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Effects of Semaglutide Versus Comparators on Cardiovascular Events Across a Continuum of Baseline Cardiovascular Risk: Combined Analysis of the SUSTAIN and PIONEER Trials

Mansoor Husain,1 Stephen C. Bain,2 Anders G. Holst,3 Thomas Mark,3 Søren Rasmussen,3 Ildiko Lingvay4

1Toronto General Hospital Research Institute, Toronto, Ontario, Canada; 2Swansea University Medical School, Swansea, UK; 3Novo Nordisk A/S, Søborg, Denmark; 4UT Southwestern Medical Center, Dallas, Texas, USA

 

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Effects of Semaglutide Versus Comparators on Cardiovascular Events Across a Continuum of Baseline Cardiovascular Risk: Combined Analysis of the SUSTAIN and PIONEER Trials

 

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Background

  • Fewer major adverse cardiovascular events (MACE) were observed with semaglutide vs placebo in cardiovascular outcomes trials (CVOTs) in subjects with type 2 diabetes (T2D) at high risk of cardiovascular (CV) events (once-weekly subcutaneous semaglutide in SUSTAIN 6; once-daily oral semaglutide in PIONEER 6).1,2
  • To better understand the CV effect of semaglutide in a broader range of subjects with T2D, including those at lower CV risk, we conducted a post hoc analysis of semaglutide and comparator (placebo, sitagliptin, exenatide extended release, insulin glargine, dulaglutide, liraglutide, and empagliflozin) data from all phase 3a SUSTAIN and PIONEER trials across the continuum of baseline CV risk characterizing a broad T2D population.

Methods

  • Data from 18 phase 3a trials of semaglutide (once-daily oral, once-weekly subcutaneous) vs active comparators or placebo in subjects with T2D were combined.1–18 Time to first adjudication-confirmed MACE (defined as death from CV causes, nonfatal myocardial infarction, or nonfatal stroke) was analyzed.1,2
  • CV risk was quantified using a CV risk score model derived from the LEADER (liraglutide vs placebo) CVOT,19 which used the definitions of adjudicated endpoints and baseline factors common to the LEADER, SUSTAIN, and PIONEER trials, and applied a Cox proportional hazards stepwise model procedure to select potential baseline predictors for time-to-first MACE.
  • This CV risk score was included as a linear effect modifier for pooled treatment groups (semaglutide vs comparators) in a Cox proportional hazards model stratified by trial program and trial type.

Results

  • Baseline characteristics differed between CVOTs and glycemic efficacy trials, especially regarding CV medical history (Table 1).
  • The LEADER-derived CV risk score predicted risk of first MACE in the semaglutide data well, both when data from the glycemic efficacy trials and CVOTs were pooled (area under the curve [AUC]: 0.77) and when they were analyzed separately (AUC: 0.68 and 0.74, respectively).
  • Relative (Figure 1) and absolute (Figure 2) risk of MACE were lower with semaglutide vs comparators across CV risk scores; the interaction p-value between CV risk score and treatment effect was nonsignificant (p=0.06).
  • The shape of the hazard ratio curve across baseline CV risk score for each MACE component was similar to that of the composite MACE endpoint (Figure 3).

Semaglutide reduced the risk of MACE vs comparators across the continuum of CV risk characterizing a broad T2D population

Conclusions

  • Semaglutide reduced the risk of MACE vs comparators across the continuum of CV risk characterizing a broad T2D population.
  • These results will help physicians to understand the CV benefits of the glucagon-like peptide-1 analog semaglutide in subjects with T2D across a broad continuum of CV risk.
References
(1) Marso et al. N Engl J Med 2016;375:1834–44
(2) Husain et al. N Engl J Med 2019;381:841–51
(3) Sorli et al. Lancet Diabetes Endocrinol 2017;5:251–60
(4) Ahrén et al. Lancet Diabetes Endocrinol 2017;5:341–54
(5) Ahmann et al. Diabetes Care 2018;41:258–66
(6) Aroda et al. Lancet Diabetes Endocrinol 2017;5:355–66
(7) Rodbard et al. J Clin Endocrinol Metab 2018;103:2291–301
(8) Kaku et al. Diabetes Obes Metab 2018;20:1202–12
(9) Seino et al. Diabetes Obes Metab 2018;20:378–88
(10) Aroda et al. Diabetes Care 2019;42:1724–32
(11) Rodbard et al. Diabetes Care 2019;42:2272–81
(12) Rosenstock et al. JAMA 2019;321:1466–80
(13) Pratley et al. Lancet 2019;394:39–50
(14) Mosenzon et al. Lancet Diabetes Endocrinol 2019;7:515–27
(15) Pieber et al. Lancet Diabetes Endocrinol 2019;7:528–39
(16) Zinman et al. Diabetes Care 2019;42:2262–71
(17) Yamada et al. Presented at The Asian Association for the Study of Diabetes, Shanghai, China, 23–25 May 2019
(18) Yabe et al. Presented at the Asian Association for the Study of Diabetes, Shanghai, China, 23–25 May 2019
(19) Marso et al. N Engl J Med 2016;375:311–22