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

Frías, Juan P.; Auerbach, Pernille; Bajaj, Harpreet S.; Fukushima, Yasushi; Lingvay, Ildiko; Macura, Stanislava; Søndergaard, Anette L.; Tankova, Tsvetalina; Tentolouris, Nikolaοs; Buse, John B.

doi:10.1016/s2213-8587(21)00174-1

Cited by 90 publications

(58 citation statements)

References 22 publications

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“…A target of HbA1c less than 7.0% was reached by, respectively, 68% versus 58% of people randomized to semaglutide 2.0-versus 1.0-mg QW. 65 High-dose dulaglutide also dose-dependently reduced HbA1c. 63,64 In AWARD-11, according to the efficacy estimand, treatment with dulaglutide 4.5-mg QW improved HbA1c by 1.87% at week 36 and by 1.83% at week 52, with 72% of people reaching an HbA1c of less than 7.0% at weeks 36 and 52.…”

Section: Glycaemic Resultsmentioning

confidence: 95%

Efficacy and safety of high‐dose glucagon‐like peptide‐1, glucagon‐like peptide‐1/glucose‐dependent insulinotropic peptide, and glucagon‐like peptide‐1/glucagon receptor agonists in type 2 diabetes

Block

Dirinck

Verhaegen

et al. 2022

Diabetes Obesity Metabolism

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Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have become agents of choice for people with type 2 diabetes (T2D) with established cardiovascular disease or in highrisk individuals. With currently available GLP-1 RAs, 51%-79% of subjects achieve an HbA1c target of less than 7.0% and 4%-27% lose 10% of body weight, illustrating the need for more potent agents. Three databases (PubMed, Cochrane, Web of Science) were searched using the MESH terms 'glucagon-like peptide-1 receptor agonist', 'glucagon receptor agonist', 'glucose-dependent insulinotropic peptide', 'dual or co-agonist', and 'tirzepatide'. Quality of papers was scored using PRISMA guidelines. Risk of bias was evaluated using the Cochrane assessment tool. An HbA1c target of less than 7.0% was attained by up to 80% with high-dose GLP-1 RAs and up to 97% with tirzepatide, with even up to 62% of people with T2D reaching an HbA1c of less than 5.7%. A body weight loss of 10% or greater was obtained by up to 50% and up to 69% with high-dose GLP-1 RAs or tirzepatide, respectively. The glucose-and weightlowering effects of the GLP-1/glucagon RA cotadutide equal those of liraglutide 1.8 mg.Gastrointestinal side effects of high-dose GLP-1 RAs and co-agonists occurred in 30%-70% of patients, mostly arising within the first 2 weeks of the first dose, being mild or moderate in severity, and transient. The development of high-dose GLP-1 RAs and the dual GLP-1/glucose-dependent insulinotropic peptide RA tirzepatide resulted in increasing numbers of people reaching HbA1c and body weight targets, with up to 62% attaining normoglycaemia with 15-mg tirzepatide. Whether this will also translate to better cardiovascular outcomes and affect treatment guidelines remains to be studied.

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Section: Glycaemic Resultsmentioning

confidence: 95%

Efficacy and safety of high‐dose glucagon‐like peptide‐1, glucagon‐like peptide‐1/glucose‐dependent insulinotropic peptide, and glucagon‐like peptide‐1/glucagon receptor agonists in type 2 diabetes

Block

Dirinck

Verhaegen

et al. 2022

Diabetes Obesity Metabolism

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“…However, a quantitative ITC of safety outcomes is intrinsically more difficult because of cross-trial differences in the assessment of adverse events. In all included trials, a similar safety profile was observed across treatment arms; adverse event rates were comparable between semaglutide 1.0 mg and dulaglutide 1.5 mg treatment arms in SUSTAIN 7 ( 4 ); dulaglutide 1.5 mg, 3.0 mg, and 4.5 mg treatment arms in AWARD-11 ( 11 ); and semaglutide 1.0 mg and 2.0 mg treatment arms in SUSTAIN FORTE ( 14 ). Furthermore, the current study did not evaluate differences in cardiovascular outcomes between treatments.…”

Section: Discussionmentioning

confidence: 76%

“…A limitation of this study is comparison of estimands across trials because there are subtle differences in the handling of intercurrent events, with different criteria for initiation of rescue medication. Furthermore, it was not possible to conduct an analysis based on the results of the treatment policy estimand in SUSTAIN FORTE ( 14 ) and SUSTAIN 7 ( 4 ), similar to the treatment-regimen estimand in AWARD-11 ( 11 ), which included efficacy data for patients regardless of treatment discontinuation or rescue medication. This was because confidence intervals and SEs for estimates on treatment level for the treatment-regimen estimand from AWARD-11 have not been published.…”

Section: Discussionmentioning

confidence: 99%

“…Semaglutide 1.0 mg has previously been compared with dulaglutide 3.0 mg and 4.5 mg using a Bucher indirect treatment comparison (ITC) ( 13 ). Semaglutide 2.0 mg has also been investigated in SUSTAIN FORTE ( 14 ) and is currently under review by the FDA and EMA.…”

mentioning

confidence: 99%

“…Although SUSTAIN 7 provides a head-to-head comparison between lower doses of semaglutide and dulaglutide ( 4 ), there are currently no head-to-head data comparing the higher doses of the 2 treatments. The objective of this study was to compare the efficacy of semaglutide 2.0 mg with dulaglutide 3.0 mg and 4.5 mg doses using an ITC based on aggregate and individual patient data (IPD) from SUSTAIN FORTE ( 14 ) and SUSTAIN 7 ( 4 ) and published aggregate data from AWARD-11 ( 11 ).…”

mentioning

confidence: 99%

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An Indirect Treatment Comparison of Semaglutide 2.0 mg vs Dulaglutide 3.0 mg and 4.5 mg Using Multilevel Network Meta-regression

Lingvay

Bauer

Baker‐Knight

et al. 2021

The Journal of Clinical Endocrinology &Amp; Metabolism

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Aims Currently no head-to-head data are available comparing semaglutide 2.0 mg with dulaglutide 3.0 mg or 4.5 mg. We conducted an indirect treatment comparison (ITC) of their effects on glycated haemoglobin (HbA1c) and body weight in patients with type 2 diabetes (T2D). Materials and methods Multilevel network meta-regression (MLNMR) was conducted, based on a connected evidence network of published results from the AWARD-11 trial and individual patient data (IPD) from the SUSTAIN FORTE and SUSTAIN 7 trials. Results Semaglutide 2.0 mg significantly reduced HbA1c versus dulaglutide 3.0 mg and 4.5 mg, with estimated treatment differences (ETD) of –0.44%-points (95% credible interval [CrI]: –0.68, –0.19) and –0.28%-points (95% CrI: –0.52, –0.03), respectively. Semaglutide 2.0 mg also significantly reduced body weight versus dulaglutide 3.0 mg and 4.5 mg with ETDs of –3.29 kg (95% CrI: –4.62, −1.96) and –2.57 kg (95% CrI: –3.90, –1.24), respectively. Odds of achieving HbA1c <7.0% were significantly greater for semaglutide 2.0 versus dulaglutide 3.0 mg (odds ratio [OR]: 2.23 [95% CrI: 1.15, 3.90]), while this did not reach significance for semaglutide 2.0 mg versus dulaglutide 4.5 mg (OR: 1.58 [95% CrI: 0.82, 2.78]). Sensitivity analyses supported the main analysis findings. Conclusions This ITC demonstrated significantly greater reductions from baseline in HbA1c and body weight with semaglutide 2.0 mg vs dulaglutide 3.0 mg and 4.5 mg. The findings of this study provide important comparative effectiveness information until randomised head-to-head studies become available.

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Association of Glucagon-Like Peptide-1 Receptor Agonist Use With Risk of Gallbladder and Biliary Diseases

Wang

Ping

et al. 2022

JAMA Intern Med

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IMPORTANCE Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have been widely recommended for glucose control and cardiovascular risk reduction in patients with type 2 diabetes, and more recently, for weight loss. However, the associations of GLP-1 RAs with gallbladder or biliary diseases are controversial.OBJECTIVE To evaluate the association of GLP-1 RA treatment with gallbladder and biliary diseases and to explore risk factors for these associations.DATA SOURCES MEDLINE/PubMed, EMBASE, Web of Science, and Cochrane Library (inception to June 30, 2021), websites of clinical trial registries (July 10, 2021), and reference lists. There were no language restrictions. STUDY SELECTION Randomized clinical trials (RCTs) comparing the use of GLP-1 RA drugs with placebo or with non−GLP-1 RA drugs in adults.DATA EXTRACTION AND SYNTHESIS Two reviewers independently extracted data according to the PRISMA recommendations and assessed the quality of each study with the Cochrane Collaboration risk-of-bias tool. Pooled relative risks (RRs) were calculated using random or fixed-effects models, as appropriate. The quality of evidence for each outcome was assessed using the GRADE (Grading of Recommendations Assessment, Development, and Evaluation) framework. MAIN OUTCOMES AND MEASURESThe primary outcome was the composite of gallbladder or biliary diseases. Secondary outcomes were biliary diseases, biliary cancer, cholecystectomy, cholecystitis, and cholelithiasis. Data analyses were performed from August 5, 2021, to September 3, 2021.RESULTS A total of 76 RCTs involving 103 371 patients (mean [SD] age, 57.8 (6.2) years; 41 868 [40.5%] women) were included. Among all included trials, randomization to GLP-1 RA treatment was associated with increased risks of gallbladder or biliary diseases (RR, 1.37; 95% CI, 1.23-1.52); specifically, cholelithiasis (RR, 1.27; 95% CI, 1.10-1.47), cholecystitis (RR, 1.36; 95% CI, 1.14-1.62), and biliary disease (RR, 1.55; 95% CI, 1.08-2.22). Use of GLP-1 RAs was also associated with increased risk of gallbladder or biliary diseases in trials for weight loss (n = 13; RR, 2.29; 95% CI, 1.64-3.18) and for type 2 diabetes or other diseases (n = 63; RR, 1.27; 95% CI, 1.14-1.43; P <.001 for interaction). Among all included trials, GLP-1 RA use was associated with higher risks of gallbladder or biliary diseases at higher doses (RR, 1.56; 95% CI, 1.36-1.78) compared with lower doses (RR, 0.99; 95% CI, 0.73-1.33; P = .006 for interaction) and with longer duration of use (RR, 1.40; 95% CI, 1.26-1.56) compared with shorter duration (RR, 0.79; 95% CI, 0.48-1.31; P = .03 for interaction).CONCLUSIONS AND RELEVANCE This systematic review and meta-analysis of RCTs found that use of GLP-1 RAs was associated with increased risk of gallbladder or biliary diseases, especially when used at higher doses, for longer durations, and for weight loss.

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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

Cited by 90 publications

References 22 publications

Efficacy and safety of high‐dose glucagon‐like peptide‐1, glucagon‐like peptide‐1/glucose‐dependent insulinotropic peptide, and glucagon‐like peptide‐1/glucagon receptor agonists in type 2 diabetes

Efficacy and safety of high‐dose glucagon‐like peptide‐1, glucagon‐like peptide‐1/glucose‐dependent insulinotropic peptide, and glucagon‐like peptide‐1/glucagon receptor agonists in type 2 diabetes

An Indirect Treatment Comparison of Semaglutide 2.0 mg vs Dulaglutide 3.0 mg and 4.5 mg Using Multilevel Network Meta-regression

Association of Glucagon-Like Peptide-1 Receptor Agonist Use With Risk of Gallbladder and Biliary Diseases

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