Discussion
Results of the randomized, open-label, highly pragmatic SEPRA trial demonstrate the effectiveness of once-weekly subcutaneous semaglutide compared with alternative treatment in glycemic control and weight loss, complementing results of phase III RCTs and observational studies and supporting the integration of semaglutide into clinical practice.
Mean HbA1c reductions among participants treated with semaglutide were −1.35% and −1.49% (primary and secondary estimands, respectively) from baseline to year 1, and −1.27% and −0.96% from baseline to year 2. In the SUSTAIN clinical trial program (SUSTAIN 1–7; 30–104 weeks), the magnitude of change in HbA1c from baseline ranged from −1.4% to −1.8% for semaglutide 1.0 mg and −1.1% to −1.5% for semaglutide 0.5 mg.5 Compared with participants in the SUSTAIN program, participants in SEPRA were slightly older and heavier, with a shorter duration of T2D and wider range of baseline HbA1c, and fewer were Hispanic; additionally, participants in SEPRA had higher rates of hypertension, ischemic heart disease and stroke, and chronic heart failure.5 8 22–26 In a meta-analysis of real-world studies, once-weekly subcutaneous semaglutide reduced HbA1c by −1.1% (26 to ~30 weeks follow-up).27 Glycemic control (HbA1c <7.0%) was maintained over time to a greater extent with semaglutide (year 1: 53.1%; year 2: 49.9%) compared with alternative treatment (45.5%–38.9%). The glycemic control observed with semaglutide compared with the physician’s choice of alternative glucose-lowering medications is notable, as others have observed waning effectiveness of long-term diabetes treatment.28 Although previous studies that used fixed-dose escalation or randomization to specific doses of semaglutide have demonstrated dose-dependent responses in HbA1c,8 26 there were minimal differences in glycemic outcomes by semaglutide dose in SEPRA, which may have been a result of this pragmatic study not being designed to assess the effect of dose on HbA1c. Specifically, similar HbA1c results at various doses of semaglutide may have occurred because patients who achieved HbA1c targets or experienced adverse events at a low dose would not necessarily increase their dose, while those who did not achieve targets may increase their dose; therefore, dose response was not formally assessed, since the randomization scheme was based on the treatment that was used and not the specific dose that was administered as was done previously.
Average weight loss with semaglutide in SEPRA (year 1: −3.57% and −4.0 kg; year 2: −3.84% and −4.44 kg) was consistent with SUSTAIN 1–7 (semaglutide 1.0 mg: −4.9 kg to −6.5 kg; semaglutide 0.5 mg: −3.5 kg to −4.6 kg) based on the doses used in SEPRA.5 Average weight loss of −4.9 kg was reported in other real-world studies (over 26 to ~30 weeks).27 The ETD for average weight loss for semaglutide versus alternative treatment was only significantly different for years 1 and 2 in the second estimand that assumed all participants were adherent, whereas the ETD for the primary estimand was only significant at year 1. These results indicate that adherence to the study drug may influence the degree of weight loss at year 2, although differences in dose escalation patterns, tolerability issues, or treatment discontinuation may have also contributed to the lack of difference in weight loss between treatment groups for the primary estimand. Additionally, in this pragmatic study, practice patterns varied, and patients and practitioners prioritized achieving HbA1c levels near 7% as opposed to maximizing the semaglutide dose to achieve greater weight loss.
PROs showed a tendency toward improvement from baseline to year 2, suggesting greater treatment satisfaction and fewer problems with perceived hyperglycemia in participants receiving semaglutide versus alternative treatment. This suggests that semaglutide may be associated with improvements in quality of life in individuals with T2D in a real-world setting. However, these results may be influenced by the open-label nature of the trial and differential loss to follow-up of less satisfied participants.
The benefits of semaglutide versus alternative treatment were observed even though only 27.5% of participants were taking semaglutide 1.0 mg, the highest dose approved for this indication at the time, at year 2. Some participants may have taken lower doses because they achieved their HbA1c target; experienced intolerable side effects, treatment inertia, and lack of attention to the titration regimen; missed follow-up appointments; or had difficulty with access due to medication shortages or insurance changes, among other possibilities. Prospective, single-arm, non-interventional, real-world studies conducted outside the US have reported a wide range (11%–71%) of participants taking semaglutide 1.0 mg.29–37 Treatment intensification occurred more frequently with higher doses of semaglutide, possibly because some participants did not achieve their glycemic target even with the highest dose of semaglutide; however, treatment intensification was less frequent with semaglutide overall compared with alternative treatment. Current guidance recommends that treatments selected at initiation or intensification should meet glycemic and weight targets established with patients through shared decision-making.3
A large number and variety of therapeutics were taken by participants in the alternative treatment group, but a majority of participants took GLP-1 RAs (71.3%), particularly dulaglutide (58.5%), or SGLT-2 inhibitors (15.5%). Although this study was not powered to compare outcomes by treatment, and alternative treatments were at the discretion of the treating physician, descriptive analyses demonstrated a relatively modest but consistent superiority in glycemic control between semaglutide and dulaglutide, and a considerably larger difference between semaglutide and SGLT-2 inhibitors. Similarly, reductions in HbA1c were greater with semaglutide at year 1 and year 2 compared with dulaglutide and SGLT-2 inhibitors. These findings are consistent with previous studies showing greater efficacy of semaglutide compared with these other therapeutics.26 38 Additionally, head-to-head studies that assessed glucose metabolism or mean change in HbA1c in patients who switched from dulaglutide or liraglutide to semaglutide compared with patients who remained on initial treatment demonstrated improved outcomes when switching to semaglutide, which is consistent with the descriptive analyses in this study demonstrating improved glycemic control with semaglutide versus dulaglutide.39 40
A total of 368 (28.8%) participants terminated SEPRA early, most commonly due to loss to follow-up (8.3%), withdrawal of consent (5.8%), or other reasons (7.9%), including issues related to COVID-19, change in insurance, or other financial concerns. Reasons for early termination were generally balanced across treatment groups. A limitation inherent in pragmatic clinical trials conducted in routine clinical practice, including SEPRA, is a lack of study participation-related incentives,13 which are common in traditional RCTs but generally antithetical to a hands-off pragmatic approach.11 13 Aspects of the SEPRA study design were implemented to minimize potential causes of missing data, such as equalizing copays and facilitating data collection by recording HbA1c data within a protocol-specified window. In addition to dropout, a certain amount of missing data was anticipated for other reasons, such as the known rate of 22%–30% non-adherence to newly prescribed antidiabetic medications reported in real-world studies.41–44 However, treatment adherence was high at years 1 (semaglutide: 81.5%; alternative treatment: 81.2%) and 2 (semaglutide: 68.3%; alternative treatment: 62.6%) (figure 1). Post hoc exploration of SEPRA participants with and without HbA1c data at year 1 found no meaningful difference in baseline demographic, clinical, and diabetes characteristics.
From a statistical perspective, a selection of predefined analytic approaches was used to decrease uncertainty due to missingness by using both imputed and observed HbA1c data. Initial sample size calculations used an estimate of 25% missing data for the primary and confirmatory HbA1c endpoints at year 1, which were slightly less than the observed proportion of 30%, but a conservative approach nonetheless, considering the use of imputed HbA1c data in the primary endpoint analysis. The observed proportion of 41% missing data at year 2 was slightly lower than the estimated 44% for the confirmatory HbA1c endpoints. The protocol-defined, prespecified analytic approach of using multiple imputation rather than repeated measures modeling was chosen based on the pragmatic study design because there were minimal required visits planned at years 1 and 2 post randomization. Additional HbA1c data from routine visits were to be collected if they occurred, but this varied by participant. The analyses using imputed data were supplemented with complete case analysis and complete case on-study analyses of observed data. All analytic approaches consistently demonstrated the superior effectiveness of semaglutide in achieving glycemic control at year 2.
A key strength of SEPRA is the highly pragmatic design, scoring 4–5 (on a scale of 1–5, with 5 being very pragmatic) across all PRECIS-2 domains,13 which bridges RCTs and observational study real-world evidence.10 This stands in contrast to the randomized trials on which general practice guidelines for the management of T2D are based, which were judged to be more explanatory than pragmatic when evaluated with PRECIS-2.45 Consistent with the pragmatic design, the trial population was more inclusive than traditional RCTs, and the follow-up period was longer than in other real-world studies (generally 6 months to 1 year).35 46 47 Regarding limitations, the COVID-19 pandemic caused recruitment challenges, and the estimated population size for power calculation was not met (target, 1387 participants; actual, 1278 participants).10 Copay equalization and supply shortages during the study may have impacted the pragmatic nature of SEPRA. Additional limitations include the open-label design, comparator heterogeneity, reliance on multiple-imputation analyses, and lack of comparison by dose of comparator GLP-1 RAs. Despite these limitations, the final design afforded an opportunity to robustly assess real-world evidence.
In conclusion, results of SEPRA confirm that semaglutide is an appropriate choice for treatment intensification among individuals with T2D who are receiving 1–2 antidiabetic medications in the USA. This trial complements findings from phase III and observational trials and supports the use of semaglutide as an effective and well-tolerated treatment option for glycemic control and weight management in real-world clinical practice.
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