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

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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.