GLP-1s may improve outcomes when added to SGLT2 therapy for HFpEF, diabetes and obesity
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Key takeaways:
- GLP-1 receptor agonists plus SGLT2 therapy may improve outcomes among patients with HFpEF, type 2 diabetes and obesity vs. SGLT2 inhibition alone.
- The results were consistent regardless of BMI and LVEF.
GLP-1 receptor agonist use on top of SGLT2 inhibition in patients with HF with preserved ejection fraction, type 2 diabetes and obesity was associated with reduced risk for adverse events vs. SGLT2 inhibition alone, researchers reported.
The benefits of adding a GLP-1 receptor agonist to SGLT2 inhibitor therapy were consistent across subgroups based on BMI and left ventricular ejection fraction, according to the study published in JACC: Heart Failure.
‘Theoretical concern’ with combination therapy
“GLP-1 receptor agonists [have] been found to improve the quality of life of patients with obesity and type 2 diabetes combined with HFpEF. However, its additive benefits for patients with HFpEF who are already on SGLT2 inhibitor treatment have not been assessed,” Rushin Patel, MD, cardiology fellow at Lahey Hospital and Medical Center at Beth Israel Lahey Health, and colleagues wrote. “In addition, despite synergistic metabolic effects noted in prior studies, including improved glycemic control and weight loss with the combination of GLP-1 receptor agonist and SGLT2 inhibitor use, there has been a theoretical concern that the combination of these agents can negate the effects of SGLT2 inhibitors on cardiac and renal workload and decrease the cardiorenal benefits because of the differential effect on ketone bodies.”
Patel and colleagues conducted a retrospective cohort study using the TriNetX research database to evaluate the effects of GLP-1 receptor agonists among patients with type 2 diabetes, BMI of 27 kg/m2 or more and HFpEF already on an SGLT2 inhibitor. Outcomes were compared with a matched cohort of patients not on a GLP-1 receptor agonist (mean age, 63 years; 44% women; 65% white). Each cohort had 7,044 patients.
The main outcomes of interest were HF exacerbation, all-cause ED visit or hospitalizations, new-onset atrial fibrillation/flutter, pulmonary hypertension, C-reactive protein levels of 5 mg/dL or more, acute kidney injury and the need for new-onset renal replacement therapy, all during a 12-month period.
Reduced risk with combination therapy
During the study period, researchers reported lower risk for all outcomes with GLP-1 receptor agonists plus SGLT2 inhibitors compared with SGLT2 inhibitors alone for patients with diabetes, HFpEF and overweight/obesity:
- HF exacerbations (absolute risk difference, 9%; HR = 0.62; 95% CI, 0.58-0.66; P < .001);
- all-cause ED visits or hospitalizations (absolute risk difference, 8%; HR = 0.74; 95% CI, 0.71-0.78; P < .001);
- all-cause mortality (absolute risk difference, –2%; HR = 0.64; 95% CI, 0.54-0.75; P < .001);
- new-onset AF/flutter (absolute risk difference, 1%; HR = 0.81; 95% CI, 0.7-0.95; P = .007);
- pulmonary hypertension (absolute risk difference, 2%; HR = 0.81; 95% CI, 0.73-0.89; P < .001);
- acute kidney injury (absolute risk difference, 6%; HR = 0.7; 95% CI, 0.65-0.75; P < .001);
- CRP of more than 5 mg/dL (absolute risk difference, 1%; HR = 0.76; 95% CI, 0.65-0.89; P = .001); and
- new renal replacement therapy (absolute risk difference, 1%; HR = 0.47; 95% CI, 0.34-0.66; P < .001).
The reported benefits associated with GLP-1 receptor agonist plus SGLT2 inhibitor therapy for this patient population were observed across most subgroups and across the full spectrum of LVEF, according to the study.
The reduced risk for new-onset AF/flutter was less significant for patients with BMI between 27 kg/m2 and 30 kg/m2.
Additionally, the reduced risk for CRP of more than 5 mg/dL was less significant for patients with elevated B-type natriuretic peptide or N-terminal pro-BNP, according to the study.
“To our knowledge, our study is the first to demonstrate an incremental benefit associated with the use of GLP-1 receptor agonists in patients with a BMI 27 kg/m2, type 2 diabetes and HFpEF already prescribed an SGLT2 inhibitor. It is important to note that despite the synergistic metabolic effects observed in prior studies, such as improved glycemic control and weight loss with the combination of GLP-1 receptor agonist and SGLT2 inhibitor use, there has been a theoretical concern that this combination may negate the effects of SGLT2 inhibitors on cardiac and renal workload, potentially decreasing the cardiorenal benefits,” the researchers wrote. “However, our study’s findings suggest that the incremental benefits of combining GLP-1 receptor agonists with SGLT2 inhibitors outweigh this theoretical concern in patients with HFpEF, overweight or obesity, and type 2 diabetes.”
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