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A Type 2 Diabetes Subtype Responsive to ACCORD Intensive Glycemia Treatment
- Source :
- Diabetes Care
- Publication Year :
- 2020
-
Abstract
- OBJECTIVE Current type 2 diabetes (T2D) management contraindicates intensive glycemia treatment in patients with high cardiovascular disease (CVD) risk and is partially motivated by evidence of harms in the Action to Control Cardiovascular Risk in Diabetes (ACCORD) trial. Heterogeneity in response to intensive glycemia treatment has been observed, suggesting potential benefit for some individuals. RESEARCH DESIGN AND METHODS ACCORD was a randomized controlled trial that investigated whether intensively treating glycemia in individuals with T2D would reduce CVD outcomes. Using a novel approach to cluster HbA1c trajectories, we identified groups in the intensive glycemia arm with modified CVD risk. Genome-wide analysis and polygenic score (PS) were developed to predict group membership. Mendelian randomization was performed to infer causality. RESULTS We identified four clinical groupings in the intensive glycemia arm, and clinical group 4 (C4) displayed fewer CVD (hazard ratio [HR] 0.34; P = 2.01 × 10−3) and microvascular outcomes (HR 0.86; P = 0.015) than those receiving standard treatment. A single-nucleotide polymorphism, rs220721, in MAS1 reached suggestive significance in C4 (P = 4.34 × 10−7). PS predicted C4 with high accuracy (area under the receiver operating characteristic curve 0.98), and this predicted C4 displayed reduced CVD risk with intensive versus standard glycemia treatment (HR 0.53; P = 4.02 × 10−6), but not reduced risk of microvascular outcomes (P < 0.05). Mendelian randomization indicated causality between PS, on-trial HbA1c, and reduction in CVD outcomes (P < 0.05). CONCLUSIONS We found evidence of a T2D clinical group in ACCORD that benefited from intensive glycemia treatment, and membership in this group could be predicted using genetic variants. This study generates new hypotheses with implications for precision medicine in T2D and represents an important development in this landmark clinical trial warranting further investigation.
- Subjects :
- Research design
Blood Glucose
medicine.medical_specialty
Cardiovascular and Metabolic Risk
endocrine system diseases
Endocrinology, Diabetes and Metabolism
Health Behavior
030209 endocrinology & metabolism
Type 2 diabetes
Proto-Oncogene Mas
law.invention
03 medical and health sciences
0302 clinical medicine
Randomized controlled trial
law
Risk Factors
Internal medicine
Diabetes mellitus
Mendelian randomization
Internal Medicine
Medicine
Humans
030212 general & internal medicine
Proportional Hazards Models
Advanced and Specialized Nursing
business.industry
Standard treatment
Hazard ratio
medicine.disease
Clinical trial
Diabetes Mellitus, Type 2
Cardiovascular Diseases
business
Subjects
Details
- ISSN :
- 19355548
- Volume :
- 44
- Issue :
- 6
- Database :
- OpenAIRE
- Journal :
- Diabetes care
- Accession number :
- edsair.doi.dedup.....0f203f4fb168ec8db8ce6276c928ac5a