Incremental benefits of GLP-1RA plus SGLT2i treatment in patients with HFpEF, T2D, and overweight/obesity

In a real-world retrospective cohort study among HFpEF patients with T2D and BMI ≥27 kg/m², adding GLP-1RAs to SGLT2 inhibitors was associated with lower risks of adverse outcomes, such as HF exacerbation, at 12 months compared with SGLT2 inhibitors only.

This summary is based on the publication of Patel R, Wadid M, Makwana B, et al. - GLP-1 Receptor Agonists Among Patients With Overweight or Obesity, Diabetes, and HFpEF on SGLT2 Inhibitors. JACC Heart Fail. 2024 Nov;12(11):1814-1826. doi: 10.1016/j.jchf.2024.07.006

Introduction and methods

Background

GLP-1RAs not only reduce the risk of MACE in patients with T2D and obesity [1-4], but have also demonstrated improved quality of life and functional capacity in patients with obesity and HFpEF but no diabetes [5]. For HFpEF patients, SGLT2 inhibitors are recommended as a first-line agent, irrespective of their diabetic status [6]. The additive benefits and potential harms of GLP-1RAs in HFpEF who are already taking SGLT2 inhibitors have not yet been established.

Aim of the study

The authors evaluated the incremental benefits and the safety of GLP-1RAs in patients with HFpEF, T2D, and overweight or obesity who were already receiving SGLT2 inhibitor therapy.

Methods

In a retrospective observational cohort study, data of 29,922 adults with T2D, BMI ≥27 kg/m², and HFpEF (LVEF ≥45%,) who were prescribed SGLT2 inhibitors were collected from the TriNetX global research network, which contains electronic health record data of ~110 million patients primarily from US healthcare institutions. The authors used propensity score matching (1:1 greedy nearest-neighbor matching) to create 2 cohorts based on GLP-1RA prescription <12 months of the HFpEF diagnosis, leaving 7044 patients in each cohort.

Outcomes

The endpoints were HF exacerbation (defined as requirement for intravenous diuretic agents or diagnosis of pulmonary edema), all-cause hospitalizations or emergency department (ED) visits, new-onset AF or atrial flutter, pulmonary hypertension, CRP ≥5 mg/dL, new-onset acute kidney injury (AKI), need for renal replacement therapy, and all-cause mortality, all assessed at 12 months. Safety assessment included the incidences of gastrointestinal symptoms, hypoglycemia, and diabetic retinopathy.

Main results

Efficacy

• Patients who were treated with both a GLP-1RA and an SGLT2 inhibitor had a lower risk of HF exacerbation than those receiving an SGLT2 inhibitor only (absolute risk reduction (ARR): 9%; relative risk reduction (RRR): 32%; HR: 0.62; 95%CI: 0.58–0.66; P<0.001).

• Furthermore, compared with patients taking SGLT2 inhibitors only, patients on GLP-1RA and SGLT2 inhibitor combination therapy also showed decreased risks of all-cause hospitalizations/ED visits (ARR: 8%; RRR: 15%; HR: 0.74; 95%CI: 0.71–0.78; P<0.001), new-onset AF/atrial flutter (ARR: 1%; RRR: 25%; HR: 0.81; 95%CI: 0.70–0.95; P=0.007), pulmonary hypertension (ARR: 2%; RRR: 21%; HR: 0.81; 95%CI: 0.73–0.89; P<0.001), CRP ≥5 mg/dL (ARR: 1%; RRR: 29%; HR: 0.76; 95%CI: 0.65–0.89; P=0.001), new-onset AKI (ARR: 6%; RRR: 29%; HR: 0.70; 95%CI: 0.65–0.75; P<0.001), need for renal replacement therapy (ARR: 1%; RRR: 50%; HR: 0.47; 95%CI: 0.34–0.66; P<0.001), and all-cause mortality (ARR: 2%; RRR: 35%; HR: 0.64; 95%CI: 0.54–0.75; P<0.001).

• The incremental beneficial effects on the risks of HF exacerbation and all-cause hospitalizations/ED visits persisted when the study population was stratified by baseline BMI, natriuretic peptide levels, or LVEF.

Safety

• Patients receiving GLP-1RA and SGLT2 inhibitor combination therapy had a higher risk of diabetic retinopathy compared with those taking SGLT2 inhibitors only (HR: 1.36; 95%CI: 1.22–1.52; P<0.001) and a lower risk of palpitations (HR: 0.74; 95%CI: 0.68–0.80; P<0.001).

• The risks of other adverse events did not differ between the 2 treatment groups (all P>0.05).

Conclusion

In this real-world retrospective cohort study, the use of GLP-1RAs in addition to SGLT2 inhibitors was associated with a lower risk of HF exacerbation (ARR: 9%; RRR: 32%) at 12 months in patients with HFpEF, T2D, and overweight/obesity, compared with SGLT2 inhibitor therapy only. The combination therapy was also associated with decreased risks of all-cause hospitalizations/ED visits, new-onset atrial arrhythmias, AKI, and need for renal replacement therapy. The authors remark that “[t]he robustness of our data is supported by the substantial number of patients included in our study, which, despite the inherent biases of real-world data, highlight a compelling signal for the benefit of GLP-1RA in this specific target population.”

Find this article online at JACC Heart Fail.

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