Semaglutide reduces cardiovascular events regardless of metformin use: a post hoc subgroup analysis of SUSTAIN 6 and PIONEER 6

Abstract

Background: Cardiovascular outcome trials (CVOTs) are conducted on a background of standard of care including metformin. These analyses sought to determine whether the cardiovascular (CV) effects of semaglutide and other glucagon-like peptide-1 receptor agonists (GLP-1RAs) vary according to baseline metformin use.

Methods: A post hoc analysis was conducted using pooled SUSTAIN 6 and PIONEER 6 CVOT data in subjects with and without metformin use at baseline. Additionally, a trial-level meta-analysis was conducted using data from seven CVOTs with GLP-1RAs-SUSTAIN 6, PIONEER 6, HARMONY OUTCOMES, LEADER, REWIND, EXSCEL and AMPLITUDE-O-including adults with type 2 diabetes at high CV risk, and a primary endpoint of time to first major adverse CV event (MACE).

Results: In the post hoc analysis, the no-metformin subgroup was older, with a higher body mass index, lower estimated glomerular filtration rate and higher CV risk at baseline vs the metformin subgroup. Hazard ratios (95% confidence intervals) for the reduction in risk of MACE with semaglutide vs placebo in the metformin and no-metformin subgroups were 0.70 (0.55;0.89) and 0.86 (0.60;1.22), respectively. No significant interaction between the treatment effect on MACE and metformin subgroup was observed. Findings for other CV endpoints were similar. In the meta-analysis, treatment effect (GLP-1RA vs placebo) on CV outcomes was no different with vs without baseline metformin (overall ratio between the hazard ratios for metformin vs no-metformin 1.09 [0.96;1.22]).

Conclusion: These findings indicate that the CV outcomes for semaglutide were similar regardless of baseline metformin use, which may also apply to all GLP-1RAs. Trial registration SUSTAIN 6 (NCT01720446), PIONEER 6 (NCT02692716).

Keywords: Cardiovascular outcome trial; Major adverse cardiovascular event; Metformin; PIONEER 6; SUSTAIN 6; Semaglutide.

Conflict of interest statement

MH reports receiving research grants from Novo Nordisk, AstraZeneca and Merck; consultancy fees for participation in advisory board meetings from AstraZeneca, Boehringer Ingelheim, Eli Lilly, Janssen, Merck, Novo Nordisk and Roche; speaker fees from AstraZeneca, Boehringer Ingelheim, Janssen, Merck and Novo Nordisk; payment for expert testimony from Novo Nordisk; and holds one patent relating to GLP-1, and has one patent pending relating to methods for inhibiting platelet aggregation using GLP-1RAs. AC reports receiving clinical research grants from Novo Nordisk; speaker fees from Novo Nordisk, Eli Lilly, AstraZeneca and Sanofi Aventis; and remuneration for participation on data safety monitoring or advisory boards for Novo Nordisk, Eli Lilly and AstraZeneca. ADR, ASPM and SR are all employees of Novo Nordisk, and SR holds stock in the company. SB reports receiving speaker fees from Novo Nordisk; and support for attending meetings and/or travel from the American Diabetes Association and the European Association for the Study of Diabetes meetings.

© 2022. The Author(s).

Figures

Fig. 1

CV risk score* according to metformin use at baseline. The light gray color indicates the overlap between the metformin and no-metformin subgroups. *Derived from a prediction model developed using independent data sets from the liraglutide CV outcomes trial and previously applied to SUSTAIN 6 and PIONEER 6 [19]. CV cardiovascular

Fig. 2

A CV outcomes/mortality by baseline metformin use (adjusted analysis); B Kaplan–Meier curves of primary outcome by baseline metformin. Figures (A) and (B) compare semaglutide with placebo. *n-numbers are based on the FAS; the number of subjects included for each endpoint analysis differed according to data availability. A Analyses for SUSTAIN 6 and PIONEER 6 are based on a Cox proportional hazards model with treatment (semaglutide, placebo) by metformin subgroup as fixed factors, stratified by trial and CV risk group (established CVD and/or CKD vs risk factors), and adjusted by baseline variables: sex (male vs female), smoker (current smoker, previous smoker, never smoked), previous MI/stroke/TIA (yes vs no), region (European Union, North America, other), antidiabetic treatment (yes vs no), diabetes duration, eGFR-MDRD and age. CI confidence interval, CKD chronic kidney disease, CV cardiovascular, CVD cardiovascular disease, eGFR-MDRD estimated glomerular filtration rate-modification of diet in renal disease, FAS full analysis set, HbA1c glycated hemoglobin, HHF hospitalization for heart failure, HR hazard ratio (semaglutide vs placebo), MACE major adverse cardiovascular event, MET metformin, MI myocardial infarction, TIA transient ischemic attack

Fig. 3

Metabolic and safety outcomes with semaglutide vs placebo by baseline metformin use. Figure compares semaglutide with placebo. Data-points are proportional to subgroup size. For change in metabolic outcomes, analyses were based on a mixed model for repeated measurements at week 80 (SUSTAIN 6) or week 83 (PIONEER 6), with treatment by subgroup adjusted for baseline value and trial nested within visits. For the safety analyses, number of events per 100 patient-years were analyzed using a negative binomial regression model with a log link and the logarithm of the observation time (100 years) as offset, with treatment by subgroup as fixed factors adjusted by trial. Dashed vertical lines represent lines of null effect (0 for ETDs and 1 for ERRs). ETD/ERR is for semaglutide vs placebo. *Defined as an episode requiring assistance of another person to actively administer carbohydrate, glucagon, or to perform other resuscitative actions. †n-numbers are based on the FAS; the number of subjects included for each analysis was smaller according to data availability.  AE adverse event, CI confidence interval, ERR estimated risk ratio, ETD estimated treatment difference, FAS full analysis set, HbA1c glycated hemoglobin, MET metformin, R events per 100 patient-years observed

Fig. 4

Meta-analysis of effect on MACE by baseline metformin: A metformin; B no-metformin; C metformin vs no-metformin. Figures A and B compare a GLP-1RA with placebo. Figure C compares the effect of metformin or no-metformin in GLP-1RA trials. Analyses for SUSTAIN 6 and PIONEER 6 are based on a Cox proportional hazards model with treatment (semaglutide, placebo) by metformin subgroup as fixed factors, stratified by trial and CV risk group (established CVD and/or CKD vs risk factors), and adjusted by baseline variables: sex (male vs female), smoker (current, previous, never), previous MI/stroke/TIA (yes vs no), region (European Union, North America, other), antidiabetic treatment (yes vs no), diabetes duration, eGFR-MDRD and age. Trial duration (median follow-up in years) was: 2.1 (SUSTAIN 6); 1.3 (PIONEER 6); 1.6 (HARMONY OUTCOMES); 3.8 (LEADER); 5.4 (REWIND); 3.2 (EXSCEL); and 1.8 (AMPLITUDE-O). A includes patients receiving metformin; B includes patients not receiving metformin; and C includes the ratio between the hazard ratios for the two different groups, metformin and no-metformin. The fixed-effect model assumes all trials are estimating a common treatment effect; the random-effect model assumes the observed estimates of treatment effect can vary across trials. CI confidence interval, CKD chronic kidney disease, CV cardiovascular, CVD cardiovascular disease, eGFR estimated glomerular filtration rate. GLP-1RA glucagon-like peptide-1 receptor agonist, HR hazard ratio (GLP-1RA vs placebo), I2 inconsistency across estimates, MACE major adverse cardiovascular event, MDRD Modification of Diet in Renal Disease, MI myocardial infarction, RHR ratio between the hazard ratios in metformin vs no-metformin groups, TIA transient ischemic attack