Abstract
Aims: Left ventricular hypertrophy (LVH) is independently associated with adverse cardiovascular outcome. The pathophysiology of LVH development remains unclear although observational studies have reported its association with blood pressure, insulin resistance (IR) and the transcription factor KLF15, a master regulator of anabolic branched chain amino acids (BCAAs) in cells. The current study aims to determine the potential of the diabetes drug metformin to ameliorate these aspects of LVH.
Methods: We used a multidisciplinary approach encompassing population genomics and a clinical randomized trial.
Results: We constructed genetic risk scores (GRS) for IR and systolic blood pressure (SBP) and, using the GoDARTS study which consists of over 10 000 patients with diabetes and over 8000 controls, found that IR and SBP GRS were significantly associated with LVH after adjustment for relevant clinical variables (IR: P = 0.012; SBP: P = 0.025). Patients with the AA genotype of the rs9838915 KLF15 variant were more likely to have LVH (OR 1.19; 95% CI 1.05–1.35, P = 0.006). This association was attenuated in used metformin users (OR 1.01; 95% CI 0.96–1.08, P = 0.64, interaction P-value 0.027), suggesting that metformin might also reduce BCAA uptake into tissues. Our analysis of BCAAs in plasma samples from a clinical trial of metformin vs. placebo confirmed this. Finally, in a randomized-controlled clinical trial, metformin reduced indexed LV mass compared to placebo (−3.1 ± 1.9 g/m1.7 vs. −1.2 ± 2.7 g/m1.7; P = 0.005) and SBP (P < 0.001).
Conclusions: We have used genomic studies to help underpin a randomized trial showing that metformin significantly reduced LV mass compared to placebo
Methods: We used a multidisciplinary approach encompassing population genomics and a clinical randomized trial.
Results: We constructed genetic risk scores (GRS) for IR and systolic blood pressure (SBP) and, using the GoDARTS study which consists of over 10 000 patients with diabetes and over 8000 controls, found that IR and SBP GRS were significantly associated with LVH after adjustment for relevant clinical variables (IR: P = 0.012; SBP: P = 0.025). Patients with the AA genotype of the rs9838915 KLF15 variant were more likely to have LVH (OR 1.19; 95% CI 1.05–1.35, P = 0.006). This association was attenuated in used metformin users (OR 1.01; 95% CI 0.96–1.08, P = 0.64, interaction P-value 0.027), suggesting that metformin might also reduce BCAA uptake into tissues. Our analysis of BCAAs in plasma samples from a clinical trial of metformin vs. placebo confirmed this. Finally, in a randomized-controlled clinical trial, metformin reduced indexed LV mass compared to placebo (−3.1 ± 1.9 g/m1.7 vs. −1.2 ± 2.7 g/m1.7; P = 0.005) and SBP (P < 0.001).
Conclusions: We have used genomic studies to help underpin a randomized trial showing that metformin significantly reduced LV mass compared to placebo
| Original language | English |
|---|---|
| Article number | 9 |
| Pages (from-to) | 724-729 |
| Number of pages | 6 |
| Journal | QJM : an International Journal of Medicine |
| Volume | 112 |
| Issue number | 9 |
| DOIs | |
| Publication status | Published - 5 Sept 2019 |
| Event | 113th Annual Meeting of the Association of Physicians of Great Britian and Ireland - University of Glasgow, Glasgow, United Kingdom Duration: 28 Mar 2019 → 29 Mar 2019 |
ASJC Scopus subject areas
- General Medicine
