GLP-1 Agonists and SGLT2 Inhibitors in HF Treatment

The management of patients with heart failure (HF) has taken an interesting and exciting turn thanks to studies demonstrating the positive effects and growing utilization of newer glucose-lowering therapies for reduction of HF outcomes — namely glucagon-like peptide 1 (GLP-1) agonists and oral sodium glucose cotransport 2 (SGLT2) inhibitors. These findings have led to a "crossover" effect among specialties wherein many HF specialists now consider themselves essential members of the healthcare team for patients with type 2 diabetes (T2D); likewise, many endocrinologists and nephrologists consider themselves integral to the care team of their patients with HF.

Many questions remain unanswered, however, regarding the therapeutic effects of GLP-1 agonists and SGLT2 inhibitors in HF. Here's an overview of what we've learned so far about the potentially beneficial role of these therapies in treating patients with HF.

Cardioprotective Benefits of Newer Antidiabetic Agents

Over the past decade, there have been several cardiovascular outcome trials (CVOTs) in patients with T2D. These studies, which were largely mandated by the US Food and Drug Administration (FDA) to evaluate long-term safety of these drugs, have contributed immensely to our growing understanding of the natural history of cardiovascular disease (CVD) among patients with T2D. The main purpose of these studies was to dispel concerns of deleterious cardiovascular (CV) signals for any new therapeutic in T2D, given some concerning analyses involving one particular class of antidiabetic agents, thiazolidinediones, particularly rosiglitazone. As expected, because these studies were designed to be event-driven, the participants typically were at high risk for CVD at baseline. So, what do the data from these leading trials tell us about the effects of GLP-1 agonists and SGLT2 inhibitors on HF?

In the LEADER trial, 9340 patients were randomly assigned to receive the GLP-1 agonist liraglutide or matching placebo over a mean follow-up of 3.8-years. The primary composite outcomes, death from CV causes, nonfatal myocardial infarction, or nonfatal stroke, occurred in a significantly lower number of patients in the liraglutide group compared with those in the placebo group. Given the concerns from earlier CVOTs of T2D drugs (eg, the SAVOR–TIMI 53 trial) on the effects of the incretin pathway on the CV system, the LEADER trial included a prespecified exploratory analysis of CV conditions, including HF. Results from this trial demonstrated a lower, albeit insignificant, hospitalization rate among patients with HF in the liraglutide group compared with patients with HF in the placebo group. Of note, in the FIGHT study, a much smaller randomized placebo-controlled clinical trial of 300 patients, liraglutide did not improve posthospitalization clinical stability of participants who had advanced HF with reduced ejection fraction (HFrEF) compared with their counterparts in the placebo group. (To determine posthospitalization clinical stability, all participants were ranked across three hierarchical tiers: time to death, time to rehospitalization for HF, and time-averaged proportional change in N-terminal pro–B-type natriuretic peptide level from baseline to 180 days.) There were no significant differences in the number of deaths in the liraglutide group (12%) vs the placebo group (11%). Moreover, the frequency of rehospitalization was slightly higher in the liraglutide group vs the placebo group (41% vs 50%, respectively).

In contrast, in the EMPA-REG OUTCOME trial, 7020 study participants were randomly assigned to receive an oral SGLT2 inhibitor (empagliflozin) or matching placebo. All of the study participants had established atherosclerotic cardiovascular disease (ASCVD), but approximately 10% also had HF at baseline. During the course of the study (median observation period, 3.1 years), the primary outcome occurred in 10.5% of the empagliflozin group as compared to 12.1% in the placebo group. The study also showed a 35% relative risk reduction in hospitalization for HF in participants receiving empagliflozin.

Assessing Preventive HF Strategies in T2D Patients

As clinicians, we are cognizant that HF is not only a major cause of morbidity and mortality from CVD but also that our patients with diabetes are at higher risk for HF-associated hospitalizations than those without diabetes, underscoring the importance of initiating appropriate and timely intervention to reduce adverse outcomes.

In 2018, the American Diabetes Association (ADA) and European Association for the Study of Diabetes (EASD) released an updated joint consensus report which emphasizes that clinicians adopt a patient-centered approach when selecting antidiabetic agents for patients with TD2. In this statement, the ADA/EASD also stress the importance of properly assessing certain risk factors at baseline, including ASCVD, HF, and chronic kidney disease (CKD). Of significance, based on evidence from the aforementioned CVOTs, the ADA and EASD now recommend prescribing GLP-1 agonists and SGLT2 inhibitors to improve outcomes in patients with T2D who also have CVD or CKD.

Moreover, in its 2021 Standards of Medical Care in Diabetes, the ADA highlights the importance of characterizing whether patients with diabetes have ASCVD or equivalent high-risk factors, CKD, or HF. Given the results from CVOTs involving the SGLT2 inhibitors (eg, EMPA-REG OUTCOME), these therapies have taken a prominent role for use in patients living with diabetes and HF, specifically those with HFrEF. As with the ADA/EASD joint consensus statement, the ADA's Standards of Medical Care in Diabetes also notes the appropriateness of prescribing either an SGLT2 inhibitor or a GLP-1 agonist to lower CV risk in patients with T2D.

Positive Results in Treating HF Patient With SGLT2 Inhibitors

Given the findings from the EMPA-REG OUTCOME trial, there has been a great deal of curiosity as to whether SGLT2 inhibitors would have a beneficial effect on HF in patients without T2D. In the DAPA-HF trial, study participants with HFrEF (EF ≤ 40%) and an N-terminal pro–B-type natriuretic peptide ≥ 600 pg/mL were randomly assigned to receive the SGLT2 inhibitor dapagliflozin (10 mg/d) or matching placebo. The primary outcome of DAPA-HF was focused on HF outcomes. Participants with HFrEF assigned to the SGLT2 group had a reduced risk of worsening HF or death from CV causes; moreover, they had better symptom scores compared with participants in the placebo group (those with and without T2D). In a similar study, EMPEROR-Reduced, participants with HFrEF (EF ≤ 40%) were randomly assigned to receive the SGLT2 inhibitor empagliflozin (10 mg/d) or placebo. Findings from this study also demonstrated a reduction in HF-associated hospitalizations and CV death in the empagliflozin group as compared to the placebo group of patients with and without T2D.

Looking Ahead

Future trials on the effects of GLP-1 and SGLT2 inhibitor agents in populations at high risk for HF are needed, particularly studies focusing on disparities of care in HF, namely exposure (or lack thereof) to SGLT2 inhibitors based on race-based estimated glomerular filtration rate calculations. In addition, the role of novel glucose-lowering therapies in patients with HF, regardless of the presence or absence of T2D, is still unclear. Although dapagliflozin has received FDA approval in the past year for use in patients with HF to reduce the risk for death and HF-associated hospitalizations, more research is required to determine the role of GLP-1 agonists, given the negative findings of the FIGHT study. It will therefore be crucial for HF specialists to become facile at prescribing these novel agents for the overall benefit of their patients living with or without T2D.

Moreover, as the evidence regarding the role of GLP-1 agonists and SGLT2 inhibitors continues to evolve, it appears that the modern care of patients with HF will do so as well, and will require an interdisciplinary team-based approach consisting of endocrinologists with a focus on CV endocrinology, nephrologists with a focus on prevention of renal disease, and clinicians specializing in HF. Such a team-based approach is paramount to improving outcomes in patients with HF.

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