| Application: | 61650, Genetic variation in sodium-glucose cotransporter 2 (SGLT2) and glucagon-like peptide-1 receptor (GLP1R) and cardiovascular outcomes |
| Title: | Genetic Variation in Sodium-glucose Cotransporter 2 and Heart Failure |
| Size: | 2.5 MB |
| Archived: | 21 Oct 2021 |
| Stability: | Complete |
| Personal: | Contains individual-level data |
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Notes
Pharmacologic inhibition of sodium-glucose cotransporter 2 (SGLT2) represents an emerging approach for the treatment of heart failure. The mechanisms by which SGLT2 inhibitors reduce the risk of heart failure are not well understood. We investigated the association of inherited polymorphisms in the SLC5A2 gene that encodes SGLT2 with the diagnosis heart failure in the UK Biobank and an additional epidemiological database (LUdwigshafen RIsk and Cardiovascular Health study [LURIC]; n = 3316). Two polymorphisms were included in a genetic score, which was associated with lower risk of heart failure in UK Biobank (odds ratio 0.97, 95% confidence interval, 0.95-0.99, P = 0.016). This association was also present in participants without type 2 diabetes or coronary artery disease (CAD). The associations of the genetic score with HbA1c, high-density lipoprotein cholesterol, uric acid, systolic blood pressure, waist circumference, and body composition mediated 35% of the effect of the score on heart failure risk. No associations of the genetic SGLT2 score with atherosclerotic cardiovascular disease outcomes or markers of volume status were observed, which was confirmed in the LURIC study. Our findings contribute to the understanding of how SGLT2 inhibitors reduce the risk of heart failure, and may stimulate future mechanistic research.Application 61650
Genetic variation in sodium-glucose cotransporter 2 (SGLT2) and glucagon-like peptide-1 receptor (GLP1R) and cardiovascular outcomes
Type 2 diabetes mellitus is a very common disease, affecting 8.5% of the adult population in 2014. Diabetes is an established risk factor for atherosclerotic cardiovascular diseases, and results in 11% of vascular deaths being attributable to diabetes. There are only two classes of medication that reduce not only elevated blood glucose as key feature of diabetes mellitus, but also the risk of cardiovascular events such as heart failure and myocardial infarction, i. e. inhibitors of the sodium-glucose cotransporter2 (so-called SGLT2 inhibitors), and activators of the glucagon-like peptide-1 receptor (so-called GLP1R agonists). It is not well understood why these medications reduce cardiovascular events, while others that also reduce blood glucose such as insulin do not. As to the high and increasing prevalence of diabetes, and the severe complications, there is a need to understand what differentiates SGLT2 inhibitors and GLP1R agonists from other treatments of diabetes mellitus. Scientific questions in medical research usually require clinical trials or laboratory experiments which are costly, complex, and potentially put patients at risk. However, some trials have already been conducted by nature. Some people have small variations in the genes that contain the information for the production of the proteins which are the target of SGLT2 inhibitors and GLP1R agonists, respectively. These genetic variants may influence how much of the protein is produced or how effective the protein works, and are inherited by chance. As treatment with SGLT2 inhibitors and GLP1R agonists affects protein function of SGLT2 and GLP1R as well, these genetic polymorphisms may serve as a proxy for treatment with these drugs - a lifelong treatment with a very low dose of medication. As such polymorphisms usually do only have very small impact on laboratory measurements such as blood glucose, large cohorts of hundreds of thousands of individuals are required to detect consequences of inheriting such polymorphisms. This research is intended to identify possible mechanisms that are responsible for the beneficial effects observed under the treatment with SGLT2 inhibitors and GLP1R agonists by using genetic variants in the genes that encode the proteins SGLT2 and GLP1R. Identifying these mechanisms may help to improve the management of type 2 diabetes mellitus, may improve the selection of patients who are most likely to benefit from certain treatments, to potentially extend the use of these drugs to patients without diabetes, and to possibly identify beneficial mechanisms that may also be targeted by future drugs.
| Lead investigator: | Dr Julius Katzmann |
| Lead institution: | University Hospital Leipzig |
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