Association of Antidiabetic Medications Targeting the Glucagon-Like Peptide 1 Pathway and Heart Failure Events in Patients With Diabetes

Abstract

Background Glucagon-like peptide-1 (GLP-1) agonists and dipeptidyl peptidase-4 (DPP-4) inhibitors (GLP-1 agents) may be protective in heart failure (HF). We set out to determine whether GLP-1 agent use is associated with HF risk in diabetics. Methods and Results Retrospective cohort study of members of a large health system. We identified >19,000 adult diabetics from January 1, 2000–July 1, 2012. GLP-1 agent users were matched 1:2 to controls using propensity matching based on age, race, gender, coronary disease, HF, diabetes duration, and number of anti-diabetic medications. The association of GLP-1 agents with time to HF hospitalization was tested with multivariable Cox regression. All-cause hospitalization and mortality were secondary endpoints. We identified 1,426 users of GLP-1 agents and 2,798 controls. Both were similar except for angiotensin-converting enzyme inhibitors/angiotensin receptor blocker (ACEi/ARB) use, number of anti-diabetic medications and age. There were 199 hospitalizations, of which 128 were for HF, and 114 deaths. GLP-1 agents were associated with reduced risk of HF hospitalization (adjusted hazard ratio [aHR] 0.51; 95% confidence interval [CI] 0.34–0.77, p=0.002), all-cause hospitalization (aHR 0.54; 95% CI 0.38–0.74, p=0.001), and death (aHR 0.31; 95% CI 0.18–0.53, p=0.001). Conclusions GLP-1 agents may reduce the risk of HF events in diabetics.

Association Between Hospitalization for Heart Failure and Dipeptidyl Peptidase 4 Inhibitors in Patients With Type 2 Diabetes: An Observational Study

“…Prior observational studies (12,(14)(15)(16)(17)(18)(19)(20)(21)(22)(23) that assessed the association between hHF and either the DPP-4i agents as a class or specific DPP-4i agents (i.e., sitagliptin) have used a wide variety of designs and patient populations with mixed results. Two studies (12,18) identified that DPP-4i treatment is associated with a reduced rate of hHF relative to other oral antihyperglycemic medications, two studies (14,16) suggested a neutral association relative to other oral antihyperglycemic medications and/or insulin, and two studies (19,20) suggested an increased rate of hHF with DPP-4i treatment relative to matched control subjects not otherwise initiating a new antihyperglycemic medication but rather in the midst of treatment with any of a range of potential antihyperglycemic medications. Notably, the designs used by the two studies that found an association between the DPP-4i treatment and an increased rate of heart failure may have created a risk of residual bias in favor of the matched control subjects; all else being equal, the matched patients did not necessarily require new pharmacotherapy to manage their diabetes.…”

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).…”

“…Effects on hospital admission for heart failure All but one retrospective cohort study 115 reported unadjusted rates of hospital admission for heart failure. The five cohort studies 13 to imprecision *Most trials had unclear risk of bias on random sequence generation and allocation concealment (web appendix 2), and the follow-up (median of 52 weeks) was not long enough for heart failure to occur in patients at low risk of cardiovascular disease.…”

Dipeptidyl peptidase-4 inhibitors and cardiovascular risks in patients with pre-existing heart failure

“…Without the inclusion of data from this trial, data on increased risks associated with DPP-4 inhibitor use are insufficient, and real-world observational studies are needed to address this knowledge gap. Some previous observational studies have suggested the patients with T2DM receiving incretin-based regimens were at increased risk of hospitalisation for HF,23 24 whereas other studies have found no such association25–27 or even a decreased risk of hospitalisation 28 29. However, only one of these studies focused on patients with pre-existing HF 24.…”