Risk of overall mortality and cardiovascular events in patients with type 2 diabetes on dual drug therapy including metformin: A large database study from the Cleveland Clinic

Abstract

Background: The aim of the present study was to assess the risk of overall mortality, coronary artery disease (CAD), and congestive heart failure (CHF) in patients with type 2 diabetes mellitus (T2DM) treated with metformin (MF) and an additional antidiabetic agent. Methods: A retrospective cohort study was conducted using an academic health center enterprise-wide electronic health record (EHR) system to identify 13 185 adult patients (>18 years) with T2DM from January 2008 to June 2013 and received a prescription for MF in combination with a sulfonylurea (SU; n = 9419), thiazolidinedione (TZD; n = 1846), dipeptidyl peptidase-4 inhibitor (DPP-4i; n = 1487), or a glucagon-like peptide-1 receptor agonist (GLP-1a; n = 433). Multivariate Cox models with propensity analysis were used to compare cohorts, with MF+SU serving as the comparator group. Results: The mean (±SD) age was 60.6 ± 12.6 years, with 54.6% male and 75.8% Caucasians. The median follow-up was 4 years. There were 1077 deaths, 1733 CAD events, and 528 CHF events in 55 100 person-years of follow-up. A higher risk of CHF was observed with MF+DPP-4i use (hazard ratio [HR] 1.104; 95% confidence interval [CI] 1.04-1.17; P = 0.001). A trend towards improved overall survival for users of MF+TZD (HR 0.86; 95% CI 0.74-1.0; P = 0.05) and MF+GLP-1a (HR 0.569; 95% CI 0.30-1.07; P = 0.08) was observed. No significant differences in the risk of CAD were identified. Conclusions: Consistent with recent studies, our results raise concern for an increased risk of CHF with use of DPP-4i.

Dipeptidyl peptidase-4 inhibitors and risk of heart failure in type 2 diabetes: systematic review and meta-analysis of randomised and observational studies

“…Effects on hospital admission for heart failure All five trials 9 evidence from observational studies Of 12 observational studies, four [109][110][111][112] reported heart failure, and eight 13-17 113-115 reported hospital admission for heart failure; nine 13-15 109-111 [113][114][115] were cohort studies and the other three 16 17 112 were nested case-control studies (fig 1). Observational studies reporting heart failure Of the four studies reporting heart failure, two prospective cohort studies 109 (table 4 and table 5).…”

“…All three cohort studies [109][110][111] reported unadjusted rates of heart failure, involving 541 events among 16 408 patients (raw event rate 3.3%). Because of the heterogeneous and indirect nature of the identified evidence-with substantial variations in comparisons and types of patients-we did not pool data across studies.…”

Do Dipeptidyl Peptidase IV (DPP-IV) Inhibitors Cause Heart Failure?

“…Overall, there were numerically more cardiovascular deaths in the treatment arm versus placebo (7 vs 4 deaths, respectively) with a total of 11 deaths in the vildagliptin arm and 4 deaths in the placebo arm. Heart failure events were reported by Krum et al 10 Four additional relevant publications on different high-risk patient cohorts were also found, one that examined patients with existing CVD drawn from a commercial claims database 14 and a second that studied Cleveland Clinic patients with documented existing CVD, 15 and a third from another commercial database examining only sitagliptin in patients with an acute cardiac event. 16 The fourth publication came from a United Kingdom general practice database.…”

“…15 The patients were followed for mortality, coronary artery disease, and congestive heart failure by documentation in the electronic health record. Combination therapy with metformin plus sulfonylurea served as the comparator group.…”

“…EXAMINE ¼ Examination of Cardiovascular Outcomes With Alogliptin Versus Standard of Care; SAVOR-TIMI 53 ¼ Saxagliptin Assessment of Vascular Outcomes Recorded in Patients with Diabetes MellitusThrombolysis in Myocardial Infarction; and VIVIDD ¼ Vildagliptin in Ventricular Dysfunction Diabetes.hospitalization for heart failure 4,5. The data from Kim et al 14 were convincingly negative in 48000 patients, whereas the data from Kannan et al15 had a relatively small number of patients using DPP-IV inhibitors (n ¼ 1487). Further, those patients were not propensity matched with those not on DPP-IV inhibitors, producing a less reliable dataset.…”