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Mantsiou C, Karagiannis T, Kakotrichi P, et al. 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. Diabetes Obes Metab. 2020 Jun 1. doi: 10.1111/dom.14108. (Systematic review)

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 HbA1c . 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 HbA1c , 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.

Discipline Area Score
Family Medicine (FM)/General Practice (GP) 6 / 7
General Internal Medicine-Primary Care(US) 6 / 7
Endocrine 6 / 7
Comments from MORE raters

Endocrine rater

A timely systematic review and meta-analysis of studies looking at combining GLP-1 agonists and SGLT2 inhibitors in treating type 2 diabetes that included 7 studies with 1913 patients. The conclusion was that the combination therapy resulted in greater HbA1c reduction, weight loss, and systolic blood pressure reduction than either class used alone, with no increase in hypoglycemia risk. Although this seems intuitive, it is good to have a review like this to show the efficacy and safety of combination therapy.

Family Medicine (FM)/General Practice (GP) rater

Can GLP-1RA and SGLT2i be safely used in the same patient? The answer appears to be yes. Whether they should be combined is not clear from this review. The outcomes on A1c, blood pressure and body weight were favorable but the authors could not draw conclusions about prevention of complications or effect on mortality. These drugs are very expensive individually, so the combination will be a substantial burden for patients or payors. Unless we find evidence that this combination will lower complications mortality, their use in combination should not be routine.
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