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

Husain M, Consoli A, De Remigis A, Pettersson Meyer AS, Rasmussen S, Bain S

Cardiovascular diabetology28 Apr 2022Cited by 16 (Europe PMC)

PMID35484580PMCIDPMC9052629DOI10.1186/s12933-022-01489-6PepBankPUB-35484580

Summary

BackgroundCardiovascular 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.MethodsA 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).ResultsIn 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]).ConclusionThese 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).

CC BYText from Europe PMC. Highlighted sentences are the source of results.

Results from this study4

4 results from studies that gave the peptide. 4 results from people.

01HumanRandomized controlled trialEfficacy outcome
In adults with type 2 diabetes at high cardiovascular risk and on metformin, semaglutide reduced the risk of major adverse cardiovascular events versus placebo.
In plain wordsIn adults with type 2 diabetes taking metformin, semaglutide lowered the risk of major heart events compared with placebo.
Peptide
Semaglutide
Outcome
DecreaseMACE risk in metformin subgroup
Study
n: not reported in source
Comparator
Placebo
Outcome group
Cardiovascular events · Cardiovascular
Studied dose
Dose not stated
Measurements
HR
0.7 ratio
metformin subgroup
Source sentences
Summary
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.
2 context sentences(design, population, supporting numbers)
Summary · context
A post hoc analysis was conducted using pooled SUSTAIN 6 and PIONEER 6 CVOT data in subjects with and without metformin use at baseline.
Summary · context
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).
Show in the study text Report a problemFND-3548458001
02HumanRandomized controlled trialEfficacy outcome
In adults with type 2 diabetes at high cardiovascular risk and not on metformin, semaglutide did not significantly reduce the risk of major adverse cardiovascular events versus placebo.
In plain wordsIn adults with type 2 diabetes not taking metformin, semaglutide did not clearly lower the risk of major heart events compared with placebo.
Peptide
Semaglutide
Outcome
No significant changeMACE risk in no-metformin subgroup
Study
n: not reported in source
Comparator
Placebo
Outcome group
Cardiovascular events · Cardiovascular
Studied dose
Dose not stated
Measurements
HR
0.86 ratio
no-metformin subgroup
Source sentences
Summary
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.
2 context sentences(design, population, supporting numbers)
Summary · context
A post hoc analysis was conducted using pooled SUSTAIN 6 and PIONEER 6 CVOT data in subjects with and without metformin use at baseline.
Summary · context
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).
Show in the study text Report a problemFND-3548458002
03HumanRandomized controlled trialEfficacy outcome
No significant interaction between the semaglutide treatment effect on MACE and baseline metformin subgroup was observed.
In plain wordsThe effect of semaglutide on major heart events did not differ significantly between people with and without metformin.
Peptide
Semaglutide
Outcome
No significant changeTreatment-by-metformin interaction on MACE
Study
n: not reported in source
Comparator
Placebo
Outcome group
Cardiovascular events · Cardiovascular
Studied dose
Dose not stated
Source sentences
Summary
No significant interaction between the treatment effect on MACE and metformin subgroup was observed.
2 context sentences(design, population, supporting numbers)
Summary · context
A post hoc analysis was conducted using pooled SUSTAIN 6 and PIONEER 6 CVOT data in subjects with and without metformin use at baseline.
Summary · context
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).
Show in the study text Report a problemFND-3548458003
04HumanRandomized controlled trialEfficacy outcome
Semaglutide findings for other cardiovascular endpoints were similar between metformin subgroups.
In plain wordsFor other heart and blood vessel outcomes, semaglutide results were similar with and without metformin.
Peptide
Semaglutide
Outcome
No significant changeOther cardiovascular endpoints by metformin subgroup
Study
n: not reported in source
Comparator
Placebo
Outcome group
Cardiovascular events · Cardiovascular
Studied dose
Dose not stated
Source sentences
Summary
Findings for other CV endpoints were similar.
2 context sentences(design, population, supporting numbers)
Summary · context
A post hoc analysis was conducted using pooled SUSTAIN 6 and PIONEER 6 CVOT data in subjects with and without metformin use at baseline.
Summary · context
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).
Show in the study text Report a problemFND-3548458004

AI wrote and checked these results. AI can make mistakes, so check important results against the source.

Registered trials2

Trials this study reports on, or that list this study as a reference. Registry data from ClinicalTrials.gov.

2 trials · 2 completed · 2 with posted results · source ClinicalTrials.gov (opens in a new tab)

CompletedPhase 3Results postedNCT02692716

A Trial Investigating the Cardiovascular Safety of Oral Semaglutide in Subjects With Type 2 Diabetes

Novo Nordisk A/Sn = 3,18317 Jan 2017 to 25 Sept 2018

Diabetes · Diabetes Mellitus, Type 2

Trial page ClinicalTrials.govUpdated 20 Jul 2022

CompletedPhase 3Results postedNCT01720446

Trial to Evaluate Cardiovascular and Other Long-term Outcomes With Semaglutide in Subjects With Type 2 Diabetes

Novo Nordisk A/Sn = 3,29721 Feb 2013 to 15 Mar 2016

Diabetes · Diabetes Mellitus, Type 2

Trial page ClinicalTrials.govUpdated 27 Jun 2019

Version history

PepBank keeps every version of the data on this study. Status changes from Retraction Watch, Europe PMC and Crossref are listed with their source.

Version 2Current
9 Oct 2026, 18:17 UTC
Study results updated
Version 1
9 Oct 2026, 03:06 UTC
First added · source update from Europe PMC

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