By Michael H. Crawford, MD
Professor of Medicine, Lucy Stern Chair in Cardiology, University of California, San Francisco
SYNOPSIS: An analysis of the Harmony Outcomes study and a meta-analysis combining it with the AMPLITUDE-O study of the addition of a glucagon-like peptide 1 receptor agonist (GLP-1 RA) in a subgroup of type 2 diabetes patients on baseline sodium-glucose cotransporter-2 (SGLT2) inhibitor therapy has shown that major adverse cardiovascular events are reduced by GLP-1 RA, regardless of baseline SGLT2 use, and there was no difference in serious adverse events.
SOURCE: Neves JS, Borges-Canha M, Vasques-Nóvoa F, et al. GLP-1 receptor agonist therapy with and without SGLT2 inhibitors in patients with type 2 diabetes. J Am Coll Cardiol 2023;82:517-525.
Sodium-glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide 1 (GLP-1) receptor agonists have been shown to reduce the risk of cardiovascular (CV) events in patients with type 2 diabetes (T2D) and atherosclerotic CV disease.1 Current guidelines recommend using either of these agents in such patients,2 but the wisdom of their use in combination is unclear. Hence, Neves et al performed a subgroup analysis of the Albiglutide and CV Outcomes in Patients with Type 2 Diabetes and CV Disease (Harmony Outcomes) trial — focusing specifically on the 575 (6%) of the enrolled patients who were on SGLT2 inhibitors at baseline.3 They also performed a meta-analysis of Harmony Outcomes (HO) and the Effect of Efpeglenatide on CV Outcomes (AMPLITUDE-O) studies, which together included 1,193 patients (9%) treated with an SGLT2 inhibitor at baseline.4
HO was a double-blind, randomized, controlled trial of patients > age 40 years with T2D who were randomized to albiglutide injected subcutaneously once a week or placebo. Patients with an estimated glomerular filtration rate (eGFR) of < 30 mL/min/1.73 m², previous pancreatitis, or risk factors for pancreatitis were excluded. HO concluded in 2018, but albiglutide was withdrawn from the market for commercial reasons not related to safety.5 The primary outcome of HO was the composite of CV death, myocardial infarction (MI), or stroke. Heart failure hospitalization was a secondary outcome.
After a median follow-up of 1.6 years, albiglutide reduced the rate of the primary outcome (HR, 0.78; 95% CI, 0.68-0.90; P < 0.001). In the subgroup analysis of those on an SGLT2 inhibitor at baseline, the primary outcome was consistent (P for interaction = 0.70). Although more patients discontinued the trial in the albiglutide group, there was no difference in serious adverse events and no difference with regard to baseline SGLT2 use. The meta-analysis of HO and AMPLITUDE-O showed that compared to placebo, GLP-1 reduced major adverse CV events without any effect from SGLT2 use (HR, 0.77; 95% CI, 0.68-0.87 sans SGLT2 and HR, 0.78; 95% CI, 0.49-1.24 on SGLT2 inhibitors; P for interaction = 0.95). Combination therapy also did not change the beneficial effects of GLP-1 receptor agonists on the observed reduction in heart failure hospitalizations (P for interaction = 0.18). The authors concluded GLP-1 receptor agonists reduced major CV events in patients with T2D, regardless of concomitant SGLT2 inhibitor use.
COMMENTARY
SGLT2 inhibitors (e.g., Farxiga, Jardiance) reduce glucose and sodium reabsorption in the urinary tubules, thereby enhancing glucose control and augmenting diuresis.6 These effects lower afterload and preload and improve cardiac hemodynamics, resulting in fewer heart failure hospitalizations. Thus, they are recommended for all patients with heart failure, regardless of diabetes status.7 GLP-1 receptor agonists (e.g., semaglutide/Ozempic) produce complimentary effects in T2D patients by reducing weight, cholesterol levels, blood pressure levels, and inflammation, which leads to reductions in stroke, myocardial infarction, and CV mortality.8 These results have piqued interest in combining these agents, especially for T2D patients. Small, randomized trials of this combination have demonstrated improved cardiometabolic parameters, such as glucose control, weight loss, and lower blood pressure.1 Thus, this subgroup analysis of HO and meta-analysis of HO plus AMPLITUDE-O is of interest.
Both analyses showed adding a GLP-1 receptor agonist reduced CV events independent of baseline SGLT2 inhibitor use, and there was no difference in adverse events. These results certainly speak to the safety of this combination, but do not exactly support the notion that the combination is better than each agent individually. One major caveat is that there were no patients in either study with heart failure caused by reduced ejection fraction. In fact, some previous studies of GLP-1 receptor agonists have shown an increase in adverse CV events in such patients treated with these agents.9 Current guidelines recommend considering starting one of the two classes of medications in T2D patients with CV disease or patients at high risk for it, but do not recommend the routine use of both.2 Interestingly, using either of these drug classes for secondary prevention in T2D is unusual. Of course, one big barrier is cost. These are expensive drugs, with insurance companies restricting their use or not covering them.10
The major weakness of the Neves et al study is the fact it was not a prespecified analysis of HO and was not considered in the randomization. The percentage of patients on combination therapy was low in HO (6%) and the meta-analysis (9%). However, this netted more than 1,000 patients for analysis. Also, albiglutide and efpeglenatide were not available for use for unclear reasons. At this point, it would seem that if there is a good reason for combining these two drugs and there are no contraindications, it could be considered with little concern for safety but uncertainty about any additional benefit on CV outcomes.
REFERENCES
1. Brown E, Heerspink HJL, Cuthbertson DJ, Wilding JPH. SGLT2 inhibitors and GLP-1 receptor agonists: Established and emerging indications. Lancet 2021;398:262-276.
2. Choi JG, Winn AN, Skandari MR, et al. First-line therapy for type 2 diabetes with sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonists: A cost-effectiveness study. Ann Intern Med 2022;175:1392-1400.
3. Hernandez AF, Green JB, Janmohamed S, et al. Albiglutide and cardiovascular outcomes in patients with type 2 diabetes and cardiovascular disease (Harmony Outcomes): A double-blind, randomised placebo-controlled trial. Lancet 2018;392:1519-1529.
4. Gerstein HC, Sattar N, Rosenstock J, et al. Cardiovascular and renal outcomes with efpeglenatide in type 2 diabetes. N Engl J Med 2021;385:896-907.
5. Bonayon ML. GlaxoSmithKline publishes new data for discontinued diabetes drug. S&P Global Market Intelligence. Oct. 2, 2018.
6. Abdul-Ghani MA, Norton L, DeFronzo RA. Renal sodium-glucose cotransporter inhibition in the management of type 2 diabetes mellitus. Am J Physiol Renal Physiol 2015;309:F889-F900.
7. Talha KM, Anker SD, Butler J. SGLT-2 inhibitors in heart failure: A review of current evidence. Int J Heart Fail 2023;5:82-90.
8. Zhao X, Wang M, Wen Z, et al. GLP-1 receptor agonists: Beyond their pancreatic effects. Front Endocrinol (Lausanne) 2021;12:721135.
9. Ferreira JP, Sharma A, Butler J, et al. Glucagon-like peptide-1 receptor agonists across the spectrum of heart failure. J Clin Endocrinol Metab 2023; Jul 6: dgad398. doi: 10.1210/clinem/dgad398. [Online ahead of print].
10. Essien UR, Singh B, Swabe G, et al. Association of prescription co-payment with adherence to glucagon-like peptide-1 receptor agonist and sodium-glucose cotransporter-2 inhibitor therapies in patients with heart failure and diabetes. JAMA Netw Open 2023;6:e2316290.
An analysis of the Harmony Outcomes study and a meta-analysis combining it with the AMPLITUDE-O study of the addition of a glucagon-like peptide 1 receptor agonist (GLP-1 RA) in a subgroup of type 2 diabetes patients on baseline sodium-glucose cotransporter-2 (SGLT2) inhibitor therapy has shown that major adverse cardiovascular events are reduced by GLP-1 RA, regardless of baseline SGLT2 use, and there was no difference in serious adverse events.
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