Long-term comparative effectiveness of once-weekly semaglutide versus alternative treatments in a real-world US adult population with type 2 diabetes: a randomized pragmatic clinical trial

Abstract

Introduction: This study evaluated the long-term effectiveness of once-weekly subcutaneous semaglutide versus alternative treatment in adults with type 2 diabetes (T2D) in routine clinical practice.

Research design and methods: The SEmaglutide PRAgmatic (SEPRA) was a 2-year, randomized, open-label, pragmatic clinical trial (NCT03596450). Adults with T2D and inadequate glycemic control on one or two oral antidiabetic medications were randomized to receive once-weekly subcutaneous semaglutide or alternative treatment (chosen by the treating physician) as add-on therapy. Endpoints included proportion of participants achieving glycated hemoglobin (HbA_1c)<7.0% at year 1 (primary endpoint) and year 2; changes in HbA_1c (percentage point), body weight, and patient-reported outcomes (PROs) at years 1 and 2; and treatment changes (baseline to year 2). Missing data were imputed for some analyses.

Results: Participants were randomized to semaglutide (n=644) or alternative treatment (n=634). Proportions of participants achieving HbA_1c <7.0% were significantly higher with semaglutide versus alternative treatment at years 1 (53.1% vs 45.5%; OR (95% CI): 1.36 (1.03 to 1.79); p=0.033) and 2 (49.9% vs 38.9%; OR (95% CI): 1.56 (1.13 to 2.16); p=0.007). Mean HbA_1c decreases were larger with semaglutide versus alternative treatment at year 1 (-1.35% vs -1.16%; estimated treatment difference (ETD) (95% CI): -0.20% (-0.39% to 0.00%); p=0.046) and year 2 (-1.27% vs -0.96%; ETD (95% CI): -0.31% (-0.57% to -0.05%); p=0.018). Semaglutide was associated with larger reductions in body weight at year 1 (-3.57% vs -1.91%; ETD (95% CI): -1.65% (-2.92% to -0.39%); p=0.010) but not year 2 (p=0.175). Treatment changes occurred less frequently with semaglutide than with alternative treatments. Some PROs indicated greater improvement with semaglutide versus alternative treatment. No new safety concerns were identified.

Conclusions: SEPRA demonstrates that semaglutide is an appropriate choice for treatment intensification among individuals with T2D in the USA who are receiving 1-2 antidiabetic medications. Findings support semaglutide as an effective and well-tolerated option in clinical practice.

Trial registration number: NCT03596450.

Keywords: Diabetes Mellitus, Type 2; Glucagon-Like Peptide 1.

Figure 1. Participant disposition (Consolidated Standards of Reporting Trials diagram). ^aOther reasons for early trial termination include: change in insurance, treating physician, or residence, financial restrictions, lost contact due to COVID-19, and the treating physician withdrew the patient. ^bIncluding 406 (63.0%) who attended within a ±6 week window around the year 1 time point. ^cHbA_1c years 1 and 2 assessments include all values collected within a ±10 week window around the years 1 and 2 visit dates. ^dIncluding 368 (57.1%) who attended within a ±6 week window around the year 2 time point. ^eIncluding 428 (67.5%) who attended within a ±6 week window around the year 1 time point. ^fIncluding 351 (55.4%) who attended within a ±6 week window around the year 2 time point. FAS, full analysis set; HbA_1c, glycated hemoglobin.

Figure 2. (A) Percentages of participants who achieved HbA_1c <7.0% (53.0 mmol/mol) at year 1 (primary endpoint) and year 2, and (B) changes from baseline in HbA_1c at year 1 and year 2. All data include imputed data for participants without HbA_1c values at years 1 and 2. ETD, estimated treatment difference; HbA_1c, glycated hemoglobin.

Figure 3. Changes from baseline to year 1 and year 2 in (A) body weight, (B) SBP, and (C) DBP. All data include imputed data for participants without HbA_1c values at years 1 and 2. DBP, diastolic blood pressure; ETD, estimated treatment difference; HbA_1c, glycated hemoglobin; SBP, systolic blood pressure.

Figure 4. PROs at year 1 and year 2 (complete case analysis). ^aMean treatment difference (semaglutide–alternative treatment). DTSQ, Diabetes Treatment Satisfaction Questionnaire; ETD, estimated treatment difference; PRO, patient-reported outcome; SF-12 v2, 12-Item Short Form Survey version 2; WPAI:GH, Work Productivity and Activity Impairment Questionnaire: General Health.