Once‐weekly semaglutide reduces the risk of cardiovascular events in people with type 2 diabetes and polyvascular disease: A post hoc analysis

The presence of polyvascular disease, defined as atherosclerosis involving two or more distinct vascular territories, is a strong, independent predictor of subsequent cardiovascular (CV) events in people living with type 2 diabetes (T2D).1-4 Semaglutide, a glucagon-like peptide-1 (GLP-1) analogue available as once-weekly (OW) subcutaneous and once-daily oral formulations, has demonstrated superior reductions in glycated haemoglobin (HbA1c) and body weight in people living with T2D compared with placebo or active comparators.5, 6 In the SUSTAIN 6 trial, OW semaglutide reduced major adverse CV events (MACE; a composite of death from CV causes, nonfatal myocardial infarction, or nonfatal stroke) in participants living with T2D who were at high CV risk.7 The aim of this post hoc analysis of the SUSTAIN 6 trial was to evaluate the effect of OW semaglutide on CV outcomes in people stratified by the number of vascular territories with atherosclerosis at baseline. The SUSTAIN 6 (NCT01720446) trial design has been previously reported.7 Adults living with T2D at high risk of a CV event were randomized to receive 0.5 or 1.0 mg OW semaglutide or placebo in addition to standard of care (median follow-up 2.1 years). The independent ethics committees and institutional review boards at each participating centre approved the trial. Participants provided informed consent. In this post hoc analysis, the SUSTAIN 6 population was stratified by the number of vascular territories (coronary, cerebrovascular or peripheral arteries) with atherosclerosis at baseline: polyvascular disease (≥2 vascular territories); single vascular disease (1 vascular territory); or no atherosclerotic CV disease. Kaplan–Meier plots of time to first event with OW semaglutide and placebo were generated for the vascular risk groups. Hazard ratios (HRs) comparing risk groups were calculated using a Cox proportional hazards model, with risk group as a fixed factor adjusted for pooled treatment groups. The treatment effect of OW semaglutide versus placebo within risk groups was estimated using the Cox proportional hazards regression model with pooled treatment, risk group, and the interaction of both as factors. However, as a post hoc analysis, associations could be made only between the treatment and outcome. No adjustment for multiple testing was performed. The interaction between treatment effect and vascular risk group was evaluated using pinteraction values. The number needed to treat (NNT) was reported where absolute risk reduction (ARR) was statistically significant, and was calculated as the inverse of the absolute difference in 2-year estimates of incidence of outcomes between OW semaglutide treatment relative to placebo. p values for differences in baseline characteristics between risk groups were calculated using a chi-squared test for categorical parameters and a Kruskal–Wallis test for continuous parameters. Of the 3297 SUSTAIN 6 participants, 640 (19.4%) had polyvascular disease, 1821 (55.2%) had vascular disease in one arterial bed and 836 (25.4%) had no vascular disease at baseline. The distribution of vascular territory involvement is shown in Figure S1. At baseline, in the polyvascular disease, single vascular disease and no vascular disease groups, the mean age ± SD was 65.8 ± 7.7, 63.8 ± 7.5 and 65.7 ± 6.7 years, respectively, and the proportions of male participants were 66.9%, 65.0% and 46.7%, respectively. Baseline body mass index and HbA1c were similar in the three groups (Table S1). The mean ± SD estimated glomerular filtration rate (eGFR) was lower for the group without vascular disease (69.3 ± 24.1) than for the single (79.4 ± 21.9), or polyvascular disease groups (71.4 ± 21.9; Table S1). The presence of polyvascular disease and single vascular disease was associated with a greater risk of MACE and expanded composite CV outcome events, compared with no vascular disease (MACE: polyvascular disease HR 2.25 [95% confidence interval {CI}1.47; 3.52] and singular vascular disease HR 1.64 [95% CI 1.11; 2.48]; expanded composite CV outcome: polyvascular disease HR 3.46 [95% CI 2.46; 4.93] and single vascular disease HR 2.22 [95% CI 1.62; 3.09], respectively; Figure S2). OW semaglutide was associated with a consistently lower risk of MACE versus placebo, across all groups (pinteraction = 0.98; Figure 1A and Figure 2). The reductions for the expanded composite CV outcome (Figure 1B and Figure 2) and individual components of MACE were consistent across polyvascular and single vascular disease subgroups (pinteraction > 0.05) and favoured treatment with OW semaglutide versus placebo (HRs < 1.0; Figure 2), results which were comparable to those in the total SUSTAIN 6 trial population (Figure 2). For people with polyvascular disease, the ARR for MACE with OW semaglutide versus placebo at 2 years was 3.37%, and for people with single and no vascular disease, the ARRs decreased to 2.02% and 0.78%, respectively (Figure 2). For people with polyvascular disease, the ARR for the expanded composite CV outcome OW semaglutide versus placebo at 2 years was 8.45% (NNT 12; Figure 2). For people with single vascular disease, the ARR decreased to 3.59% (NNT 28) and for no vascular disease, no statistically significant effect was observed (Figure 1B and Figure 2). This analysis shows that treatment with OW semaglutide compared with placebo was associated with a consistent reduction in CV outcomes across polyvascular and single vascular disease groups; the risk reductions were similar to those observed in the total SUSTAIN 6 trial population.7 In SUSTAIN 6, people with polyvascular disease had a >2 times greater risk of MACE than those without vascular disease, and a 3.5 times greater risk of expanded composite CV outcome events. These findings are consistent with prior studies showing higher risk of CV events in people with T2D and polyvascular disease.2, 4 Importantly, the ARR for MACE and expanded composite CV outcome events with OW semaglutide was greater in people with polyvascular disease, and the NNTs to prevent one expanded composite CV outcome event were notably low (12 and 28 for polyvascular and single vascular disease, respectively). Hence, people with T2D and polyvascular disease may derive greater absolute benefit from semaglutide treatment owing to their higher CV risk. Results from this analysis are generally consistent with observations from a post hoc analysis of the LEADER trial, demonstrating that the GLP-1 receptor agonist liraglutide consistently reduced the risk of CV events in people with polyvascular and single vascular disease and that the magnitude of benefit may be related to the extent of vascular disease.4 Similarly, the sodium-glucose cotransporter-2 inhibitor empagliflozin has also been shown to consistently reduce the risk of all-cause mortality, CV and heart failure outcomes versus placebo, regardless of the number of vascular beds affected, and the ARR for all-cause mortality and CV death or heart failure was greater in people with polyvascular disease.8 The present study further supports the use of OW semaglutide for the treatment of T2D and CV risk in a broad population with established CV disease and suggests benefits regardless of vascular risk status. However, this study has some limitations. First, the duration of SUSTAIN 6 was relatively short, making it difficult to draw long-term conclusions. Second, the analysis was not pre-specified and should be considered hypothesis-generating. Finally, the study was not powered for subgroup analyses and the number of events in certain vascular risk groups were small, which may partly explain the wider CIs and neutral responses across risk groups. A neutral response in people without vascular disease could also be attributable to the lower baseline risk, therefore, a longer treatment period along with a larger sample size might be required to establish any potential effect. Further studies on the effects of OW semaglutide treatment on CV outcomes in real-world populations and cohorts with higher CV risk, such as people with acute coronary syndrome, would be valuable. In conclusion, this analysis demonstrates that the beneficial effect of OW semaglutide on CV events in people living with T2D compared with placebo was, in general, consistent irrespective of baseline degree of atherosclerosis. This post hoc analysis also suggests that those with more advanced atherosclerosis derived the greatest absolute benefit from OW semaglutide in the SUSTAIN 6 trial. All authors contributed to the interpretation of data, and to the writing and critical revisions of the manuscript at all stages of development. All authors approved the final submitted manuscript. We thank all the participants, investigators, and study-site staff, and Aarti Shah (AXON Communications) for editorial assistance (funded by Novo Nordisk A/S). This study was funded by Novo Nordisk A/S. The sponsor was involved in the study design and data collection only. Matthew A. Cavender has received research support from Amgen, Boehringer-Ingelheim, CSL Behring and Janssen, and consulting fees from Bayer, CSL Behring, Novo Nordisk and Zoll. Thomas Jon Jensen, Anja Birk Kuhlman and Søren Rasmussen are full-time employees of Novo Nordisk A/S. Thomas Jon Jensen and Søren Rasmussen hold stock in Novo Nordisk A/S. Subodh Verma has received grants, consulting fees and/or honoraria from Amarin, Amgen, AstraZeneca, Bayer, Boehringer-Ingelheim, the Canadian Medical and Surgical Knowledge Translation Research Group, Eli Lilly, HLS Therapeutics, Janssen, Merck, Novartis, Novo Nordisk, Pfizer, PhaseBio, Sanofi and S & L Solutions Event Management Inc. The authors declare that there are no other relationships or activities that might bias, or be perceived to bias, their work. The data that support the findings of this study are available from the corresponding author upon reasonable request. DATA S1: Supporting Information. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.

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