Precision medicine in diabetes: Pharmacogenetic studies of large randomised controlled trials of diabetes therapies

糖尿病精准医学：糖尿病治疗大型随机对照试验的药物遗传学研究

• 批准号: MR/T032014/1
• 负责人: Ewan Pearson
• 金额: $ 43.11万
• 依托单位: University of Dundee
• 依托单位国家: 英国
• 项目类别: Research Grant
• 财政年份: 2020
• 资助国家: 英国
• 起止时间: 2020 至 无数据
• 项目状态: 已结题
• 来源: https://gtr.ukri.org/projects?ref=MR%2FT032014%2F1
• 关键词: Precision; medicine; diabetes; Pharmacogenetic; studies

In the treatment of type 2 diabetes, there are five non-insulin therapies available for use after metformin. These are called sulphonylureas (SU), thiazolidinediones, dipeptidyl-peptidase 4 inhibitors (DPP4i), Sodium Glucose Transporter 2 inhibitors (SGLT2i) and GLP-1 Receptor Agonists (GLP-1RA). The latest guidelines aim to guide treatment choice based upon risks (e.g. of low blood sugar or weight gain), cost (e.g. SU are cheap and could be used in low and middle income countries), and benefit (e.g. reduction in risk of heart failure or heart attack with GLP-1RA and SGLT2i) however there is considerable variation in who benefits, and who is harmed, from any of these treatments. We have established that blood sugar response to diabetes treatments is highly "genetic" and have identified examples where genetic variants alter how well the diabetes drugs work. As we move to a time in the near future when genetic information will be available for a patient when the doctor prescribes a drug, it will be possible to take into account this genetic information when choosing the best medication for a patient with diabetes.To date, genetic studies of drug response in diabetes have been limited to observational studies. These studies are limited in their ability to study newer drugs, and despite including genetics, are still prone to bias and noise seen in real-world studies. The present UK-Canada collaboration brings together, for the first time, genetic data on randomised controlled trials (RCT) of the newer diabetes agents, including trials that established the cardiovascular benefit of SGLT2i and GLP-1RA. Currently we have access to data from participants to SGLT2i trials (Dapagliflozin and Empagliflozin, n=10,943), GLP-1RA trials (Albiglutide, Lixisenatide, Dulaglutide n=16,596), DPP-4 inhibitor trials (Saxagliptin, n=3048). These unique resources are only available to the principal applicants and provide considerable power to identify genetic variants that alter blood sugar response, side effects and cardiovascular outcome of these drugs that are expensive and increasingly used in the UK and Canada.We will undertake studies of multiple drug related responses including glycaemic response, weight reduction, blood pressure reduction, nausea/vomiting, thrush, renal outcomes and cardiovascular outcomes. First, we will undertake genetic studies looking at nearly 5 million genetic variants for each trial participant to identify associations that will provide mechanistic insight into drug action as well as variants that may be used in the clinic to predict who will respond well or poorly to medication. Second, we will then look at combinations of genetic variants that increase risk of diabetes due to a common underlying cause - called partitioned polygenic scores (pPS) - and investigate how different pPS alter response and outcome to the diabetes drugs. Finally, we will use the genetic information to ask questions in relation to how the newer diabetes drugs work (via what mechanism) and in particular how they improve cardiovascular outcomes. By identifying genetic variants or pPS that alter response and outcomes of SGLT2i, DPP-4i and GLP-1RA, and undertaking more complex mechanistic studies in large highly powered clinical trials, we will provide a major advance in precision medicine in diabetes. This will enable better targeting of treatment for better patient outcomes at reduced cost to the health care system.

在2型糖尿病的治疗中，二甲双胍之后有五种非胰岛素疗法可供使用。这些药物被称为磺脲类（SU）、噻唑烷二酮类、二肽基肽酶4抑制剂（DPP 4 i）、钠葡萄糖转运蛋白2抑制剂（SGLT 2 i）和GLP-1受体激动剂（GLP-1 RA）。最新指南旨在根据风险（如低血糖或体重增加）、成本（如SU价格低廉，可用于低收入和中等收入国家）和获益（如GLP-1 RA和SGLT 2 i降低心力衰竭或心脏病发作风险）指导治疗选择，但这些治疗的受益者和受损者存在相当大的差异。我们已经确定，糖尿病治疗的血糖反应是高度“遗传”的，并确定了遗传变异改变糖尿病药物作用的例子。在不久的将来，当医生给病人开药时，病人的遗传信息就可以被利用，在为糖尿病病人选择最佳药物时，就有可能考虑到这些遗传信息。迄今为止，关于糖尿病药物反应的遗传学研究仅限于观察性研究。这些研究在研究新药方面的能力有限，尽管包括遗传学，但仍然容易受到现实世界研究中的偏见和噪音的影响。目前的英国-加拿大合作首次汇集了新型糖尿病药物随机对照试验（RCT）的遗传数据，包括确定SGLT 2 i和GLP-1 RA心血管获益的试验。目前，我们可以访问SGLT 2 i试验（达格列净和恩格列净，n= 10，943）、GLP-1 RA试验（阿必鲁肽、利格列汀、杜洛克汀，n= 16，596）、DPP-4抑制剂试验（沙格列汀，n=3048）受试者的数据。这些独特的资源仅提供给主要申请人，并提供相当大的力量来识别改变血糖反应的遗传变异，这些药物的副作用和心血管结局，这些药物价格昂贵，在英国和加拿大越来越多地使用。我们将进行多种药物相关反应的研究，包括贫血反应，体重减轻，血压降低，恶心/呕吐，鹅口疮，肾脏结局和心血管结局。首先，我们将进行遗传学研究，研究每个试验参与者的近500万个遗传变异，以确定相关性，这些相关性将为药物作用提供机制性见解，以及可能用于临床的变异，以预测谁对药物的反应良好或不良。其次，我们将研究遗传变异的组合，这些变异会增加糖尿病的风险，这是由于一个共同的潜在原因-称为分区多基因评分（pPS）-并研究不同的pPS如何改变对糖尿病药物的反应和结果。最后，我们将使用遗传信息来询问与新的糖尿病药物如何工作（通过什么机制）有关的问题，特别是它们如何改善心血管结局。通过鉴定改变SGLT 2 i、DPP-4 i和GLP-1 RA的反应和结局的遗传变异或pPS，并在大型高效能临床试验中进行更复杂的机制研究，我们将在糖尿病精准医学方面取得重大进展。这将使治疗更有针对性，以降低医疗保健系统的成本，获得更好的患者结果。

项目成果

Treatment effect heterogeneity following type 2 diabetes treatment with GLP1-receptor agonists and SGLT2-inhibitors: a systematic review.

• DOI: 10.1038/s43856-023-00359-w
• 发表时间: 2023-10-05
• 期刊: COMMUNICATIONS MEDICINE
• 作者: Young, Katherine G;McInnes, Eram Haider;Massey, Robert J;Kahkoska, Anna R;Pilla, Scott J;Raghavan, Sridharan;Stanislawski, Maggie A;Tobias, Deirdre K;McGovern, Andrew P;Dawed, Adem Y;Jones, Angus G;Pearson, Ewan R;Dennis, John M
• 通讯作者: Dennis, John M

New Insights Into the Genetics of Glycemic Response to Metformin

二甲双胍血糖反应遗传学的新见解

• DOI: 10.2337/dci23-0060
• 发表时间: 2024
• 期刊: Diabetes Care
• 影响因子: 16.2
• 作者: Pearson E

Precision Medicine in Diabetes.

糖尿病精准医学。

• DOI: 10.1007/164_2022_590
• 发表时间: 2023
• 期刊: Handbook of experimental pharmacology
• 作者: Dawed AY