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. 2020 Sep 30;19(1):156.
doi: 10.1186/s12933-020-01106-4.

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

Mansoor Husain  1 , Stephen C Bain  2 , Anders Gaarsdal Holst  3 , Thomas Mark  3 , Søren Rasmussen  3 , Ildiko Lingvay  4
Affiliations

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

Mansoor Husain et al. Cardiovasc Diabetol. .

Abstract

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.

Keywords: Cardiovascular; MACE; Oral semaglutide; PIONEER; Risk prediction model; SUSTAIN; Subcutaneous semaglutide; Type 2 diabetes.

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Conflict of interest statement

MH received advisory board fees from AstraZeneca, Boehringer Ingelheim, Janssen, Merck, Novo Nordisk and Roche; research grants from AstraZeneca, Merck and Novo Nordisk; and speaker fees from Boehringer Ingelheim, Janssen and Novo Nordisk. SCB received honoraria fees, teaching and research grants from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Merck Sharp & Dohme, Novo Nordisk and Sanofi; funding for development of educational programs from Elsevier and Medscape; he also provided expert advice from All-Wales Medicines Strategy Group and National Institute for Health and Care Excellence (NICE) UK; and is a shareholder of Glycosmedia. AGH was a full-time employee of Novo Nordisk for the majority of manuscript development, and is a Novo Nordisk shareholder. TM was a full-time employee of Novo Nordisk for the majority of manuscript development, and is a Novo Nordisk shareholder. SM is an employee of Novo Nordisk and owns stock in the company. IL received grant support from Merck, Mylan, Novo Nordisk, Pfizer and Sanofi, personal fees from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Intarcia, Janssen, Mannkind, Novo Nordisk, Sanofi, TARGETPharma and Valeritas; and non-financial support from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Jannsen, Novo Nordisk, Pfizer and Sanofi.

Figures

Fig. 1
Fig. 1
Relative risk of MACE as a function of baseline CV risk and distribution of subjects. Hazard ratio for treatment effect (semaglutide vs comparator) and 95% CI estimated using a stratified Cox proportional hazards model including effects of treatment, CV risk score and interaction between both. The x-axis shows the CV risk score derived from subjects’ baseline characteristics in the semaglutide trials. Data on graph cut off at the 5th and 95th percentile of the whole dataset. Hazard ratio value of 1.00 is indicated by a horizontal dashed line. Underlying histograms: distribution of subjects in the glycemic efficacy trials or CVOTs across baseline CV risk scores (histogram data for 439 subjects not shown, as these subjects had a CV risk score of < –3.0 or > 0.0). CI confidence interval, CV cardiovascular, CVOT cardiovascular outcomes trial, HR hazard ratio, MACE major adverse cardiovascular events
Fig. 2
Fig. 2
Relative risk of each individual MACE component as a function of CV risk. Hazard ratios for treatment effect (semaglutide vs comparators) across all SUSTAIN and PIONEER trials analyzed. Hazard ratios (semaglutide vs comparators) and 95% CIs estimated using a stratified Cox proportional hazards model including effects of treatment, CV risk score and interaction between both. The x-axis shows the CV risk score derived from subjects’ baseline characteristics in the semaglutide trials. Data on graph cut off at the 5th and 95th percentile of the whole dataset. Hazard ratio value of 1.00 is indicated by a horizontal dashed line. CI confidence interval, CV cardiovascular, HR hazard ratio, MACE major adverse cardiovascular events, MI myocardial infarction
Fig. 3
Fig. 3
Estimated yearly risk of MACE as a function of CV risk. Absolute yearly MACE probabilities for semaglutide and comparators, respectively, estimated using a non-stratified Cox proportional hazards model including effects of treatment, CV risk score and interaction between both. The x-axis shows the CV risk score derived from subjects’ baseline characteristics in the semaglutide trials. Data on graph cut off at the 5th and 95th percentile of the whole dataset. CV cardiovascular, MACE major adverse cardiovascular events, NNT number needed to treat to avoid one MACE during 1 year
See this image and copyright information in PMC

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