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Comparative Study
. 2025 Dec;27(12):7431-7440.
doi: 10.1111/dom.70151. Epub 2025 Sep 24.

Effectiveness of oral semaglutide versus empagliflozin for the management of type 2 diabetes. PIONEER-2 trial emulation with real-world data

Gian Paolo Fadini  1   2 , Enrico Longato  3 , Sara Poletto  3 , Andrea Giaccari  4 , Mariangela Ghiani  5 , Marco Strazzabosco  6 , Maddalena Trombetta  7 , Giuseppe Penno  8 , Angelo Avogaro  1 , Anna Solini  9 , Agostino Consoli #  10   11 ; GLIMPLES study investigators and DARWIN‐Renal study investigators
Collaborators, Affiliations
Comparative Study

Effectiveness of oral semaglutide versus empagliflozin for the management of type 2 diabetes. PIONEER-2 trial emulation with real-world data

Gian Paolo Fadini et al. Diabetes Obes Metab. 2025 Dec.

Abstract

Background and aims: Oral semaglutide and empagliflozin are commonly used for the management of type 2 diabetes (T2D), but head-to-head comparisons in real-world settings are limited. We aimed to emulate the PIONEER-2 trial using electronic health records to compare the effectiveness and persistence of oral semaglutide versus empagliflozin.

Methods: This was a retrospective multicentre study using electronic health records from Italian diabetes clinics. New users of oral semaglutide or empagliflozin were matched 1:2 and followed for up to 18 months. The primary outcome was HbA1c change; secondary outcomes included weight change and treatment persistence. Analyses used mixed models for repeated measures under both treatment policy and trial product estimands.

Results: After matching, we included new users of oral semaglutide (n = 105) or empagliflozin (n = 207). Mean age was 65 years, diabetes duration 10 years, baseline HbA1c 7.6%, BMI 29 kg/m2, and 94% were on metformin. Only 28.6% of new users of oral semaglutide reached the 14 mg dose and 31.4% of empagliflozin new users reached the 25 mg dose. HbA1c reduction was significantly greater with oral semaglutide than with empagliflozin (mean difference - 0.35%, p <0.001). Weight loss over time was similar, with oral semaglutide showing a modest advantage at 18 months among persistent patients. Persistence was lower for semaglutide (HR for discontinuation 1.47, p = 0.007).

Conclusions: Under routine care, new users of oral semaglutide achieved better glycaemic control compared with empagliflozin new users, with similar weight loss but lower treatment persistence. These findings support the results of PIONEER-2 and its transferability to clinical practice.

Keywords: cohort study; empagliflozin; real‐world evidence; semaglutide.

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Conflict of interest statement

GPF received honoraria, lecture, or advisory board fees from AstraZeneca, Boehringer, Guidotti, Lilly, Novartis, Novo Nordisk, and Sanofi. AG has received lecture fees from AstraZeneca, Lilly, and Novo Nordisk. GP reports consulting, advisory board, or speaking honoraria from Eli Lilly, consulting or participation on advisory boards for Bayer, and consulting for Novo Nordisk. AA received research grants, lecture, or advisory board fees from Merck Sharp & Dohme, AstraZeneca, Novartis, Boehringer‐Ingelheim, Sanofi, Mediolanum, Janssen, Novo Nordisk, Lilly, Servier, and Takeda. AS served on the advisory board of Novo Nordisk, Sankyo, and Sanofi and received speaker fees from AstraZeneca, Bayer, Lilly, Novo Nordisk, and Sanofi. AC received grants from AstraZeneca, Lilly, and Novo Nordisk. He also received speaker fees and provided advisory board services for Abbott, AstraZeneca, Boehringer Ingelheim Pharmaceuticals, Lilly, Merck Sharp & Dohme, Menarini, Novo Nordisk, Sanofi, Sigma‐Tau, and Takeda. EL, SP, MG, MS, and MT have nothing to disclose.

Figures

FIGURE 1
FIGURE 1
Glycaemic efficacy of oral semaglutide versus empagliflozin. Results are presented for the treatment policy estimand (A)–(C) and for the trial product estimand (D)–(F). (A) and (D) Estimated absolute change in HbA1c over time. (B) and (E) Estimated changes from baseline in HbA1c at months 9 and 18. (C) and (F) Estimated proportions of patients achieving HbA1c <6.5% (48 mmol/mol) at months 9 and 18. CI, confidence interval; ETD, estimated treatment difference.
FIGURE 2
FIGURE 2
Body weight change and targets with oral semaglutide versus empagliflozin. Results are presented for the treatment policy estimand (A)–(C) and for the trial product estimand (D)–(F). (A) and (D) Estimated absolute change in body weight over time. (B) and (E) Estimated changes from baseline in body weight at months 9 and 18. (C) and (F) Estimated proportions of patients achieving weight reduction of 5% or more at months 9 and 18. CI, confidence interval; ETD, estimated treatment difference.
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