Efficacy of Once-Weekly Semaglutide vs Empagliflozin Added to Metformin in Type 2 Diabetes: Patient-Level Meta-analysis

Abstract

Context: No head-to-head trials have directly compared once-weekly (OW) semaglutide, a human glucagon-like peptide-1 analog, with empagliflozin, a sodium-glucose co-transporter-2 inhibitor, in type 2 diabetes (T2D).

Objective: We indirectly compared the efficacy of OW semaglutide 1 mg vs once-daily (OD) empagliflozin 25 mg in patients with T2D inadequately controlled on metformin monotherapy, using individual patient data (IPD) and meta-regression methodology.

Design, setting, participants, and interventions: IPD for patients with T2D receiving metformin monotherapy and randomized to OW semaglutide 1 mg (SUSTAIN 2, 3, 8 trials), or to OD empagliflozin 25 mg (PIONEER 2 trial) were included. Meta-regression analyses were adjusted for potential prognostic factors and effect modifiers.

Main outcome measures: The primary efficacy outcomes were change from baseline to end-of-treatment (~1 year) in HbA1c (%-point) and body weight (kg). Responder outcomes and other clinically relevant efficacy measures were analyzed.

Results: Baseline characteristics were similar between OW semaglutide (n = 995) and empagliflozin (n = 410). Our analyses showed that OW semaglutide significantly reduced mean HbA1c and body weight vs empagliflozin (estimated treatment difference: -0.61%-point [95% confidence interval (CI): -0.72; -0.49] and -1.65 kg [95% CI: -2.22; -1.08], respectively; both P < 0.0001). Complementary analyses supported the robustness of these results. A significantly greater proportion of patients on OW semaglutide vs empagliflozin also achieved HbA1c targets and weight-loss responses.

Conclusions: This indirect comparison suggests that OW semaglutide 1 mg provides superior reductions in HbA1c and body weight vs OD empagliflozin 25 mg in patients with T2D when added to metformin monotherapy.

Trial registration: ClinicalTrials.gov NCT01930188 NCT01885208 NCT03136484 NCT02863328.

Keywords: GLP-1 receptor agonist; SGLT-2 inhibitor; indirect comparison; individual patient data; type 2 diabetes.

Figure 1.

Standard of evidence for some examples of direct and indirect comparisons (10, 12).

Figure 2.

Disposition of patients inadequately controlled on metformin monotherapy included in the IPD MR. Abbreviation: IPD MR, individual patient data meta-regression.

Figure 3.

Change from baseline in a) HbA_1c and b) body weight with OW semaglutide 1 mg vs OD empagliflozin 25 mg at week 52. *The primary analysis used data from all randomized patients while on treatment without rescue medication, adjusted for potential prognostic factors and effect modifiers listed in Table 2. ^†The unadjusted analysis used data from all randomized patients while on treatment without rescue medication, not adjusted for potential prognostic factors and effect modifiers listed in Table 2. ^‡Complementary analysis 1 used “in-trial” data (data from all randomized patients irrespective of treatment discontinuation or use of rescue medication). ^§Complementary analysis 2 included patient data from SUSTAIN 8 and PIONEER 2 only (both 52 weeks in duration; n = 394 for OW semaglutide). Abbreviations: CI, confidence interval; ETD, estimated treatment difference; OD, once-daily; OW, once-weekly; SE, standard error.