GLP-1 RAs Show Survival and Cardiovascular Benefits in Patients With HFrEF and Diabetes

A comprehensive real-world analysis suggests that GLP-1 receptor agonists (GLP-1 RAs) provide significant protection against mortality and major cardiovascular events for individuals with both type 2 diabetes (T2DM) and heart failure with reduced ejection fraction (HFrEF).

The observational study, led by Cleveland Clinic researchers and published in American Heart Journal Plus: Cardiology Research and Practice, indicates that these agents may fill an important therapeutic gap for a high-risk population that has historically been inadequately represented in major clinical trials. “These findings offer reassurance that GLP-1 receptor agonists are not only safe for stable patients with HFrEF but may even be helpful in improving long-term clinical outcomes,” says study co-author Gautam Shah, MD, a Cleveland Clinic staff cardiologist. “We look forward to potential validation of these findings in prospective studies.”

The rationale: Addressing clinical uncertainty

While GLP-1 RAs have become a cornerstone of managing T2DM and atherosclerotic cardiovascular disease, their specific utility in HFrEF has remained a subject of debate. Previous dedicated clinical trials, such as FIGHT and LIVE, both of which studied the GLP-1 RA agent liraglutide, failed to demonstrate significant clinical or echocardiographic improvements in patients with advanced systolic dysfunction. Instead, there was some evidence of potential worsening of heart failure stability and arrhythmia burden with the use of liraglutide in these patients with advanced HFrEF.

Conversely, recent data from the SELECT trial suggested cardiovascular benefits with semaglutide in patients with heart failure as well as overweight or obesity (but without diabetes), although only a third of these patients had HFrEF and most of those participants had relatively mild heart failure symptoms.

Given these conflicting signals, the investigators sought to clarify the impact of GLP-1 RAs using a large-scale, real-world cohort. The goal was to determine whether the cardioprotective effects seen in broader diabetic populations would translate to the vulnerable population of patients with concomitant HFrEF.

Study design: A robust observational approach

The researchers used the TriNetX global health research network, accessing de-identified electronic medical records for approximately 136 million patients, predominantly in the U.S. They identified adults with a diagnosis of T2DM and a documented left ventricular ejection fraction (LVEF) of 40% or less.

To minimize potential bias in this retrospective analysis, the authors used an active-comparator new-user design in which they compared only patients starting either of two drug classes — a GLP-1 RA (semaglutide, dulaglutide, liraglutide, exenatide, albiglutide) or a dipeptidyl peptidase-4 (DPP4) inhibitor (saxagliptin, alogliptin, sitagliptin, linagliptin).

Using propensity score matching (1:1), they balanced the two groups across various parameters, including age, body mass index, baseline LVEF, comorbidities and use of guideline-directed medical therapy. This resulted in a final matched cohort of 26,196 patients (13,098 for each drug class), with a mean age of approximately 66.5 years and about 73.3% prevalence of ischemic heart disease. Just over a third of patients were women.

Results: Sizeable reductions in mortality and morbidity

Over five years of follow-up, the GLP-1 RA group showed significantly superior outcomes across all primary and secondary end points relative to the DPP4 inhibitor group:

• All-cause mortality. Use of a GLP-1 RA was associated with a 38% relative reduction in the risk of death (hazard ratio = 0.62; 95% CI, 0.59-0.66; P < .001). The absolute risk reduction was 11% (13.3% vs. 24.3%), translating to a number needed to treat of just 9.1 to prevent one death.
• Hospitalizations and heart failure. Patients on a GLP-1 RA experienced a 29% relative reduction in all-cause hospitalizations and a 17% lower risk of heart failure exacerbations (P < .001 for both).
• Atherosclerotic events. The risk of acute myocardial infarction was reduced by 13% with GLP-1 RA use relative to DPP4 inhibitor use (P < .001), while the incidence of cerebrovascular accidents fell by 14% (P = .002).
• Arrhythmia outcomes. Interestingly, the incidences of both atrial fibrillation and ventricular arrhythmias (including ventricular tachycardia and fibrillation) were significantly lower among GLP-1 RA users. “This finding is particularly relevant in view of previous concerns about the potential chronotropic effects of GLP-1 RA drugs,” Dr. Shah notes.

The survival advantage with GLP-1 RAs appeared early in the treatment course and continued to widen over the five-year duration. Subgroup analyses confirmed the consistency of the advantage regardless of age, sex or baseline renal function. Notably, the mortality benefit was more pronounced in patients using semaglutide and in patients taking an SGLT2 inhibitor in addition to a GLP-1 RA, suggesting a possible synergistic effect between these two drug classes.

Conclusions and caveats

“This study provides some real-world reassurance for the use of GLP-1 RAs to treat type 2 diabetes in stable patients with heart failure with reduced ejection fraction,” notes co-author Amanda Vest, MBBS, MPH, Section Head of Heart Failure and Transplantation Cardiology at Cleveland Clinic. The authors suggest that the agents’ mechanisms of benefit likely extend beyond glycemic control. They note that potential pathways include reductions in epicardial adipose tissue, direct anti-inflammatory effects on cardiomyocytes and improved endothelial function.

“However, there remains a clear need to study the GLP-1 RA medications, particularly those used for the treatment of obesity, specifically in patients with HFrEF given the safety concerns that have been raised, particularly for patients with recent hospitalizations in the LIVE trial,” Dr. Vest adds. “Despite reassuring findings regarding ventricular arrhythmias in the current analysis, concerns raised by LIVE and a recent small propensity-matched cohort study make it important that patients with an indication for an implantable defibrillator receive that therapy before initiating a GLP-1 RA, particularly at the obesity doses of these medications, which are typically higher than those used in type 2 diabetes.”

As an observational study, this investigation’s results are considered only hypothesis-generating, and the authors acknowledge limitations such as the lack of granular data on medication adherence, dosage and New York Heart Association functional class. However, the use of a large cohort, rigorous propensity matching and validation through sensitivity analysis add significant weight to the findings.

“This research suggests that GLP-1 RA therapy may be an effective tool for reducing death and hospitalization in patients with concomitant type 2 diabetes and HFrEF,” Dr. Shah concludes. “If these findings are prospectively confirmed, they would make a compelling argument for a proactive approach to incorporating these agents into the care of patients with reduced systolic function.”