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

在2型糖尿病的治疗中，二甲双胍之后有五种非胰岛素治疗方法可供使用。这些药物被称为磺脲类药物（SU）、噻唑烷二酮类药物、二肽基肽酶4抑制剂（DPP4i）、葡萄糖转运蛋白2钠抑制剂（SGLT2i）和GLP-1受体激动剂（GLP-1RA）。最新指南旨在根据风险（例如低血糖或体重增加）、成本（例如苏类药物价格便宜，可在低收入和中等收入国家使用）和效益（例如使用GLP-1RA和SGLT2i可降低心力衰竭或心脏病发作的风险）来指导治疗选择，但在这些治疗中谁受益、谁受到伤害方面存在相当大的差异。我们已经确定血糖对糖尿病治疗的反应是高度“遗传”的，并且已经确定了基因变异改变糖尿病药物效果的例子。在不久的将来，当医生开药时，患者的遗传信息将会被获取，在为糖尿病患者选择最佳药物时，将有可能考虑到这些遗传信息。迄今为止，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，但在现实世界的研究中仍然容易出现偏见和噪音。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SGLT2i和GLP-1RA心血管益处的试验。目前，我们获得了SGLT2i试验（达格列净和恩帕列净，n=10,943）、GLP-1RA试验（阿比鲁肽、利昔那肽、杜拉鲁肽，n=16,596）、DPP-4抑制剂试验（沙格列汀，n=3048）的参与者数据。这些独特的资源仅供主要申请人使用，并提供了相当大的能力来识别改变这些药物的血糖反应、副作用和心血管结局的遗传变异，这些药物在英国和加拿大的使用越来越昂贵。我们将开展多种药物相关反应的研究，包括血糖反应、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，我们将进行基因研究，观察每个试验参与者的近500万个基因变异，以确定它们之间的关联，这些关联将提供药物作用的机制洞察，以及可能在临床中用于预测谁对药物反应良好或不良的变异。其次，我们将研究由于一个共同的潜在原因（称为分区多基因评分（pPS））而增加糖尿病风险的遗传变异组合，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，我们将利用遗传信息来询问有关新的糖尿病药物如何起作用的问题（通过什么机制），特别是它们如何改善心血管疾病的结局。通过识别改变SGLT2i、DPP-4i和GLP-1RA的反应和结果的遗传变异或pPS，并在大型高强度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，以降低卫生保健系统的成本，获得更好的患者结果。

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.