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Treatment of Type 2 Diabetes with SodiumGlucose Co-Transporter 2 Inhibitors plus Glucagon-Like Peptide-1 Receptor Agonists

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Background: The 2 drug classes of glucagon-like peptide-1 receptor agonists (GLP1RAs) and sodium-glucose co-transporter 2 (SGLT2) inhibitors are approved for type 2 diabetes, but their concomitant use was not sufficiently studied.
Aim: To assess the safety and efficacy of the combination of GLP-1RAs and SGLT2 inhibitors in type 2 diabetes.
Methods: Systematic review of English literature by search of electronic databases: Pub/MEDLINE from 2000 until July 27, 2020. Search terms included GLP-1 receptor agonists, SGLT2 inhibitors, combination therapy, add-on therapy, type 2 diabetes, efficacy, safety. Randomized trials were included with more focus on double-blind, placebo-controlled trials. Post-hoc analysis and consensus guidelines are also reviewed.
Results: One randomized trial evaluated the co-initiation of weekly exenatide plus dapagliflozin in patients with type 2 diabetes uncontrolled on metformin. After 52 weeks, the reduction in glycated hemoglobin (HbA1c) levels with the combination therapy was less than additive being 1.75%, 1.36%, and 1.23% with weekly exenatide + dapagliflozin, weekly exenatide + placebo and dapagliflozin + placebo, respectively. Two randomized trials evaluated the sequential addition of GLP-1 RA to ongoing SGLT2 inhibitor therapy. Both trials reported greater HbA1c reduction averaging 0.8-1.4% compared with SGLT2 inhibitor + placebo. The combination of GLP-1 RA + SGLT2 inhibitor caused significant weight loss of approximately 3.3 kg, which was slightly less than additive, and 4.5 mmHg reduction in systolic blood pressure (SBP), which was more than additive. In general, the adverse effects of combination therapy were expected, with no emergence of unusual adverse effects. The least tolerated combination included semaglutide due to relatively high rates of gastrointestinal adverse events and mild hypoglycemia.
Conclusion: Combination therapy of GLP-1 RA plus SGLT2 inhibitor is overall effective and safe. Further studies are needed to examine the effects of this combination on cardiovascular (CV), renal and mortality outcomes.

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