Semaglutide reduces the risk of major adverse cardiovascular events consistently across baseline triglyceride levels in patients with type 2 diabetes: Post hoc analyses of the SUSTAIN 6 and PIONEER 6 trials

Epidemiological studies have shown that elevated triglycerides (TGs) is associated with higher cardiovascular (CV) risk1, 2 and may help to identify patients at persistent risk of CV events despite treatment with statins and other evidence-based therapies.3, 4 Evidence suggests that some, but not all, pharmacological treatments that appear to reduce TGs might also reduce the occurrence of fatal or non-fatal CV events in individuals at high risk. TG-lowering approaches with fibrates have not been shown to be beneficial,4, 5 while data from the Reduction of Cardiovascular Events with Icosapent Ethyl–Intervention Trial (REDUCE-IT) showed a significant benefit of icosapent ethyl in statin-treated, mild-moderately hypertriglyceridaemic patients with CV disease or diabetes with additional risk factors.6 Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have a proven benefit in risk reduction of major adverse CV event (MACE; a composite of CV death, non-fatal myocardial infarction [MI] or non-fatal stroke),7 and have been shown to have a modest effect on TGs,8 but this has not been characterized across varying TG levels.​ Semaglutide (Novo Nordisk, Denmark) is a long-acting human GLP-1 analogue approved for the treatment of type 2 diabetes (T2D), available in either a once-weekly (OW) subcutaneous (s.c.) or once-daily (OD) oral formulation.9, 10 The randomized CV outcome trials SUSTAIN 6 and PIONEER 6 investigated s.c. and oral semaglutide, respectively, versus placebo in participants with T2D and established or at high risk of CV disease.8, 11, 12 Both trials were similar in population and design. To understand whether GLP-1RAs reduce the risk of MACE in T2D across baseline TG levels, this post hoc analysis investigated the effect of semaglutide versus placebo on the primary endpoint and its components (time to first MACE comprising CV death, non-fatal MI or non-fatal stroke), using pooled data from these two trials categorized by baseline TG levels. To understand if GLP-1RAs affect TG levels in people with T2D, a second analysis investigated the effect on the change in TG levels over time. The trial designs for SUSTAIN 6 (NCT01720446) and PIONEER 6 (NCT02692716) have been reported previously.8, 11, 12 Briefly, adults with T2D at high risk of a CV event were randomized to receive either semaglutide or placebo, in addition to standard of care. CV risk was defined as age 50 years or older and established CV disease or chronic kidney disease (CKD) or at least 60 years of age with CV risk factors. In the time- and event-driven SUSTAIN 6 trial, participants received OW s.c. semaglutide 0.5 mg or 1.0 mg (median follow-up of 2 years), while the event-driven PIONEER 6 participants received OD oral semaglutide 14 mg (median observation time of 15.9 months). At baseline, categorical TG groups used cut-off values based on low- and high-risk levels as per European Society of Cardiology and European Atherosclerosis Society guidelines for the management of dyslipidaemia (≤ 151, > 151-≤ 205 and > 205 mg/dL).13 Using ‘in-trial’ data and all randomized patients, risk of first MACE and its components by categorical baseline TG levels in SUSTAIN 6 and PIONEER 6 and time to first MACE by TG levels as a continuum at baseline for semaglutide and placebo in SUSTAIN 6 and ​PIONEER 6 were analysed. Change in TG levels to end-of-trial from baseline were analysed in SUSTAIN 6 and PIONEER 6 (pooled) according to the following time points: weeks 30, 44, 56, 80 and 104 for SUSTAIN 6 and weeks 26, 50 and 83 for PIONEER 6. Data and treatment arms (semaglutide vs. placebo) were pooled across the two trials, except for change in TG levels from baseline, which were analysed according to trial. Change in TG levels from baseline across trial duration were evaluated on both untransformed and log-transformed data using a mixed model for repeated measurements including treatment and baseline TG by trial visit for each trial respectively​. The effect of semaglutide versus placebo on time to first MACE and its components was estimated in a Cox regression with treatment by the categorical TG levels as a fixed factor stratified by trial. The effect of semaglutide versus placebo on first MACE for TG levels as a continuum was evaluated in a Cox quadratic spline regression model with TG level by treatment as a covariate stratified by trial. P values less than .05 were considered significant. No adjustment for multiplicity was performed. Out of 6480 participants (SUSTAIN 6, n = 3297; PIONEER 6, n = 3183), 6417 had baseline TG measurements and were included in the post hoc analysis (3191 [49.7%] ≤ 151; 1459 [22.7%] > 151-≤ 205; and 1767 [27.5%] > 205 mg/dL). Additional baseline characteristics are shown in Table 1. The median (range) baseline TG levels were 108.6 (10.7-151.3), 175.3 (152.2-204.7) and 272.3 (205.6-3378) mg/dL for the low, medium and high baseline TG subgroups, respectively. Participants in the high TG subgroup (> 205 mg/dL) at baseline had significantly greater (P < .01) body weight (95.0 kg) and non-high density lipoprotein (151.9 mg/dL) compared with participants across the other subgroups (TG ≤ 151 mg/dL, 89.0 kg and 103.4 mg/dL; TG > 151-≤ 205 mg/dL, 92.8 kg and 125.1 mg/dL, respectively) (Table 1). In line with previous studies,1, 2 there was an association between high TG levels and CV risk. In the placebo and treatment arms, the incidence rate (IR) of MACE increased with increasing TG levels, with the highest MACE IR occurring in the highest TG subgroup (Figure 1). Although treatment with semaglutide reduced the risk of MACE and its components versus placebo across all TG groups (interaction P values > .05 for all endpoints), the only significant reduction of MACE was in the 151 mg/dL or less TG subgroup, which may be because of a lack of statistical power in the higher TG subgroups (Figure 1). These findings were consistent when evaluating TGs as a continuous variable for first MACE (Figure S1). Semaglutide reduced TG levels versus placebo in both trials. In SUSTAIN 6, from baseline to week 104, TG levels were reduced by 14.8 mg/dL with semaglutide versus ​5.4 mg/dL with placebo (estimated difference –9.4 mg/dL, P = .024; adjusted for baseline body weight and change from baseline body weight −4.5, P = .299). In PIONEER 6, from baseline to week 83, TG levels were reduced by 16.4 mg/dL with semaglutide versus 6.5 mg/dL with placebo (estimated difference –9.9 mg/dL, P = .005; adjusted for baseline body weight and change from baseline body weight –3.1, P = .397), which indicated mediation from change in body weight during both trials. Geometric mean ratio to baseline plots for TGs by treatment week according to trial are shown in Figure S2. This post hoc analysis of pooled SUSTAIN 6 and PIONEER 6 trial data showed that the risk of first MACE increased with increasing baseline TG levels in people with T2D with established or at high risk of CV disease. Semaglutide significantly reduced TG levels from baseline in the SUSTAIN 6 and PIONEER 6 populations, and there was a reduction in risk of first MACE with semaglutide versus placebo irrespective of TG subgroup (interaction P value > .05). SV, LAL and DLB were involved in study conduct and data collection. SV, SR and MMM analysed or interpreted data. SV, LAL, DLB, MMM, J-PD and SR drafted and critically revised the manuscript. SV is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. The authors thank the patients participating in the SUSTAIN 6 and PIONEER 6 trials, the investigators, all trial sites staff, and all Novo Nordisk A/S employees involved in the trial. We also thank Sarah White and Daniella Pfeifer from AXON Communications for editorial assistance, funded by Novo Nordisk A/S. This work was supported by Novo Nordisk A/S. SV has received grants or honoraria from Amarin, Amgen, AstraZeneca, Bayer, Boehringer-Ingelheim, Eli Lilly, HLS Therapeutics, Janssen, Merck, Novo Nordisk, Pfizer, PhaseBio, Sanofi, Sun Pharmaceuticals and TKTWG. MMM, SR and J-PD are employees of Novo Nordisk A/S and MMM and SR are also shareholders in Novo Nordisk A/S. LAL has received research funding from, served on advisory board panels for and/or has provided CME for Amarin, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, HLS, Kowa, Lexicon, Merck, Novo Nordisk, Pfizer, Sanofi and Servier. DLB discloses the following relationships – Advisory Board: Angiowave, Bayer, Boehringer Ingelheim, Cardax, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, High Enrol, Janssen, Level Ex, McKinsey, Medscape Cardiology, Merck, MyoKardia, NirvaMed, Novo Nordisk, PhaseBio, PLx Pharma, Regado Biosciences and Stasys; Board of Directors: Angiowave (stock options), Boston VA Research Institute, Bristol Myers Squibb (stock), DRS.LINQ (stock options), High Enrol (stock), Society of Cardiovascular Patient Care and TobeSoft; Chair: Inaugural Chair, American Heart Association Quality Oversight Committee; Consultant: Broadview Ventures; Data Monitoring Committees: Acesion Pharma, Assistance Publique-Hôpitaux de Paris, Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute, for the PORTICO trial, funded by St. Jude Medical, now Abbott), Boston Scientific (Chair, PEITHO trial), Cleveland Clinic (including for the ExCEED trial, funded by Edwards), Contego Medical (Chair, PERFORMANCE 2), Duke Clinical Research Institute, Mayo Clinic, Mount Sinai School of Medicine (for the ENVISAGE trial, funded by Daiichi Sankyo; for the ABILITY-DM trial, funded by Concept Medical), Novartis, Population Health Research Institute; Rutgers University (for the NIH-funded MINT Trial); Honoraria: American College of Cardiology (Senior Associate Editor, Clinical Trials and News, ACC.org; Chair, ACC Accreditation Oversight Committee), Arnold and Porter law firm (work related to Sanofi/Bristol-Myers Squibb clopidogrel litigation), Baim Institute for Clinical Research (formerly Harvard Clinical Research Institute; RE-DUAL PCI clinical trial steering committee funded by Boehringer Ingelheim; AEGIS-II executive committee funded by CSL Behring), Belvoir Publications (Editor in Chief, Harvard Heart Letter), Canadian Medical and Surgical Knowledge Translation Research Group (clinical trial steering committees), Cowen and Company, Duke Clinical Research Institute (clinical trial steering committees, including for the PRONOUNCE trial, funded by Ferring Pharmaceuticals), HMP Global (Editor in Chief, Journal of Invasive Cardiology), Journal of the American College of Cardiology (Guest Editor; Associate Editor), K2P (Co-Chair, interdisciplinary curriculum), Level Ex, Medtelligence/ReachMD (CME steering committees), MJH Life Sciences, Oakstone CME (Course Director, Comprehensive Review of Interventional Cardiology), Piper Sandler, Population Health Research Institute (for the COMPASS operations committee, publications committee, steering committee, and USA national co-leader, funded by Bayer), Slack Publications (Chief Medical Editor, Cardiology Today's Intervention), Society of Cardiovascular Patient Care (Secretary/Treasurer), WebMD (CME steering committees), Wiley (steering committee); Other: Clinical Cardiology (Deputy Editor), NCDR-ACTION Registry Steering Committee (Chair), VA CART Research and Publications Committee (Chair); Patent: Sotagliflozin (named on a patent for sotagliflozin assigned to Brigham and Women's Hospital who assigned to Lexicon; neither I nor Brigham and Women's Hospital receive any income from this patent); Research Funding: Abbott, Acesion Pharma, Afimmune, Aker Biomarine, Amarin, Amgen, AstraZeneca, Bayer, Beren, Boehringer Ingelheim, Boston Scientific, Bristol-Myers Squibb, Cardax, CellProthera, Cereno Scientific, Chiesi, CinCor, CSL Behring, Eisai, Ethicon, Faraday Pharmaceuticals, Ferring Pharmaceuticals, Forest Laboratories, Fractyl, Garmin, HLS Therapeutics, Idorsia, Ironwood, Ischemix, Janssen, Javelin, Lexicon, Lilly, Medtronic, Merck, Moderna, MyoKardia, NirvaMed, Novartis, Novo Nordisk, Owkin, Pfizer, PhaseBio, PLx Pharma, Recardio, Regeneron, Reid Hoffman Foundation, Roche, Sanofi, Stasys, Synaptic, The Medicines Company, Youngene and 89Bio; Royalties: Elsevier (Editor, Braunwald's Heart Disease); Site Co-Investigator: Abbott, Biotronik, Boston Scientific, CSI, Endotronix, St. Jude Medical (now Abbott), Philips, SpectraWAVE, Svelte and Vascular Solutions; Trustee: American College of Cardiology; and unfunded research: FlowCo, Takeda. The peer review history for this article is available at https://www.webofscience.com/api/gateway/wos/peer-review/10.1111/dom.15081. SV is the guarantor of this work and, as such, had full access to all the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Figure S1. Time to first MACE (hazard ratio by triglycerides at baseline) in SUSTAIN 6 and PIONEER 6 (pooled) Figure S2. Geometric mean ratio to baseline for triglycerides (mg/dL) by treatment week and EOT in (A) SUSTAIN 6 and (B) PIONEER 6. 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.