Semaglutide and cardiovascular outcomes by baseline HbA1c in diabetes: the SUSTAIN 6 and PIONEER 6 trials

Abstract

Certain glucagon-like peptide-1 receptor agonists reduce major adverse cardiovascular events (MACE) compared with placebo in people with type 2 diabetes at high cardiovascular (CV) risk,1 and diabetes and cardiology guidelines recommend their use (or that of sodium–glucose co-transporter 2 inhibitors) in this population regardless of baseline glycated haemoglobin (HbA1c).2,3 This post hoc analysis of the SUSTAIN 6 (once-weekly subcutaneous [s.c.] semaglutide)4 and PIONEER 6 (once-daily oral semaglutide)5 CV outcomes trials aimed to evaluate the treatment effect of the glucagon-like peptide-1 analogue semaglutide vs. placebo on MACE by baseline HbA1c. Data were pooled for participants with type 2 diabetes and established CV disease or high CV risk in the SUSTAIN 6 and PIONEER 6 trials. Participants received s.c. semaglutide (0.5 or 1.0 mg)/oral semaglutide (14 mg) or volume-matched placebo; detailed trial descriptions can be found elsewhere.4,5 The primary outcome for both trials was time to first MACE: a composite of CV death, non-fatal myocardial infarction (MI), or non-fatal stroke. Secondary outcomes included time to occurrence of individual MACE components. Additional efficacy outcomes included change from baseline in HbA1c and body weight to Week 80 for SUSTAIN 6 and Week 83 in PIONEER 6 (final study visit), which were the visits closest in each trial. Continuous variables are presented as means unless otherwise indicated. A quadratic spline function of baseline HbA1c by treatment was used to analyse treatment effect on time to first MACE across a continuum of baseline HbA1c values in a Cox proportional hazards model. Linear splines were used to analyse treatment effect across individual MACE components due to the low number of events. Time to first MACE and its components were also compared between baseline HbA1c subgroups [<8% and ≥8% (<64 and ≥64 mmol/mol)]; cut-offs were selected close to the median in a Cox proportional hazards model, with treatment by subgroup as a fixed factor. Key predictors of CV-renal disease at baseline were added as covariates: sex, glucose-lowering therapy, smoking, previous stroke or MI, region, age, diabetes duration, estimated glomerular filtration rate, and continuous HbA1c. The subgroup analysis comparing HbA1c of <8% and ≥8% (<64 and ≥64 mmol/mol) was adjusted based on these predictors using inverse probability weighting. Heterogeneity in treatment effect across HbA1c of <8% and ≥8% (<64 and ≥64 mmol/mol) subgroups was indicated by interaction P-values, with P < .05 indicating a significant interaction. No adjustment for multiplicity was performed. Estimated treatment differences (ETDs) in change in HbA1c and body weight from baseline with semaglutide vs. placebo across baseline HbA1c values were assessed using a mixed model with the quadratic spline of baseline HbA1c. This study was conducted in accordance with the Declaration of Helsinki and the Guidelines for Good Pharmacoepidemiology Practices, and approved by the institutional review boards and ethics committees for each participating centre. All participants provided written informed consent to participate in the SUSTAIN 6 (NCT01720446) and PIONEER 6 (NCT02692716) trials. Of the 6480 participants included in the analysis, 3239 received semaglutide and 3241 received placebo (followed for a median of 2.1 years in SUSTAIN 6 and 15.9 months in PIONEER 6). At baseline, mean age was 65.4 years, 64.5% were male, 44.5% had experienced a previous CV event, mean diabetes duration was 14.4 years, and mean HbA1c was 8.4% (69 mmol/mol). Detailed baseline characteristics for each individual trial are available elsewhere.4,5 Major adverse cardiovascular events were experienced by 391 (6.0%) participants during the in-trial period; 169 (5.2%) events occurred in the semaglutide and 222 (6.8%) in the placebo group. As previously published, the overall hazard ratio (HR) [95% confidence interval (CI)] was 0.76 [0.62; 0.92], with the largest effect seen for non-fatal stroke (HR 0.65 [0.43; 0.97]).6 Across a continuum of baseline HbA1c values (6.5–12.6% [48–114 mmol/mol]), the HR for MACE favoured semaglutide compared with placebo (Figure 1A), with a similar trend observed for individual MACE components: 59 (1.8%) CV deaths, 84 (2.6%) non-fatal MIs, and 39 (1.2%) non-fatal strokes with semaglutide vs. 76 (2.3%), 95 (2.9%), and 60 (1.9%) with placebo, respectively (Figure 1B–D). Risk of (A) major adverse cardiovascular events, (B) cardiovascular death, (C) non-fatal myocardial infarction, and (D) non-fatal stroke by baseline HbA1c, and estimated treatment difference in HbA1c (E) and body weight (F) with semaglutide vs. placebo across baseline HbA1c values in the pooled SUSTAIN 6 and PIONEER 6 population. *n = 169 semaglutide; n = 222 placebo. †n = 59 semaglutide; n = 76 placebo. One participant receiving semaglutide was not included owing to a missing HbA1c value at baseline. ‡n = 84 semaglutide; n = 95 placebo. §n = 39 semaglutide; n = 60 placebo. For the components of major adverse cardiovascular events, multiple events in the same participant were reported separately unlike overall major adverse cardiovascular events, which was time to first event. The lower and upper x-axis boundaries of the grey box correspond to the 2.5 and 97.5 percentiles (HbA1c of >6.1% and <12.2% [>43 and <110 mmol/mol], respectively); therefore, 95% of the data are included in the grey box. Major adverse cardiovascular events were a composite of cardiovascular death, non-fatal myocardial infarction, and non-fatal stroke. Time to first occurrence of major adverse cardiovascular events was analysed using a Cox proportional hazards model with a quadratic spline function of baseline HbA1c by treatment. Time to first occurrence of major adverse cardiovascular event components was analysed using a Cox proportional hazards model with a linear spline function of baseline HbA1c by treatment. Change in HbA1c and body weight at Week 80/83 was analysed using a mixed model with the quadratic spline of baseline HbA1c. CI, confidence interval; ETD, estimated treatment difference; HR, hazard ratio; n, number of participants with an event. When comparing participants with HbA1c <8% (<64 mmol/mol; n = 2826) vs. the ≥8% (≥64 mmol/mol) subgroup (n = 3626), CV deaths, non-fatal MIs, and non-fatal strokes occurred in 47 (1.7%) vs. 87 (2.4%), 66 (2.3%) vs. 113 (3.1%), and 37 (1.3%) vs. 62 (1.7%) participants, respectively. In the adjusted analysis for MACE, for the baseline HbA1c <8% (<64 mmol/mol) subgroup, HRs [95% CI] for MACE, CV death, non-fatal MI, and non-fatal stroke were 0.80 [0.57; 1.11], 0.87 [0.49; 1.56], 0.98 [0.60; 1.59], and 0.52 [0.26; 1.05], respectively, compared with 0.72 [0.56; 0.93] (Pinteraction = .65), 0.70 [0.46; 1.07] (Pinteraction = .55), 0.83 [0.57; 1.20] (Pinteraction = .60), and 0.74 [0.44; 1.22] (Pinteraction = .44) in the baseline HbA1c ≥8% (≥64 mmol/mol) subgroup, indicating no significant difference in treatment effect between subgroups. Semaglutide reduced HbA1c and body weight from baseline to Week 80/83 vs. placebo, regardless of baseline HbA1c (Figure 1E and F). When comparing HbA1c subgroups, changes in HbA1c in participants with baseline HbA1c <8% (<64 mmol/mol; ETD −0.64 [95% CI −0.73; −0.55]) were less pronounced than those with HbA1c ≥8% (≥64 mmol/mol; ETD −0.94 [95% CI −1.02; −0.86]; Pinteraction < .001). Reductions in body weight were similar across HbA1c subgroups (ETD −3.78 kg [95% CI −4.19; −3.38] for HbA1c <8% [<64 mmol/mol], and ETD −3.45 kg [95% CI −3.81; −3.09] for HbA1c ≥8% [≥64 mmol/mol]; Pinteraction = .22). The present analyses support semaglutide use regardless of HbA1c values, in line with current diabetes and cardiology guidelines.2,3 The analyses suggest that baseline HbA1c values do not modify the treatment benefit of semaglutide vs. placebo on MACE; semaglutide reduced MACE across a continuum of baseline HbA1c, and a trend for risk reduction was observed for individual MACE components regardless of baseline HbA1c. In addition, semaglutide effects on blood glucose control and body weight over time are significantly different vs. placebo regardless of baseline HbA1c levels. We thank all the participants, investigators, and study-site staff and Leni Vandekerckhove (AXON Communications) for editorial assistance (funded by Novo Nordisk A/S). L.G.M. has received consulting and speaker fees for participation in advisory board, lectures and clinical trials supported and funded by Amgen, AstraZeneca, Bayer AG, Boeringher-Ingelheim, Novartis, Novo Nordisk, and Sanofi, and received research grants from Amgen and Bayer AG. D.L.B. discloses the following relationships – Advisory Board: Angiowave, Bayer, Boehringer Ingelheim, Cardax, CellProthera, Cereno Scientific, Elsevier Practice Update Cardiology, High Enroll, Janssen, Level Ex, McKinsey, Medscape Cardiology, Merck, MyoKardia, NirvaMed, Novo Nordisk, PhaseBio, PLx Pharma, Regado Biosciences, Stasys; Board of Directors: Angiowave (stock options), Boston VA Research Institute, Bristol Myers Squibb (stock), DRS.LINQ (stock options), High Enroll (stock), Society of Cardiovascular Patient Care, 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, 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, Vascular Solutions; Trustee: American College of Cardiology; Unfunded Research: FlowCo, Takeda. J-P.D., K.E. and S.R. were full-time employees of Novo Nordisk during manuscript development. M.C.P. has received grants from Boehringer Ingelheim, Roche, SQ Innovations, AstraZeneca, Novartis, Novo Nordisk, Medtronic, Boston Scientific, and Pharmacosmos, and received consulting and speaker fees from Boehringer Ingelheim, Novartis, AstraZeneca, Novo Nordisk, Abbvie, Bayer, Takeda, Corvia, Cardiorentis, Pharmacosmos, Siemens, and Vifor. T.V. has received consulting and speaker fees from Amgen, AstraZeneca, BMS, Boehringer Ingelheim, Eli Lilly, Gilead, Mundipharma, Novo Nordisk, and Sun Pharmaceuticals. The data that support the findings of this study are available from the corresponding author upon reasonable request. This study was funded by Novo Nordisk. Ethical approval was not required. SUSTAIN 6 (NCT01720446) and PIONEER 6 (NCT02692716) are registered with ClinicalTrials.gov.

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