Biomarker Changes Associated With Both Dulaglutide and Cardiovascular Events in the REWIND Randomized Controlled Trial: A Nested Case-Control Post Hoc Analysis.

OBJECTIVE: The glucagon-like peptide-1 receptor agonist dulaglutide reduced MACE in the Researching Cardiovascular Events with a Weekly Incretin in Diabetes (REWIND) trial. This article expores the relationship of selected biomarkers to both dulaglutide and major adverse cardiovascular events (MACE). RESEARCH DESIGN AND METHODS: In this post hoc analysis, stored fasting baseline and 2-year plasma samples from 824 REWIND participants with MACE during follow-up and 845 matched non-MACE participants were analyzed for 2-year changes in 19 protein biomarkers. Two-year changes in 135 metabolites were also analyzed in 600 participants with MACE during follow-up and in 601 matched non-MACE participants. Linear and logistic regression models were used to identify proteins that were associated with both dulaglutide treatment and MACE. Similar models were used to identify metabolites that were associated with both dulaglutide treatment and MACE. RESULTS: Compared with placebo, dulaglutide was associated with a greater reduction or lesser 2-year rise from baseline in N-terminal prohormone of brain natriuretic peptide (NT-proBNP), growth differentiation factor 15 (GDF-15), high-sensitivity C-reactive protein, and a greater 2-year rise in C-peptide. Compared with placebo, dulaglutide was also associated with a greater fall from baseline in 2-hydroxybutyric acid and a greater rise in threonine (P < 0.001). Increases from baseline in two of the proteins (but neither metabolite) were associated with MACE, including NT-proBNP (OR 1.267; 95% CI 1.119, 1.435; P < 0.001) and GDF-15 (OR 1.937; 95% CI 1.424, 2.634; P < 0.001). CONCLUSIONS: Dulaglutide was associated with a reduced 2-year rise from baseline of NT-proBNP and GDF-15. Higher rises of these biomarkers were also associated with MACE.

Biomarkers of Prevalent and Incident Cognitive Dysfunction in People with Dysglycemia: Data from the ORIGIN Trial.

BACKGROUND: Diabetes and cardiovascular disease increase the risk of incident cognitive dysfunction. Identification of novel biochemical markers for cognitive dysfunction may identify people at the highest risk while yielding insights regarding the pathophysiology of cognitive dysfunction. OBJECTIVE: To identify cardiovascular biomarkers in serum that are independent predictors of cognitive dysfunction in individuals with dysglycemia. METHODS: This analysis was conducted in 8,365 participants in the Outcome Reduction with an Initial Glargine Intervention (ORIGIN) trial whose stored serum was analyzed for 238 cardio-metabolic biomarkers and completed a baseline Mini-Mental State Examination (MMSE). Fine and Gray sub distribution hazard models accounting for the competing risk of death accounting for clinical risk factors and the baseline MMSE were used to identify biomarkers that predicted incident cognitive dysfunction (MMSE < 24 or dementia) using forward selection with an inclusion p-value < 0.0002 to account for multiplicity. RESULTS: During a median follow-up period of 6.2 years, 939 individuals developed cognitive dysfunction. After accounting for 17 clinical risk factors, glargine allocation, and the baseline MMSE, three biomarkers (α-2 Macroglobulin, HR 1.19; 95% CI 1.12, 1.27; Macrophage Inflammatory Protein 1α, HR 1.11; 95% CI 1.06, 1.16; and Growth Hormone, HR 0.91; 95% CI 0.87, 0.96) independently predicted incident cognitive dysfunction (p < 0.0002). Addition of these biomarkers to a model that included clinical risk factors, however, did not improve the ability to predict cognitive dysfunction. CONCLUSION: Addition of independent biomarkers to clinical risk factors for cognitive dysfunction in people with dysglycemia did not predict incident cognitive dysfunction better than clinical risk factors alone.

Growth Differentiation Factor 15 as a Novel Biomarker for Metformin.

OBJECTIVE: Metformin is a commonly used glucose-lowering drug. However, apart from glycemic measures, no biomarker for its presence or dose has been identified. RESEARCH DESIGN AND METHODS: A total of 237 biomarkers were assayed in baseline serum from 8,401 participants (2,317 receiving metformin) in the Outcome Reduction with Initial Glargine Intervention (ORIGIN) trial. Regression models were used to identify biomarkers for metformin use. RESULTS: Growth differentiation factor 15 (GDF15) was strongly linked to metformin, such that the odds of metformin use per SD increase in level varied from 3.73 (95% CI 3.40, 4.09) to 3.94 (95% CI 3.59, 4.33) depending on the other included variables. For the remaining 25 linked biomarkers, the odds ranged from 0.71 to 1.24. A 1.64 ng/mL higher GDF15 level predicted a 188-mg higher metformin dose (P < 0.0001). CONCLUSIONS: GDF15 levels are a biomarker for the use of metformin in people with dysglycemia, and its concentration reflects the dose of metformin.