Exploring potential mediators of the cardiovascular benefit of dulaglutide in type 2 diabetes patients in REWIND.

Konig M, Riddle MC, Colhoun HM, Branch KR, Atisso CM, Lakshmanan MC, Mody R, Raha S, Gerstein HC

Cardiovascular diabetology25 Sept 2021Cited by 51 (Europe PMC)

PMID34563178PMCIDPMC8466679DOI10.1186/s12933-021-01386-4PepBankPUB-34563178

Summary

BackgroundThe REWIND trial demonstrated cardiovascular (CV) benefits to patients with type 2 diabetes and multiple CV risk factors or established CV disease. This exploratory analysis evaluated the degree to which the effect of dulaglutide on CV risk factors could statistically account for its effects on major adverse cardiovascular events (MACE) in the REWIND trial.MethodsPotential mediators of established CV risk factors that were significantly reduced by dulaglutide were assessed in a post hoc analysis using repeated measures mixed models and included glycated hemoglobin (HbA1c), body weight, waist-to-hip ratio, systolic blood pressure, low-density lipoprotein (LDL), and urine albumin/creatinine ratio (UACR). These factors, for which the change in level during follow-up was significantly associated with incident MACE, were identified using Cox regression modeling. Each identified variable was then included as a covariate in the Cox model assessing the effect of dulaglutide on MACE to estimate the degree to which the hazard ratio of dulaglutide vs placebo was attenuated. The combined effect of the variables associated with attenuation was assessed by including all variables in an additional Cox model.ResultsAlthough all evaluated variables were significantly improved by treatment, only changes in HbA1c and UACR were associated with MACE and a reduction in the effect of dulaglutide on this outcome was observed. The observed hazard ratio for MACE for dulaglutide vs placebo reduced by 36.1% by the updated mean HbA1c, and by 28.5% by the updated mean UACR. A similar pattern was observed for change from baseline in HbA1c and UACR and a reduction of 16.7% and 25.4%, respectively in the hazard ratio for MACE with dulaglutide vs placebo was observed. When HbA1c and UACR were both included, the observed hazard ratio reduced by 65.4% for the updated mean and 41.7% for the change from baseline with no HbA1c-UACR interaction (P interaction = 0.75 and 0.15, respectively).ConclusionsTreatment-induced improvement in HbA1c and UACR, but not changes in weight, systolic blood pressure, or LDL cholesterol, appear to partly mediate the beneficial effects of dulaglutide on MACE outcomes. These observations suggest that the proven effects of dulaglutide on cardiovascular disease benefit are partially related to changes in glycemic control and albuminuria, with residual unexplained benefit. Clinicaltrials.gov; Trial registration number: NCT01394952. URL: https://clinicaltrials.gov/ct2/show/NCT01394952.

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

Results from this study8

1 result from studies that gave the peptide. 1 result from people.

01HumanObservational studyEfficacy outcome
In REWIND patients with type 2 diabetes, all evaluated cardiovascular risk factors were significantly improved by dulaglutide treatment.
In plain wordsIn patients with diabetes, dulaglutide treatment improved all the cardiovascular risk factors that were evaluated.
Peptide
Dulaglutide (Trulicity)
Outcome
DecreaseRisk factor response
Study
n: not reported in source
Analysis
Exploratory
Outcome group
Cardiometabolic risk factors · Cardiovascular
Studied dose
Dose not stated
Source sentences
Summary
Although all evaluated variables were significantly improved by treatment,
1 context sentence(design, population, supporting numbers)
Summary · context
Potential mediators of established CV risk factors that were significantly reduced by dulaglutide were assessed in a post hoc analysis
Show in the study text Report a problemFND-3456317808

Studies that did not test the peptide alone7

In this study, Dulaglutide (Trulicity) was a lab tool or a carrier, part of a mix, or the subject of a lab method. These results are not evidence about taking Dulaglutide (Trulicity).

02HumanNot a test of Dulaglutide (Trulicity) aloneObservational studyMechanism
In REWIND patients with diabetes, updated mean HbA1c statistically attenuated the dulaglutide versus placebo MACE effect by 36.1%.
In plain wordsIn patients with diabetes, average HbA1c partly explained the cardiovascular effect of dulaglutide compared with placebo.
Peptide
Dulaglutide (Trulicity)
Outcome
DecreaseHbA1c mediation using updated mean
Study
n: not reported in source
Comparator
Placebo
Analysis
Exploratory
Outcome group
Cardiovascular events · Cardiovascular
Measurements
Attenuation of dulaglutide versus placebo MACE hazard ratio by updated mean HbA1c
36.1%
updated mean HbA1c
Source sentences
Summary
The observed hazard ratio for MACE for dulaglutide vs placebo reduced by 36.1% by the updated mean HbA1c, and by 28.5% by the updated mean UACR.
1 context sentence(design, population, supporting numbers)
Summary · context
This exploratory analysis evaluated the degree to which the effect of dulaglutide on CV risk factors could statistically account for its effects on major adverse cardiovascular events (MACE) in the REWIND trial.
In this study, Dulaglutide (Trulicity) was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Dulaglutide (Trulicity).
Show in the study text Report a problemFND-3456317801
03HumanNot a test of Dulaglutide (Trulicity) aloneObservational studyMechanism
In REWIND patients with diabetes, updated mean UACR statistically attenuated the dulaglutide versus placebo MACE effect by 28.5%.
In plain wordsIn patients with diabetes, average urine albumin ratio partly explained the cardiovascular effect of dulaglutide compared with placebo.
Peptide
Dulaglutide (Trulicity)
Outcome
DecreaseUACR mediation using updated mean
Study
n: not reported in source
Comparator
Placebo
Analysis
Exploratory
Outcome group
Cardiovascular events · Cardiovascular
Measurements
Attenuation of dulaglutide versus placebo MACE hazard ratio by updated mean UACR
28.5%
updated mean UACR
Source sentences
Summary
The observed hazard ratio for MACE for dulaglutide vs placebo reduced by 36.1% by the updated mean HbA1c, and by 28.5% by the updated mean UACR.
1 context sentence(design, population, supporting numbers)
Summary · context
This exploratory analysis evaluated the degree to which the effect of dulaglutide on CV risk factors could statistically account for its effects on major adverse cardiovascular events (MACE) in the REWIND trial.
In this study, Dulaglutide (Trulicity) was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Dulaglutide (Trulicity).
Show in the study text Report a problemFND-3456317802
04HumanNot a test of Dulaglutide (Trulicity) aloneObservational studyMechanism
In REWIND patients with diabetes, HbA1c change statistically attenuated the dulaglutide versus placebo MACE effect by 16.7%.
In plain wordsIn patients with diabetes, HbA1c change partly explained the cardiovascular effect of dulaglutide compared with placebo.
Peptide
Dulaglutide (Trulicity)
Outcome
DecreaseHbA1c change mediation
Study
n: not reported in source
Comparator
Placebo
Analysis
Exploratory
Outcome group
Cardiovascular events · Cardiovascular
Measurements
Attenuation of dulaglutide versus placebo MACE hazard ratio by HbA1c change from baseline
16.7%
HbA1c change from baseline
Source sentences
Summary
A similar pattern was observed for change from baseline in HbA1c and UACR and a reduction of 16.7% and 25.4%, respectively in the hazard ratio for MACE with dulaglutide vs placebo was observed.
1 context sentence(design, population, supporting numbers)
Summary · context
This exploratory analysis evaluated the degree to which the effect of dulaglutide on CV risk factors could statistically account for its effects on major adverse cardiovascular events (MACE) in the REWIND trial.
In this study, Dulaglutide (Trulicity) was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Dulaglutide (Trulicity).
Show in the study text Report a problemFND-3456317803
05HumanNot a test of Dulaglutide (Trulicity) aloneObservational studyMechanism
In REWIND patients with diabetes, UACR change statistically attenuated the dulaglutide versus placebo MACE effect by 25.4%.
In plain wordsIn patients with diabetes, urine albumin ratio change partly explained the cardiovascular effect of dulaglutide compared with placebo.
Peptide
Dulaglutide (Trulicity)
Outcome
DecreaseUACR change mediation
Study
n: not reported in source
Comparator
Placebo
Analysis
Exploratory
Outcome group
Cardiovascular events · Cardiovascular
Measurements
Attenuation of dulaglutide versus placebo MACE hazard ratio by UACR change from baseline
25.4%
UACR change from baseline
Source sentences
Summary
A similar pattern was observed for change from baseline in HbA1c and UACR and a reduction of 16.7% and 25.4%, respectively in the hazard ratio for MACE with dulaglutide vs placebo was observed.
1 context sentence(design, population, supporting numbers)
Summary · context
This exploratory analysis evaluated the degree to which the effect of dulaglutide on CV risk factors could statistically account for its effects on major adverse cardiovascular events (MACE) in the REWIND trial.
In this study, Dulaglutide (Trulicity) was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Dulaglutide (Trulicity).
Show in the study text Report a problemFND-3456317804
06HumanNot a test of Dulaglutide (Trulicity) aloneObservational studyMechanism
In REWIND patients with diabetes, joint HbA1c and UACR updated means attenuated the dulaglutide versus placebo MACE effect by 65.4%.
In plain wordsIn patients with diabetes, combined average HbA1c and urine albumin ratio partly explained the dulaglutide cardiovascular effect compared with placebo.
Peptide
Dulaglutide (Trulicity)
Outcome
DecreaseCombined updated-mean mediation
Study
n: not reported in source
Comparator
Placebo
Analysis
Exploratory
Outcome group
Cardiovascular events · Cardiovascular
Measurements
Attenuation of dulaglutide versus placebo MACE hazard ratio by HbA1c and UACR together
65.4%
updated mean, HbA1c and UACR both included
Source sentences
Summary
When HbA1c and UACR were both included, the observed hazard ratio reduced by 65.4% for the updated mean and 41.7% for the change from baseline with no HbA1c-UACR interaction (P interaction = 0.75 and 0.15, respectively).
1 context sentence(design, population, supporting numbers)
Summary · context
This exploratory analysis evaluated the degree to which the effect of dulaglutide on CV risk factors could statistically account for its effects on major adverse cardiovascular events (MACE) in the REWIND trial.
In this study, Dulaglutide (Trulicity) was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Dulaglutide (Trulicity).
Show in the study text Report a problemFND-3456317805
07HumanNot a test of Dulaglutide (Trulicity) aloneObservational studyMechanism
In REWIND patients with diabetes, joint HbA1c and UACR changes attenuated the dulaglutide versus placebo MACE effect by 41.7%.
In plain wordsIn patients with diabetes, combined HbA1c and urine albumin changes partly explained the dulaglutide cardiovascular effect compared with placebo.
Peptide
Dulaglutide (Trulicity)
Outcome
DecreaseCombined change mediation
Study
n: not reported in source
Comparator
Placebo
Analysis
Exploratory
Outcome group
Cardiovascular events · Cardiovascular
Measurements
Attenuation of dulaglutide versus placebo MACE hazard ratio by HbA1c and UACR together
41.7%
change from baseline, HbA1c and UACR both included
Source sentences
Summary
When HbA1c and UACR were both included, the observed hazard ratio reduced by 65.4% for the updated mean and 41.7% for the change from baseline with no HbA1c-UACR interaction (P interaction = 0.75 and 0.15, respectively).
1 context sentence(design, population, supporting numbers)
Summary · context
This exploratory analysis evaluated the degree to which the effect of dulaglutide on CV risk factors could statistically account for its effects on major adverse cardiovascular events (MACE) in the REWIND trial.
In this study, Dulaglutide (Trulicity) was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Dulaglutide (Trulicity).
Show in the study text Report a problemFND-3456317806
08HumanNot a test of Dulaglutide (Trulicity) aloneObservational studyMechanism
In REWIND patients with diabetes, the mediation model found no HbA1c-UACR interaction for the dulaglutide effect.
In plain wordsIn patients with diabetes, HbA1c and urine albumin ratio showed no interaction in explaining the dulaglutide effect.
Peptide
Dulaglutide (Trulicity)
Outcome
No significant changeHbA1c-UACR interaction
Study
n: not reported in source
Analysis
Exploratory
Outcome group
Cardiovascular events · Cardiovascular
Measurements
P interaction HbA1c-UACR
0.75
updated mean
P interaction HbA1c-UACR
0.15
change from baseline
Source sentences
Summary
When HbA1c and UACR were both included, the observed hazard ratio reduced by 65.4% for the updated mean and 41.7% for the change from baseline with no HbA1c-UACR interaction (P interaction = 0.75 and 0.15, respectively).
1 context sentence(design, population, supporting numbers)
Summary · context
This exploratory analysis evaluated the degree to which the effect of dulaglutide on CV risk factors could statistically account for its effects on major adverse cardiovascular events (MACE) in the REWIND trial.
In this study, Dulaglutide (Trulicity) was a lab tool or a carrier, part of a mix, or the subject of a lab method. This result is not evidence about taking Dulaglutide (Trulicity).
Show in the study text Report a problemFND-3456317807

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

Registered trials1

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

1 trial · 1 completed · 1 with posted results · source ClinicalTrials.gov (opens in a new tab)

CompletedPhase 3Results postedNCT01394952

Researching Cardiovascular Events With a Weekly Incretin in Diabetes (REWIND)

Eli Lilly and Companyn = 9,90122 Jul 2011 to 21 Aug 2018

Cardiovascular Disease · Diabetes Mellitus, Type 2

Trial page ClinicalTrials.govUpdated 8 Oct 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
22 Oct 2026, 02:25 UTC
Study results updated
Version 1
21 Oct 2026, 18:59 UTC
First added · source update from Europe PMC

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Exploring potential mediators of the cardiovascular benefit of dulaglutide in type 2 diabetes patients in REWIND.

Summary

Results from this study8

Studies that did not test the peptide alone7

Registered trials1

Researching Cardiovascular Events With a Weekly Incretin in Diabetes (REWIND)

Version history

Subjects

Publication types

MeSH terms

Keywords