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GLP-1 Agonists With SGLT2 Inhibitors in Diabetes
Quick Takes
- GLP-1 receptor agonists demonstrate benefit in patients with T2D via reduction in major adverse CV events independent of background SGLT2i use.
- Combination therapy may further CV outcomes in patients with T2D.
Study Questions:
Is the effect of glucagon-like peptide-1 receptor agonists (GLP-1 RAs) on cardiovascular (CV) outcomes in patients with type 2 diabetes (T2D) independent of sodium-glucose cotransporter-2 inhibitor (SGLT2i) use?
Methods:
This was a post hoc analysis of the double-blind randomized controlled trial, Harmony Outcomes, which was conducted between July 2015–March 2018. A total of 9,462 patients aged ≥40 years with T2D, established CV disease (CVD), and a glycated hemoglobin (HbA1c) >7% were included and randomized 1:1 to receive albiglutide or matching placebo and all outcomes were studied in patients with and without baseline SGLT2i use. Main exclusion criteria included an estimated glomerular filtration rate <30 mL/min/1.73 m2 and previous pancreatitis or risk factors for pancreatitis.
The primary outcome was the composite of CV death, myocardial infarction (MI), or stroke. Secondary outcomes included the composite of CV death, MI, unstable angina, or stroke, the composite of all-cause mortality, MI, or stroke, the individual components of the primary outcome, and all-cause mortality. A meta-analysis based on post hoc analysis of Harmony Outcomes and AMPLITUDE-O (efpeglenatide) was conducted using 13,538 patients with T2D for analysis, of which 8.8% were on baseline SGLT2i. Safety events of albiglutide compared to placebo stratified by baseline SGLT2i use were also analyzed.
Results:
In the primary analysis, albiglutide significantly reduced the composite of CV death, MI, or stroke compared to placebo (7% vs. 9%; hazard ratio [HR], 0.78; 95% confidence interval [CI], 0.68-0.9; p < 0.001). Of the patients randomized, 6.1% were treated with an SGLT2i at baseline. Baseline characteristics were well balanced between albiglutide and placebo groups; however, those with background SGLT2i use were younger, more likely to be male, had a higher body mass index, lower HbA1c, more frequent history of coronary artery disease, and less frequent history of heart failure (HF) and peripheral artery disease.
Baseline SGLT2i use did not change the effect of albiglutide on the primary outcome compared to placebo (no baseline SGLT2i HR, 0.78; 95% CI, 0.67-0.9 vs. baseline SGLT2i HR, 0.89; 95% CI, 0.45-1.77; interaction p = 0.7). The effect of albiglutide on the secondary outcomes compared to placebo was not modified by baseline SGLT2i use (interaction p > 0.1). Similarly, adverse effects were not significantly different between treatment groups and there was no variance based on baseline SGLT2i use (interaction p > 0.1). In the meta-analysis, the primary outcome was reduced by GLP-1 RAs compared to placebo (HR, 0.77; 95% CI, 0.76-0.92) without significant interaction based on background SGLT2i use (interaction p = 0.95). The meta-analysis also revealed that GLP-1 RAs reduced the risk of HF hospitalization compared to placebo (HR, 0.69; 95% CI, 0.54-0.88) without interaction from baseline SGLT2i use (interaction p = 0.18).
Conclusions:
The risk of adverse CV events was reduced by treatment with a GLP-1 RA in patients with T2D and CVD independent of background SGLT2i use.
Perspective:
This exploratory analysis supports that GLP-1 RAs retain CV benefit despite baseline SGLT2i use in patients with T2D and CVD. These findings suggest the potential for additional CV risk protection by utilizing combination therapy. Current guidelines recommend that patients with T2D and established CVD be treated with either SGLT2i or GLP-1 RA; however, the role of combination therapy has been less well-defined. These drug classes possess complementary mechanisms of action and have each independently demonstrated CV benefit in addition to positive metabolic effects. Prior studies (DURATION-8, AWARD-10, SUSTAIN 9) have demonstrated the metabolic benefit of combination therapy; however, this meta-analysis represents the largest patient experience with combination therapy in terms of CV outcomes. Further studies on combination therapy should utilize currently available GLP-1 RA, as both albiglutide and efpeglenatide are currently unavailable.
Clinical Topics: Diabetes and Cardiometabolic Disease, Heart Failure and Cardiomyopathies, Prevention, Vascular Medicine, Atherosclerotic Disease (CAD/PAD), Acute Heart Failure
Keywords: Angina, Unstable, Coronary Artery Disease, Diabetes Mellitus, Type 2, Glucagon-Like Peptide-1 Receptor, Glycated Hemoglobin A, Heart Failure, Metabolic Syndrome, Patient Care Team, Peripheral Arterial Disease, Primary Prevention, Sodium-Glucose Transporter 2 Inhibitors, Stroke
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