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

Autor: Hertzel C. Gerstein, Manige Konig, Charles Atisso, Kelley R. Branch, Matthew C. Riddle, Helen M. Colhoun, Reema Mody, Mark Lakshmanan, Sohini Raha
Rok vydání: 2021
Předmět:
Blood Glucose
Male
Glucagon-like peptide-1
medicine.medical_specialty
Time Factors
Recombinant Fusion Proteins
Endocrinology
Diabetes and Metabolism
Glucagon-Like Peptides
Type 2 diabetes
Cardiovascular
Risk Assessment
chemistry.chemical_compound
Internal medicine
medicine
Diseases of the circulatory (Cardiovascular) system
Albuminuria
Humans
Hypoglycemic Agents
Dulaglutide
Aged
Original Investigation
Mediators
Glycated Hemoglobin
business.industry
Proportional hazards model
Diabetes
Hazard ratio
Repeated measures design
Middle Aged
medicine.disease
Immunoglobulin Fc Fragments
Treatment Outcome
Diabetes Mellitus
Type 2
chemistry
Cardiovascular Diseases
Heart Disease Risk Factors
RC666-701
Creatinine
Female
Glycated hemoglobin
medicine.symptom
Cardiology and Cardiovascular Medicine
business
Biomarkers
Mace
medicine.drug
Zdroj: Cardiovascular Diabetology
Cardiovascular Diabetology, Vol 20, Iss 1, Pp 1-7 (2021)
ISSN: 1475-2840
DOI: 10.1186/s12933-021-01386-4
Popis: Background The 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. Methods Potential 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. Results Although 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). Conclusions Treatment-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
Databáze: OpenAIRE
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