Glucagon-like peptide-1 receptor agonists and sodium-glucose co-transporter-2 inhibitors as combination therapy for type 2 diabetes: A systematic review and meta-analysis

Aim: To assess the efficacy and safety of combination therapy with a glucagon-like peptide-1 receptor agonist (GLP-1 RA) and a sodium-glucose co-transporter-2 inhibitor (SGLT2i) in patients with type 2 diabetes.

Methods: We searched Medline, Embase, the Cochrane Library and grey literature sources up to 2 December 2019 for randomized controlled trials in adults with type 2 diabetes assessing the combination of GLP-1RA and SGLT2i, either as co-initiation therapy or as add-on to each other, against placebo or an active comparator. The primary outcome was change in HbA_1c . Secondary outcomes included change in body weight, blood pressure and estimated glomerular filtration rate, and incidence of severe hypoglycaemia, all-cause mortality, cardiovascular mortality, myocardial infarction, stroke and hospitalization for heart failure. We pooled data using random effects meta-analyses.

Results: Seven trials (1913 patients) were eligible. Compared with GLP-1RA, GLP-1RA/SGLT2i combination therapy was associated with a greater reduction in HbA1c (weighted mean difference -0.61%, 95% CI -1.09% to -0.14%, four studies), body weight (-2.59 kg, -3.68 to -1.51 kg, three studies) and systolic blood pressure (-4.13 mmHg, -7.28 to -0.99 mmHg, four studies). Compared with SGLT2i, GLP-1RA/SGLT2i combination therapy reduced HbA1c (-0.85%, -1.19% to -0.52%, six studies) and systolic blood pressure (-2.66 mmHg, -5.26 to -0.06 mmHg, six studies), but not body weight (-1.46 kg, -2.94 to 0.03 kg, five studies). After excluding data for one trial that had a considerably longer duration than the remaining studies, body weight was also reduced versus SGLT2i (-1.79 kg, -2.99 to -0.59 kg, five studies). Combination therapy did not increase the incidence of severe hypoglycaemia. Data for mortality and cardiovascular outcomes were scarce.

Conclusions: GLP-1RA/SGLT2i combination therapy seems to reduce HbA_1c , body weight and systolic blood pressure without increasing the risk of severe hypoglycaemia compared with either GLP-1RA or SGLT2i. No conclusions can be made regarding long-term effectiveness or the effect on cardiovascular outcomes.