Effects of Semaglutide on Stroke Subtypes in Type 2 Diabetes: Post Hoc Analysis of the Randomized SUSTAIN 6 and PIONEER 6.

Strain WD, Frenkel O, James MA, Leiter LA, Rasmussen S, Rothwell PM, Sejersten Ripa M, Truelsen TC, Husain M

Stroke18 May 2022Cited by 62 (Europe PMC)

PMID35582947PMCIDPMC9389936DOI10.1161/strokeaha.121.037775PepBankPUB-35582947

Summary

BackgroundGLP-1 RA (glucagon-like peptide-1 receptor agonists), including semaglutide, may reduce stroke risk in people with type 2 diabetes. This post hoc analysis examined the subcutaneous and oral semaglutide effects, versus placebo, on stroke and its subtypes in people with type 2 diabetes at high cardiovascular risk.MethodsSUSTAIN 6 (Trial to Evaluate Cardiovascular and Other Long-Term Outcomes With Semaglutide in Subjects With Type 2 Diabetes) and PIONEER 6 (Peptide Innovation for Early Diabetes Treatment) were randomized cardiovascular outcome trials of subcutaneous and oral semaglutide in people with type 2 diabetes at high cardiovascular risk, respectively. Time to first stroke and stroke subtypes were analyzed using a Cox proportional hazards model stratified by trial with pooled treatment as a factor. The impact of prior stroke, prior myocardial infarction or stroke, age, sex, systolic blood pressure, estimated glomerular filtration rate, and prior atrial fibrillation on treatment effects was assessed using interaction P values. Risk of major adverse cardiovascular event was analyzed according to prior stroke.ResultsA total of 106/6480 participants had a stroke (1.0 event/100 patient-years of observation [PYO]). Semaglutide reduced incidence of any stroke versus placebo (0.8 versus 1.1 events/100 PYO; hazard ratio, 0.68 [95% CI, 0.46-1.00]; P=0.048), driven by significant reductions in risk of small-vessel occlusion (0.3 versus 0.7 events/100 PYO; hazard ratio, 0.51 [95% CI, 0.29-0.89]; P=0.017). Hazard ratios for risk of any stroke with semaglutide versus placebo were 0.60 (95% CI, 0.37-0.99; 0.5 versus 0.9 events/100 PYO) and 0.89 (95% CI, 0.47-1.69; 2.7 versus 3.0 events/100 PYO) in those without and with prior stroke, respectively. Except for prior atrial fibrillation (P_interaction=0.025), no significant interactions were observed between treatment effects on risk of any stroke and subgroups investigated, or between treatment effects on risk of major adverse cardiovascular event and prior stroke (P_interaction >0.05 for all).ConclusionsSemaglutide reduced incidence of any first stroke during the trials versus placebo in people with type 2 diabetes at high cardiovascular risk, primarily driven by small-vessel occlusion prevention. Semaglutide treatment, versus placebo, lowered the risk of stroke irrespective of prior stroke at baseline.RegistrationURL: https://www.Clinicaltrialsgov; Unique identifier: NCT01720446 and NCT02692716.

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

Results from this study7

7 results from studies that gave the peptide. 7 results from people.

01HumanRandomized controlled trialEfficacy outcome
In adults with type 2 diabetes at high cardiovascular risk, semaglutide reduced the incidence of any stroke versus placebo (hazard ratio 0.68).
In plain wordsIn adults with type 2 diabetes at high heart risk, semaglutide lowered the rate of stroke compared with placebo.
Peptide
Semaglutide
Outcome
DecreaseAny stroke
Study
n = 6,480
Comparator
Placebo
Outcome group
Cardiovascular events · Cardiovascular
Studied dose
Dose not stated · subcutaneous and oralAs given in this study (human).
Measurements
Hazard ratio
0.68 HR
any stroke
95% CI
0.46 to 1 HR
any stroke
Source sentences
Summary
Semaglutide reduced incidence of any stroke versus placebo (0.8 versus 1.1 events/100 PYO; hazard ratio, 0.68 [95% CI, 0.46-1.00]; P=0.048)
1 context sentence(design, population, supporting numbers)
Summary · context
This post hoc analysis examined the subcutaneous and oral semaglutide effects, versus placebo, on stroke and its subtypes in people with type 2 diabetes at high cardiovascular risk.
Show in the study text Report a problemFND-3558294701
02HumanRandomized controlled trialEfficacy outcome
In adults with type 2 diabetes at high cardiovascular risk, semaglutide significantly reduced the risk of small-vessel occlusion stroke versus placebo (hazard ratio 0.51).
In plain wordsIn adults with type 2 diabetes at high heart risk, semaglutide lowered the rate of small-vessel blockage strokes compared with placebo.
Peptide
Semaglutide
Outcome
DecreaseSmall-vessel occlusion stroke
Study
n = 6,480
Comparator
Placebo
Outcome group
Cardiovascular events · Cardiovascular
Studied dose
Dose not stated · subcutaneous and oralAs given in this study (human).
Measurements
Hazard ratio
0.51 HR
small-vessel occlusion
95% CI
0.29 to 0.89 HR
small-vessel occlusion
Source sentences
Summary
driven by significant reductions in risk of small-vessel occlusion (0.3 versus 0.7 events/100 PYO; hazard ratio, 0.51 [95% CI, 0.29-0.89]; P=0.017)
1 context sentence(design, population, supporting numbers)
Summary · context
This post hoc analysis examined the subcutaneous and oral semaglutide effects, versus placebo, on stroke and its subtypes in people with type 2 diabetes at high cardiovascular risk.
Show in the study text Report a problemFND-3558294702
03HumanRandomized controlled trialEfficacy outcome
In adults with type 2 diabetes without prior stroke, semaglutide reduced the risk of any stroke versus placebo (hazard ratio 0.60).
In plain wordsIn adults with type 2 diabetes and no earlier stroke, semaglutide lowered the rate of stroke compared with placebo.
Peptide
Semaglutide
Outcome
DecreaseAny stroke in participants without prior stroke
Study
n: not reported in source
Comparator
Placebo
Outcome group
Cardiovascular events · Cardiovascular
Studied dose
Dose not stated · subcutaneous and oralAs given in this study (human).
Measurements
Hazard ratio
0.6 HR
without prior stroke
95% CI
0.37 to 0.99 HR
without prior stroke
Source sentences
Summary
Hazard ratios for risk of any stroke with semaglutide versus placebo were 0.60 (95% CI, 0.37-0.99; 0.5 versus 0.9 events/100 PYO) and 0.89 (95% CI, 0.47-1.69; 2.7 versus 3.0 events/100 PYO) in those without and with prior stroke, respectively.
1 context sentence(design, population, supporting numbers)
Summary · context
This post hoc analysis examined the subcutaneous and oral semaglutide effects, versus placebo, on stroke and its subtypes in people with type 2 diabetes at high cardiovascular risk.
Show in the study text Report a problemFND-3558294703
04HumanRandomized controlled trialEfficacy outcome
In adults with type 2 diabetes with prior stroke, the hazard ratio for any stroke with semaglutide versus placebo was 0.89 with a confidence interval that included 1.
In plain wordsIn adults with type 2 diabetes and an earlier stroke, semaglutide did not clearly change the rate of stroke compared with placebo.
Peptide
Semaglutide
Outcome
No significant changeAny stroke in participants with prior stroke
Study
n: not reported in source
Comparator
Placebo
Outcome group
Cardiovascular events · Cardiovascular
Studied dose
Dose not stated · subcutaneous and oralAs given in this study (human).
Measurements
Hazard ratio
0.89 HR
with prior stroke
95% CI
0.47 to 1.69 HR
with prior stroke
Source sentences
Summary
Hazard ratios for risk of any stroke with semaglutide versus placebo were 0.60 (95% CI, 0.37-0.99; 0.5 versus 0.9 events/100 PYO) and 0.89 (95% CI, 0.47-1.69; 2.7 versus 3.0 events/100 PYO) in those without and with prior stroke, respectively.
1 context sentence(design, population, supporting numbers)
Summary · context
This post hoc analysis examined the subcutaneous and oral semaglutide effects, versus placebo, on stroke and its subtypes in people with type 2 diabetes at high cardiovascular risk.
Show in the study text Report a problemFND-3558294704
05HumanRandomized controlled trialOther
In adults with type 2 diabetes at high cardiovascular risk, prior atrial fibrillation significantly modified the effect of semaglutide on any stroke (interaction P=0.025).
In plain wordsIn adults with type 2 diabetes at high heart risk, the effect of semaglutide on stroke differed depending on earlier atrial fibrillation.
Peptide
Semaglutide
Outcome
MixedTreatment-effect interaction with prior atrial fibrillation
Study
n: not reported in source
Comparator
Placebo
Outcome group
Cardiovascular events · Cardiovascular
Studied dose
Dose not stated · subcutaneous and oralAs given in this study (human).
Source sentences
Summary
Except for prior atrial fibrillation (P_interaction=0.025)
1 context sentence(design, population, supporting numbers)
Summary · context
This post hoc analysis examined the subcutaneous and oral semaglutide effects, versus placebo, on stroke and its subtypes in people with type 2 diabetes at high cardiovascular risk.
Show in the study text Report a problemFND-3558294705
06HumanRandomized controlled trialOther
In adults with type 2 diabetes at high cardiovascular risk, no significant interactions were observed between semaglutide effects on any stroke and the other investigated subgroups.
In plain wordsIn adults with type 2 diabetes at high heart risk, semaglutide's effect on stroke did not differ across most subgroups.
Peptide
Semaglutide
Outcome
No significant changeTreatment-effect interaction with other subgroups
Study
n: not reported in source
Comparator
Placebo
Outcome group
Cardiovascular events · Cardiovascular
Studied dose
Dose not stated · subcutaneous and oralAs given in this study (human).
Source sentences
Summary
no significant interactions were observed between treatment effects on risk of any stroke and subgroups investigated
1 context sentence(design, population, supporting numbers)
Summary · context
This post hoc analysis examined the subcutaneous and oral semaglutide effects, versus placebo, on stroke and its subtypes in people with type 2 diabetes at high cardiovascular risk.
Show in the study text Report a problemFND-3558294706
07HumanRandomized controlled trialEfficacy outcome
In adults with type 2 diabetes at high cardiovascular risk, no significant interaction was found between semaglutide effects on major adverse cardiovascular events and prior stroke.
In plain wordsIn adults with type 2 diabetes at high heart risk, semaglutide's effect on major heart events did not differ by earlier stroke.
Peptide
Semaglutide
Outcome
No significant changeMajor adverse cardiovascular event risk by prior stroke
Study
n: not reported in source
Comparator
Placebo
Outcome group
Cardiovascular events · Cardiovascular
Studied dose
Dose not stated · subcutaneous and oralAs given in this study (human).
Source sentences
Summary
or between treatment effects on risk of major adverse cardiovascular event and prior stroke (P_interaction >0.05 for all).
1 context sentence(design, population, supporting numbers)
Summary · context
This post hoc analysis examined the subcutaneous and oral semaglutide effects, versus placebo, on stroke and its subtypes in people with type 2 diabetes at high cardiovascular risk.
Show in the study text Report a problemFND-3558294707

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
11 Oct 2026, 00:50 UTC
Study results updated
Version 1
9 Oct 2026, 03:06 UTC
First added · source update from Europe PMC

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