the HF outcome. At last we pooled the data and analyzed their different effects and mechanisms on heart failure outcomes. Although DPP-4is did not increase the risk of HHF in T2D patients with a history of HF, they were associated with a significantly higher risk of HHF among patients without history of HF. Some GLP-1RAs reduced the risk of macrovascular events, but none of these drugs reduced the risk of HHF in patients with T2D irrespective of their HF history. It was not clarified whether SGLT-1/2is can improve the prognosis of macrovascular events in patients with T2D, but these drugs reduced the risk of HHF regardless of patients' histories of HF. This information may be useful or referential for the "precise" selection of hyperglycemic medications. Further researches still needed to clarify the mechanisms of these anti-diabetic medications.

Keywords: cardiovascular benefit; cardiovascular outcome trials; heart failure; hypoglycemic agents; type 2 diabetes.

Figure 1

The effect of DPP-4is on HHF in type 2 diabetic patients with and without history of HF. CVOT, cardiovascular outcome trial; HHF, hospitalization for heart failure; HF, heart failure; EF, ejection fraction; pi, p value of interaction; SAVOR TIMI 53, The Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes Mellitus (SAVOR)–Thrombolysis in Myocardial Infarction (TIMI) 53 trial; EXAMINE, Examination of Cardiovascular Outcomes with Alogliptin versus Standard of Care; TECOS, The Effect on Cardiovascular Outcomes in Type 2 Diabetes of Sitagliptin; CARMELINA, The Cardiovascular and Renal Microvascular Outcome Study with Linagliptin.

Figure 2

The effect of GLP-1RAs on HHF in type 2 diabetic patients with and without history of HF. CVOT, cardiovascular outcome trial; HHF, hospitalization for heart failure; HF, heart failure; Pi, p value of interaction; ELIXA, The Evaluation of Lixisenatide in Acute Coronary Syndrome; EXSCEL, Exenatide Study of Cardiovascular Event Lowering; LEADER, Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results; SUSTAIN-6, Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes; Harmony, Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease; REWIND, Dulaglutide and cardiovascular outcomes in type 2 diabetes.

Figure 3

The effect of SGLT-2is or SGLT-2/1is on HHF in type 2 diabetic patients with and without history of HF. CVOT, cardiovascular outcome trial; HHF, hospitalization for heart failure; HF, heart failure; EF, ejection fraction; pi, p value of interaction; EMPA-REG OUTCOME, The Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients; CANVAS, The Canagliflozin Cardiovascular Assessment Study; DECLARE, The Dapagliflozin Effect on Cardiovascular Events.

Figure 4

A schematic picture of the manuscript. The use of DPP-4i increases the risk of hospitalization for heart failure in T2D patients without prior heart failure, but present a neutral effect in T2D patients with prior heart failure. The use of GLP-1RA presents a neutral effect on the risk of hospitalization for heart failure no matter the heart failure status of T2D patients. SGLT-2i reduces the risk of hospitalization for heart failure no matter the heart failure status of T2D patients.