Glycemic efficacy and safety of glucagon-like peptide-1 receptor agonist on top of sodium-glucose co-transporter-2 inhibitor treatment compared to sodium-glucose co-transporter-2 inhibitor alone: A systematic review and meta-analysis of randomized controlled trials

Objective: Sodium-glucose co-transporter-2 inhibitors (SGLT-2i) and glucagon-like peptide-1 receptor agonists (GLP-1RAs) are now considered as key players in the treatment of type 2 diabetes mellitus (T2DM). The purpose of this meta-analysis was to provide precise effect estimates regarding the safety and efficacy of the addition of a GLP-1RA on top of SGLT-2i treatment.

Research design and methods: PubMed and CENTRAL, along with grey literature sources, were searched from their inception to May 2019 for randomized controlled trials (RCTs) with a duration ≥ 12 weeks, evaluating the safety and efficacy of addition of a GLP-1RA on a SGLT-2i compared to SGLT-2i alone in patients with T2DM. We also used the Grading of Recommendations Assessment, Development and Evaluation (GRADE) approach to assess the credibility of our summary estimates.

Results: We identified three eligible RCTs, pooling data retrieved from 1,042 patients with T2DM in total. Administration of the maximum dose of a GLP-1RA on top of SGLT-2i treatment compared to SGLT-2i alone resulted in significant decrease in HbA1c by 0.91% (95% CI; -1.41 to -0.42) [GRADE: moderate], in body weight by 1.95 kg (95% CI; -3.83 to -0.07) [GRADE: moderate], in fasting plasma glucose by 1.53 mmol/L (95% CI; -2.17 to -0.88) [GRADE: moderate] and in systolic blood pressure levels by 3.64 mm Hg (95% CI -6.24 to -1.03). No significant effects on lipid profile and diastolic blood pressure were demonstrated. A significant increase in the risk for any hypoglycemia (RR: 2.62, 95% CI; 1.15-5.96, I² = 33%) [GRADE: moderate] and for nausea (RR: 3.21, 95% CI; 1.36-7.54, I² = 63%) [GRADE: moderate] and a non-significant increase in the risk for diarrhoea (RR: 1.64, 95% CI; 0.98-2.75, I² = 0%) [GRADE: low] were documented. No other safety issues were identified.

Conclusions: This meta-analysis suggests that a GLP-1RA/SGLT-2i combination, if tolerated, exerts significant beneficial effects on glycemic control and body weight loss, however increasing the risk for any hypoglycemia and gastrointestinal adverse events.