Glucagon-like Peptide-1 Receptor Agonists versus Sodium-Glucose Cotransporter Inhibitors for Treatment of T2DM

Abstract

Context Cardiovascular outcome trials (CVOT) of glucagon-like peptide-1 receptor agonists (GLP-1 RA) and sodium-glucose cotransporter 2 inhibitors (SGLT2i) demonstrated reduction of major adverse cardiovascular events (MACE), cardiovascular deaths (CVD), and renal outcomes. Objective Assist in the prescribing decision regarding severity of illness and risk for adverse events. Design Meta-analysis of the major CVOT and previous meta-analyses. Main Outcome Measures Six trials of GLP-1 RA (51 762 subjects) and 4 trials of SGLT2i (33 457 subjects) showed both drug classes reduced MACE and CVD versus controls, with neither class preferred (comparison GLP1-RA vs SGLT2i: relative rate [rr] MACE 1.09, 95% confidence interval [CI] 0.97, 1.22, P = ns; rr CVD 1.04, 95% CI 0.87, 1.24, P = ns). Hospitalization for heart failure (HHF) improved with SGLT2i (rr 0.68, CI 0.61, 0.76, P < 0.001) but not with GLP-1 RA, (rr 0.93, CI 0.86,1.03, P = ns). Meta-regression suggested benefits of the SGLT2i on CVD and HHF were accentuated with the underlying rate of MACE in the cohort (i.e., >10 events/1000pt*year). GLP-1 RA and SGLT2i showed reduction in renal outcomes (GLP-1 RA rr 0.83, CI 0.75, 0.91, p ≤ 0.001, SGLT2i rr 0.67, CI 0.57, 0.79, P < 0.001) without a preferential difference (GLP-1 RA vs SGLT2i, rr 1.24, CI 0.95, 1.61, P = ns; relative difference (rd) 0.005, CI -0.011, 0.021, P = ns). Serious adverse events for SGLT2i were mycotic genital infections in women (number needed to harm [NNH] = 13 and diabetic ketoacidosis NNH = 595. Gastrointestinal intolerance was the serious adverse event in the GLP1-RA class (NNH = 35). Conclusion GLP-1 RA and SGLT2i classes showed similar reduction in MACE, CVD, and renal outcomes. SGLT2i have advantages over GLP-1 RA in reduction in HHF.

Effects of GLP-1 receptor agonists and SGLT-2 inhibitors on cardiac structure and function: a narrative review of clinical evidence

“…SGLT-2i were associated with a reduced rate of HHF (HR 0.59; 95% CI 0.35–0.99; p = 0.048) [ 74 ], which is similar in size to what has been reported by the trials comparing SGLT-2i to placebo. Symmetrically, an increased risk of HHF for subjects on GLP-1Ra vs. SGLT-2i emerges from a recent meta-analysis of all available clinical trials (OR: 1.38 95% CI 1.12–1.69; p = 0.002) [ 75 ]. This data indirectly confirms the small/neutral effect of GLP-1Ra and the major effect of SGLT-2i in HF prevention and treatment.…”

An Overview of Similarities and Differences in Metabolic Actions and Effects of Central Nervous System Between Glucagon-Like Peptide-1 Receptor Agonists (GLP-1RAs) and Sodium Glucose Co-Transporter-2 Inhibitors (SGLT-2is)

“…Trials that have examined efficacy of GLP-1RA therapies include Evaluation of Lixisenatide in Acute Coronary Syndrome [ELIXA] trial, 47 Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results [LEADER] trial, 6 Trial to Evaluate Cardiovascular and Other Long-term Outcomes with Semaglutide in Subjects with Type 2 Diabetes [SUSTAIN-6], 49 oral administration of semaglutide in the Trial Investigating the Cardiovascular Safety of Oral Semaglutide in Subjects With Type 2 Diabetes [PIONEER-6], 50 once-weekly exenatide in the Exenatide Study of Cardiovascular Event Lowering [EXSCEL] trial, 51 albiglutide in the Harmony Outcomes trial, 52 and dulaglutide in the Researching Cardiovascular Events With a Weekly Incretin in Diabetes [REWIND] trial, 53 among others. Current progress in clinical trials and outcomes of GLP-1RA have been extensively reviewed elsewhere, 54 , 55 with results of these trials indicating that GLP-1RA therapy does not only guarantee cardiovascular safety but also has considerable benefits. Thus, recent ADA and CDC guidelines have recommended use of GLP-1RAs for treatment of T2D patients with high risk of atherosclerosis and coronary heart disease.…”

“…Results from such clinical trials have been summarized elsewhere. 54 , 55 Functionally, these classes of drugs strongly and selectively inhibit reabsorption of glucose by renal SGLT-2, thereby resulting in glucosuria, and rearrangement of bodily hemodynamics, such as reduction of arterial blood pressure, depletion of interstitial fluid rather than blood volume that improves both preload and afterload in heart failure, and neuroendocrine factors like the RAAS system. 58 , 59 Based on FDA specifications, it is evident that patients treated with canagliflozin, dapagliflozin, empagliflozin exhibit a 24-hour glucosuria of about 100, 70, and 64g, respectively, which correspondingly cause about 400, 280, and 256Kcal/d of energy loss.…”

Does race/ethnicity influence the impact of new glucose-lowering agents on cardiovascular outcomes? a comparison between Asian versus White patients

“…Two classes of glucoselowering agents have proven their efficacy in reducing major cardiovascular adverse events [MACEs; nonfatal myocardial infarction, nonfatal stroke, cardiovascular (CV) mortality]: sodium-glucose cotransporter type 2 inhibitors (SGLT2is) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) (2). Several reports compared the efficacy of the two pharmacological approaches and emphasized the existence of some crucial differences between these two drug families (3)(4)(5)(6). Both classes now occupy a preferred place in the algorithm for the management of T2DM, especially in patients at high or very high CV risk (7).…”