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GLP-1 Agonist Therapy With SGLT2 Inhibitors in Diabetes
Quick Takes
- Albiglutide reduced major adverse CV events in patients with T2D compared to placebo regardless of baseline treatment with an SGLT2 inhibitor.
- A meta-analysis of Harmony Outcomes (albiglutide) and AMPLITUDE-O (efpeglenatide) trials showed consistent reductions in major adverse CV events with GLP-1 receptor agonist treatment with or without baseline SGLT2i use.
Study Questions:
Do glucagon-like peptide-1 receptor agonists (GLP-1 RAs) reduce cardiovascular (CV) events in patients with type 2 diabetes (T2D) regardless of background sodium-glucose cotransporter-2 inhibitor (SGLT2i) treatment?
Methods:
This study was a post hoc analysis of the Harmony Outcomes randomized controlled trial, which evaluated the CV safety of the albiglutide in patients with T2D. Harmony Outcomes randomized patients aged ≥40 years with T2D and established CV disease and a glycated hemoglobin (HbA1c) >7.0% to receive either albiglutide or placebo. Patients with an estimated glomerular filtration rate <30 mL/min/1.73 m2 and patients with prior pancreatitis or risk factors for pancreatitis were excluded.
The primary outcome in this analysis was the same as in Harmony Outcomes, a composite of CV death, myocardial infarction (MI), or stroke. Additional secondary outcomes including composite of CV death or heart failure (HF) hospitalization; composite of CV death, MI, unstable angina, or stroke; composite of all-cause mortality, MI, or stroke; the individual components of the primary outcome; and all-cause mortality were also evaluated. A trial-level meta-analysis including Harmony Outcomes as well as AMPLITUDE-O, an exploratory analysis of the CV outcomes of efpeglenatide, was also conducted. Study populations were divided into two subgroups according to SGLT2i use at baseline for analysis.
Results:
Harmony Outcomes randomized a total of 9,462 participants, of which 575 (6.1%) were receiving an SGLT2i at baseline. Patients treated with an SGLT2i were younger (62.9 vs. 64.2 years), had lower HbA1c (8.5 vs. 8.8), more frequent history of coronary artery disease (78.6% vs. 70%) and MI (51.8% vs. 46.8%), and less frequent history of HF (15.1% vs. 20.6%) and peripheral arterial disease (19.5% vs. 25.2%) compared to patients not receiving an SGLT2i. SGLT2i-treated patients were also more frequently treated with metformin, dipeptidyl peptidase 4 inhibitors, beta-blockers, and statins. The effect of albiglutide on reducing the incidence of the primary outcome was consistent with or without baseline use of an SGLT2i: hazard ratio (HR) 0.78, 95% confidence interval (CI) 0.67-0.90 without SGLT2i and HR 0.89, 95% CI 0.45-1.77 with SGLT2i use (p-interaction = 0.70). Secondary outcomes and adverse effects were also not affected by use of an SGLT2i.
The meta-analysis of Harmony Outcomes and AMPLITUDE-O included 13,538 patients, of which 1,193 (8.8%) were treated with an SGLT2i at baseline. Compared to placebo, GLP-1 agonist therapy reduced the incidence of the primary outcome (HR 0.77, 95% CI 0.76-0.92) and was consistent with or without baseline use of an SGLT2i (p-interaction = 0.95). A similar pattern was observed for secondary outcomes including HF hospitalization.
Conclusions:
In patients with T2D and CV disease, GLP-1 RAs reduced CV events regardless of baseline SGLT2i treatment without increased risk of serious adverse events. Results support further research to evaluate the potential added value of combination therapy.
Perspective:
Previous randomized controlled trials have shown additive benefits of GLP-1 RAs and SGLT2i on metabolic outcomes in patients with T2D including additional reductions in HbA1c, weight, and blood pressure. The complementary mechanisms of action of GLP-1 RA and SGTL2i supports the hypothesis that the combination also has additive effects on CV events. AMPLITUDE-O provided initial data on the effects of an exendin-4-based GLP-1 RA on the CV outcomes according to baseline SGLT2i use. The present analysis evaluated a different GLP-1 RA (human GLP-1-based) and the meta-analysis of both trials significantly increased the number of SGLT2i-treated patients, which adds evidence to support the efficacy and safety of GLP-1 RAs when added to SGLT2i therapy.
Clinical Topics: Cardiovascular Care Team, Diabetes and Cardiometabolic Disease, Heart Failure and Cardiomyopathies, Prevention, Vascular Medicine, Atherosclerotic Disease (CAD/PAD), Acute Heart Failure
Keywords: Angina, Unstable, Body Mass Index, Coronary Artery Disease, Diabetes Mellitus, Type 2, Glomerular Filtration Rate, Glucagon-Like Peptide-1 Receptor, Glycated Hemoglobin A, Heart Failure, Metabolic Syndrome, Myocardial Infarction, Pancreatitis, Patient Care Team, Peripheral Arterial Disease, Primary Prevention, Sodium-Glucose Transporter 2 Inhibitors
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