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Applying REWIND CVD criteria to SUSTAIN 6 and PIONEER 6: an exploratory analysis of CV outcomes with semaglutide

Subodh Verma1; Udi Fainberg2; Mansoor Husain3*; Søren Rasmussen2; Lars Rydén4; Maria Sejersten Ripa2; John B. Buse5

1St. Michael’s Hospital and University of Toronto, Toronto, ON, Canada; 2Novo Nordisk A/S, Søborg, Denmark; 3Ted Rogers Centre for Heart Research, Toronto General Hospital Research Institute, Toronto, ON, Canada; 4Karolinska University Hospital, Solna, Stockholm, Sweden; 5University of North Carolina School of Medicine, Chapel Hill, NC, USA
*Presenting author

 

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Applying REWIND CVD criteria to SUSTAIN 6 and PIONEER 6: an exploratory analysis of CV outcomes with semaglutide

 

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Background

  • In the REWIND CV outcomes trial (CVOT), the glucagon-like peptide-1 receptor agonist (GLP-1 RA) dulaglutide reduced CV risk compared with placebo in patients with T2D, in the overall trial population and in both the established CVD and CV risk factor subgroups.1
  • The SUSTAIN 6 and PIONEER 6 CVOTs of the GLP-1 RA semaglutide also included patients with established CVD and CV risk factors, but used different definitions from REWIND for these subgroups.2,3
  • There was no evidence of heterogeneity in treatment effects across CV risk subgroups in the SUSTAIN 6 and PIONEER 6 trials; however, uncertainty of the CV effect of semaglutide in patients with only CV risk factors remains.2,3
  • This post hoc exploratory analysis of SUSTAIN 6 and PIONEER 6 aimed to assess the impact of semaglutide on CV outcomes in subgroups of patients defined using the REWIND CVD criteria.

Methods

  • REWIND, SUSTAIN 6 and PIONEER 6 were randomized, double-blind, placebo-controlled trials investigating the effects of GLP-1 RA (REWIND: dulaglutide; SUSTAIN 6: subcutaneous semaglutide; PIONEER 6: oral semaglutide) versus placebo on CV outcomes in patients with T2D.1-3
  • We compared CV outcomes with semaglutide versus placebo in a pooled population of SUSTAIN 6 and PIONEER 6 patients, re-categorized as having established CVD or CV risk factors at baseline using REWIND CVD criteria.1
  • Inclusion and exclusion criteria for SUSTAIN 6, PIONEER 6 and REWIND are shown in Table 1, and criteria for the established CVD and CV risk factor subgroups in SUSTAIN 6, PIONEER 6 and REWIND are shown in Table 2.
  • Notably, patients with solely prior hemorrhagic stroke, prior transient ischemic attack, chronic kidney disease (CKD) or chronic heart failure (HF) – who were categorized as having established CVD in SUSTAIN 6 and PIONEER 6 – were included in the CV risk factor subgroup in this analysis according to REWIND CVD criteria.
  • The REWIND inclusion criteria (Table 1) are not identical to the established CVD and CV risk factor subgroup criteria described in the main analysis of REWIND (Table 2).
  • Age criteria for the subgroups from SUSTAIN 6 and PIONEER 6 (≥60 years for patients with CV risk factors, and ≥50 years for patients with established CVD) were not applied so that the re-categorized subgroup of patients with CV risk factors could include patients aged <60 years.
  • A sensitivity analysis applying age criteria from SUSTAIN 6 and PIONEER 6, and therefore excluding patients aged <60 years in the re-categorized CV risk factor subgroup, was also performed (data not shown).
  • The primary endpoint was a composite of major adverse CV events (MACE), comprising first occurrence of CV death, nonfatal myocardial infarction (MI) or nonfatal stroke.
  • Secondary endpoints included all-cause death, CV death and expanded MACE, defined as MACE, revascularization (coronary or peripheral) and hospitalization for unstable angina or HF.
  • A Cox proportional hazards model stratified on trial group and with pooled treatment groups as a fixed factor was used for this analysis.

Results

  • A total of 6480 patients were included in the pooled analysis (SUSTAIN 6: 3297; PIONEER 6: 3183).
  • When using REWIND CVD criteria, compared with the original SUSTAIN 6 and PIONEER 6 criteria, less patients were categorized as having established CVD (Figure 1).
  • The majority re-categorized from the established CVD to the CV risk factor subgroup by the REWIND CVD criteria were patients with prior transient ischemic attack, CKD or chronic HF.
  • The risk of MACE appeared lower with semaglutide compared with placebo across both subgroups (Figures 2, 3).
  • Consistent effects of semaglutide across subgroups were observed for other endpoints (p interaction >0.05 for all endpoints) (Figure 3).
  • The sensitivity analysis applying age criteria also showed similar results for treatment effects across subgroups (p-interaction >0.05 for all endpoints).
  • Given the different inclusion criteria between trials, definitive re‑categorization of SUSTAIN 6 and PIONEER 6 patients could not be achieved.

Conclusions

  • In this post hoc analysis of a pooled patient population from the SUSTAIN 6 (NCT01720446) and PIONEER 6 (NCT02692716) trials, semaglutide appeared to reduce cardiovascular (CV) risk in subgroups of patients with established CV disease (CVD) and CV risk factors as defined by REWIND (NCT01394952) CVD criteria.
  • This suggests that the CV effects of semaglutide may extend to both primary and secondary prevention in patients with type 2 diabetes (T2D), consistent with observations for dulaglutide in REWIND.
  • Comparison of results across trials is not an easy exercise and raises important questions of how patients should be classified according to CV risk in future trials.
References
(1) Gerstein et al. Lancet 2019;394:121–30
(2) Marso et al. N Engl J Med 2016;375:1834–44
(3) Husain et al. N Engl J Med 2019;381:841–51