Safety and efficacy of oral semaglutide versus dulaglutide in Japanese patients with type 2 diabetes (PIONEER 10): an open-label, randomised, active-controlled, phase 3a trial

Yabe, Daisuke; Nakamura, Jiro; Kaneto, Hideaki; Deenadayalan, Srikanth; Navarria, Andrea; Gislum, Mette; Inagaki, Nobuya; Arisaka, Tomoyuki; Asakura, Takeshi; Azuma, Naoto; Fukuda, Sumiaki; Fukushima, Yasushi; Harada, Norio; Inoue, Shin‐ichiro; Ishida, Hideyuki; Ishii, Hiroshi; Ishikawa, San‐e; Jinnouchi, Hideaki; Kaneko, Shuji; Kanno, K.; Kato, Mai; Kato, Yoichiro; Kawada, Tatsushi; Kim, H; Kiyosue, Arihiro; Matsuoka, Osamu; Miho, Otoya; Nakamoto, S.; Nakamura, Susumu; Nakanishi, Shuhei; Nishimura, Hideki; Numata, Akira; Ohama, Tohru; Okabe, Tomoko; Okuguchi, Fuminobu; Osonoi, Takeshi; Sasaki, Takuma; Seino, Hiroaki; Shin, Koki; Shiraiwa, Toshihiko; Sugiura, Toshiyuki; Wada, Seiki; Yamauchi, Akira

doi:10.1016/s2213-8587(20)30074-7

Cited by 122 publications

(172 citation statements)

References 23 publications

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“…Trial designs and endpoints for the SUSTAIN and PIONEER phase 3a glycaemic efficacy trials (SUSTAIN 1–5 and two SUSTAIN JAPAN trials, and PIONEER 1–5, 7–8 and the two PIONEER Japanese trials [9 and 10]) are summarized in Tables S2 and S3, and have also been reported previously …”

Section: Methodsmentioning

confidence: 99%

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Semaglutide (SUSTAIN and PIONEER) reduces cardiovascular events in type 2 diabetes across varying cardiovascular risk

Husain

Bain

Jeppesen

et al. 2020

Diabetes Obesity Metabolism

129

106

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Aim To investigate the effects of semaglutide versus comparators on major adverse cardiovascular events (MACE: cardiovascular [CV] death, nonfatal myocardial infarction [MI] and nonfatal stroke) and hospitalization for heart failure (HF) in the SUSTAIN (subcutaneous semaglutide) and PIONEER (oral semaglutide) trials across subgroups of varying CV risk. Methods Post hoc analyses of individual patient‐level data combined from SUSTAIN 6 and PIONEER 6 were performed to assess MACE and HF. MACE were analysed in subjects with and without: established CV disease and/or chronic kidney disease; prior MI or stroke; and prior HF. MACE in the SUSTAIN and PIONEER glycaemic efficacy trials were also assessed. Results In SUSTAIN 6 and PIONEER 6 combined, the hazard ratio (HR) for effect of semaglutide versus placebo on overall MACE was 0.76 (95% CI 0.62, 0.92), which was mainly driven by the effect on nonfatal stroke (HR 0.65 [95% CI 0.43, 0.97]). The HR for hospitalization for HF was 1.03 (95% CI 0.75, 1.40). The HRs for MACE were <1.0 in all subgroups, except for those with prior HF (HR 1.06 [95% CI 0.72, 1.57]); P‐values for interaction of subgroup on treatment effect were >0.05, except for HF (0.046). In the combined glycaemic efficacy trials, the HR for effect of semaglutide versus comparators on MACE was 0.85 (95% CI 0.55, 1.33). Conclusions In SUSTAIN and PIONEER combined, glucagon‐like peptide‐1 analogue semaglutide showed consistent effects on MACE versus comparators across varying CV risk. No effect of semaglutide on MACE was observed in subjects with prior HF.

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Section: Methodsmentioning

confidence: 99%

“…The half‐life (~7 days) and clinical effects of semaglutide are similar irrespective of mode of administration . Both formulations lowered HbA1c and body weight versus comparators across the continuum of care in subjects with T2D in the SUSTAIN (s.c.) and PIONEER (oral) phase 3a clinical trial programmes.…”

Section: Introductionmentioning

confidence: 98%

Semaglutide (SUSTAIN and PIONEER) reduces cardiovascular events in type 2 diabetes across varying cardiovascular risk

Husain

Bain

Jeppesen

et al. 2020

Diabetes Obesity Metabolism

129

106

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“…Trial information (including aims, designs and interventions) can be found in the publications of the individual trials [8][9][10][11][12][13][14][15][21][22][23][24][25][26][27][28][29][30].…”

Section: Combined Semaglutide Trial Datamentioning

confidence: 99%

“…Both formulations were extensively studied in clinical trial programs: s.c. semaglutide in nine SUSTAIN phase 3a clinical trials (SUSTAIN 1-6, two Japanese trials and the China Multi-Regional Clinical Trial) [8][9][10][11][12][13][14][15][16] and four phase 3b clinical trials (SUSTAIN 7-10) [17][18][19][20] and oral semaglutide in the 10 PIONEER phase 3a clinical trials (PIO-NEER 1-10; PIONEER 9 and 10 were conducted in Japan) [21][22][23][24][25][26][27][28][29][30] to date. Both clinical trial programs included cardiovascular outcomes trials (CVOTs): SUSTAIN 6 (s.c. semaglutide) and PIONEER 6 (oral semaglutide) [13,26].…”

Section: Introductionmentioning

confidence: 99%

Effects of semaglutide on risk of cardiovascular events across a continuum of cardiovascular risk: combined post hoc analysis of the SUSTAIN and PIONEER trials

Husain

Bain

Holst

et al. 2020

Cardiovasc Diabetol

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Background Semaglutide is a glucagon-like peptide-1 (GLP-1) analog treatment for type 2 diabetes (T2D) available in subcutaneous (s.c.) and oral formulations. Two cardiovascular (CV) outcomes trials showed that in subjects with T2D at high risk of CV events there were fewer major adverse CV events (MACE; defined as CV death, non-fatal stroke, non-fatal myocardial infarction) with semaglutide than with placebo (hazard ratio [95% CI]: 0.74 [0.58;0.95] for once-weekly s.c. semaglutide and 0.79 [0.57;1.11] for once-daily oral semaglutide). However, there is little evidence for an effect of semaglutide on MACE in subjects not at high risk of CV events. This post hoc analysis examined CV effects of semaglutide in subjects across a continuum of baseline CV risk. Methods Data from the s.c. (SUSTAIN) and oral (PIONEER) semaglutide phase 3a clinical trial programs were combined according to randomized treatment (semaglutide or comparators) and analyzed to assess time to first MACE and its individual components. A CV risk model was developed with independent data from the LEADER trial (liraglutide vs placebo), considering baseline variables common to all datasets. Semaglutide data were analyzed to assess effects of treatment as a function of CV risk predicted using the CV risk prediction model. Results The CV risk prediction model performed satisfactorily when applied to the semaglutide data set (area under the curve: 0.77). There was a reduced relative and absolute risk of MACE for semaglutide vs comparators across the entire continuum of CV risk. While the relative risk reduction tended to be largest with low CV risk score, the largest absolute risk reduction was for intermediate to high CV risk score. Similar results were seen for relative risk reduction of the individual MACE components and also when only placebo comparator data were included. Conclusion Semaglutide reduced the risk of MACE vs comparators across the continuum of baseline CV risk in a broad T2D population. Trial registrations ClinicalTrials.gov identifiers: NCT02054897, NCT01930188, NCT01885208, NCT02128932, NCT02305381, NCT01720446, NCT02207374, NCT02254291, NCT02906930, NCT02863328, NCT02607865, NCT02863419, NCT02827708, NCT02692716, NCT02849080, NCT03021187, NCT03018028, NCT03015220.

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“…Approval was based on a suite of phase 3a clinical trials referred to as the Peptide InnOvatioN for Early diabEtes tReatment (PIONEER) program. The PIONEER program included eight multinational studies (PIONEER 1-8) (Figure 3) [117,118,119,120,121,122,123,124] and two studies in people from Japan with T2D (PIONEER 9 and 10) [125,126]. Over 9,500 adults with T2D were randomized in these studies to evaluate the effect of oral semaglutide as monotherapy and as add-on to various background therapies, including metformin, sulfonylureas, SGLT2 inhibitors, thiazolidinediones, and insulin.…”

Section: Development Of Oral Semaglutidementioning

confidence: 99%

GLP-1 receptor agonists in the treatment of type 2 diabetes: role and clinical experience to date

Brunton

Wysham

2020

Postgraduate Medicine

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Glucagon-like peptide-1 (GLP-1) is a hormone of the incretin system responsible for a variety of glucoregulatory effects, including glucose-dependent secretion of insulin and inhibition of glucagon release, the effects of which are impaired in people with type 2 diabetes (T2D). Targeting this deficiency using GLP-1 receptor agonists (GLP-1RAs) is a well-established approach in T2D, with over a decade of clinical experience now accrued. This article reviews the evidence for subcutaneous GLP-1RAs and their role in T2D treatment, and explores the rationale for an oral GLP-1RA from a primary care perspective. Clinical trials and real-world studies with subcutaneous GLP-1RAs indicate that these agents have good glycated hemoglobin (HbA 1c)-lowering efficacy, an inherently low potential for hypoglycemia, and reduce body weight. Cardiovascular outcomes trials have established cardiovascular safety, and three GLP-1RAs have been proven to reduce the risk of major adverse cardiovascular events (MACE) in patients with established cardiovascular disease or at high cardiovascular risk. The most common adverse events associated with GLP-1RAs are gastrointestinal effects, which tend to occur soon after initiation and decline over time. T2D treatment guidelines recommend GLP-1RAs as a therapeutic option in various settings, including in those patients: i) not achieving HbA 1c targets after first-line metformin and lifestyle modifications; ii) at high risk of/with established atherosclerotic cardiovascular disease (regardless of HbA 1c ; GLP-1RAs of proven benefit); iii) not achieving HbA 1c targets on basal insulin if not already receiving a GLP-1RA. Despite the known benefits of GLP-1RAs, adherence and persistence rates are suboptimal, potentially due in part to injection-related concerns. With some patients having a preference for oral medications, the development of an oral GLP-1RA is a logical approach to improving treatment options for patients with T2D. Co-formulation of semaglutide with an absorption enhancer has enabled the development and recent approval of the first oral GLP-1RA, oral semaglutide, which has the potential to expand use of GLP-1RAs in clinical practice.

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Safety and efficacy of oral semaglutide versus dulaglutide in Japanese patients with type 2 diabetes (PIONEER 10): an open-label, randomised, active-controlled, phase 3a trial

Cited by 122 publications

References 23 publications

Semaglutide (SUSTAIN and PIONEER) reduces cardiovascular events in type 2 diabetes across varying cardiovascular risk

Semaglutide (SUSTAIN and PIONEER) reduces cardiovascular events in type 2 diabetes across varying cardiovascular risk

Effects of semaglutide on risk of cardiovascular events across a continuum of cardiovascular risk: combined post hoc analysis of the SUSTAIN and PIONEER trials

GLP-1 receptor agonists in the treatment of type 2 diabetes: role and clinical experience to date

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