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Randomized Controlled Trial
. 2021 Sep;9(9):563-574.
doi: 10.1016/S2213-8587(21)00174-1. Epub 2021 Jul 21.

Efficacy and safety of once-weekly semaglutide 2·0 mg versus 1·0 mg in patients with type 2 diabetes (SUSTAIN FORTE): a double-blind, randomised, phase 3B trial

Juan P Frías  1 , Pernille Auerbach  2 , Harpreet S Bajaj  3 , Yasushi Fukushima  4 , Ildiko Lingvay  5 , Stanislava Macura  2 , Anette L Søndergaard  2 , Tsvetalina I Tankova  6 , Nikolaos Tentolouris  7 , John B Buse  8
Affiliations
Randomized Controlled Trial

Efficacy and safety of once-weekly semaglutide 2·0 mg versus 1·0 mg in patients with type 2 diabetes (SUSTAIN FORTE): a double-blind, randomised, phase 3B trial

Juan P Frías et al. Lancet Diabetes Endocrinol. 2021 Sep.

Abstract

Background: Semaglutide is an effective treatment for type 2 diabetes; however, 20-30% of patients given semaglutide 1·0 mg do not reach glycaemic treatment goals. We aimed to investigate the efficacy and safety of once-weekly semaglutide 2·0 mg versus 1·0 mg in adults with inadequately controlled type 2 diabetes on a stable dose of metformin with or without a sulfonylurea.

Methods: We did a 40-week, randomised, active-controlled, parallel-group, double-blind, phase 3B trial (SUSTAIN FORTE) at 125 outpatient clinics in ten countries. Participants (≥18 years) with inadequately controlled type 2 diabetes (HbA1c 8·0-10·0%) with metformin and with or without sulfonylurea were randomly assigned (1:1) by an interactive web-response system to 2·0 mg or 1·0 mg once-weekly semaglutide. Participants, site personnel, the clinical study group, and investigators were masked to the randomised treatment. Outcomes included change from baseline at week 40 in HbA1c (primary outcome) and bodyweight (secondary confirmatory outcome), evaluated through trial product estimand (no treatment discontinuation or without rescue medication) and treatment policy estimand (regardless of treatment discontinuation or rescue medication) strategies. This study is registered with ClinicalTrials.gov, NCT03989232; EudraCT, 2018-004529-96; and WHO, U1111-1224-5162.

Findings: Between June 19 and Nov 28, 2019, of 1515 adults assessed for eligibility, 961 participants (mean age 58·0 years [SD 10·0]; 398 [41%] women) were included. Participants were randomly assigned to once-weekly semaglutide 2·0 mg (n=480 [50%]) or 1·0 mg (n=481 [50%]); 462 (96%) patients in the semaglutide 2·0 mg group and 471 (98%) in the semaglutide 1·0 mg group completed the trial. Mean baseline HbA1c was 8·9% (SD 0·6; 73·3 mmol/mol [SD 6·9]) and BMI was 34·6 kg/m2 (SD 7·0). Mean change in HbA1c from baseline at week 40 was -2·2 percentage points with semaglutide 2·0 mg and -1·9 percentage points with semaglutide 1·0 mg (estimated treatment difference [ETD] -0·23 percentage points [95% CI -0·36 to -0·11]; p=0·0003; trial product estimand) and -2·1 percentage points with semaglutide 2·0 mg and -1·9 percentage points with semaglutide 1·0 mg (ETD -0·18 percentage points [-0·31 to -0·04]; p=0·0098; treatment policy estimand). Mean change in bodyweight from baseline at week 40 was -6·9 kg with semaglutide 2·0 mg and -6·0 kg with semaglutide 1·0 mg (ETD -0·93 kg [95% CI -1·68 to -0·18]; p=0·015; trial product estimand) and -6·4 kg with semaglutide 2·0 mg and -5·6 kg with semaglutide 1·0 mg (ETD -0·77 kg [-1·55 to 0·01]; p=0·054; treatment policy estimand). Gastrointestinal disorders were the most commonly reported adverse events (163 [34%] in the 2·0 mg group and 148 [31%] in the 1·0 mg group). Serious adverse events were similar between treatment groups, reported for 21 (4%) participants given semaglutide 2·0 mg and 25 (5%) participants given semaglutide 1·0 mg. Three deaths were reported during the trial (one in the semaglutide 1·0 mg group and two in the semaglutide 2·0 mg group).

Interpretation: Semaglutide 2·0 mg was superior to 1·0 mg in reducing HbA1c, with additional bodyweight loss and a similar safety profile. This higher dose provides a treatment intensification option for patients with type 2 diabetes treated with semaglutide in need of additional glycaemic control.

Funding: Novo Nordisk.

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Conflict of interest statement

Declarations of interest JPF reports grants and personal fees from Novo Nordisk; grants from AstraZeneca, BMS, Janssen, Novartis, Oramed, and Pfizer; and grants and personal fees from Boehringer Ingelheim, Eli Lilly, Merck KGaA, and Sanofi. HSB reports trial fees paid to his institution by Novo Nordisk; speaking honoraria from Eli Lilly and Novo Nordisk; and trial fees paid to his institution by Amgen, AstraZeneca, Boehringer Ingelheim, Ceapro, Eli Lilly, Gilead, Janssen, Kowa Pharmaceuticals, Madrigal Pharmaceuticals, Merck KGaA, Novo Nordisk, Pfizer, Sanofi, and Tricida. IL reports grants, personal fees, and non-financial support from Novo Nordisk; grants, personal fees, and non-financial support from Novo Nordisk and Sanofi; personal fees and non-financial support from Eli Lilly, Sanofi, AstraZeneca, Boehringer Ingelheim, and Janssen; personal fees from Intercept, Intarcia, TARGETPharma, Mannkind, Valeritas, Bayer, and Zealand Pharma, grants; and non-financial support from Merck and Pfizer, and grants from Mylan. TIT reports lecture fees and advisory board membership for Boehringer Ingelheim, AstraZeneca, Novo Nordisk, Sanofi, Eli Lilly, Novartis, and MSD. NT reports consultation fees from MSD, clinical trial fees from AstraZeneca, Eli Lilly, Boehringer Ingelheim, Sanofi, and Novo Nordisk, and unrestricted grants from Eli Lilly, Boehringer Ingelheim, ELPEN, and TrigoCare. ALS, PA, and SM are full-time employees of Novo Nordisk and own shares in the company. JBB reports a grant and non-financial support from Novo Nordisk; contracted consulting fees and travel support paid to the University of North Carolina (contract between University of North Carolina and the companies) from Adocia, AstraZeneca, Eli Lilly, Fractyl, Intarcia Therapeutics, Lexicon, MannKind, Metavention, Novo Nordisk, Sanofi, Senseonics, vTv Therapeutics, and Zafgen; research contracts, largely for clinical trials, and travel support paid to the University of North Carolina (contract between University of North Carolina and the companies) from AstraZeneca, Eli Lilly, Intarcia Therapeutics, Johnson & Johnson, Lexicon, NovaTarg, Novo Nordisk, Sanofi, Theracos, Tolerion, and vTv Therapeutics; consulting fees from Cirius Therapeutics, Fortress Biotech, Moderna, Pendulum Therapeutics, and Zealand Pharma; stock or options in lieu of payments for consulting and travel support for consulting activities from Mellitus Health, Pendulum Therapeutics, PhaseBio, Praetego, and Stability Health; and grants and non-financial support from the National Institutes of Health, Juvenile Diabetes Research Foundation International, Patient Centered Outcomes Research Institute, and the American Diabetes Association. YF declares no competing interests. The authors have not been paid or received compensation for their authorship.

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