Grant Abstract: Genetics of Response to Canagliflozin

Grant Number: 5R01DK118942-02
PI Name: Taylor
Project Title: Genetics of Response to Canagliflozin

Abstract: Sodium-glucose cotransporter-2 inhibitors are the most recently approved class of antidiabetic drugs. These drugs have an attractive efficacy profile – including a decreased risk of major adverse cardiovascular events in addition to glucose-lowering, weight loss, and blood pressure-lowering. However, SGLT2 inhibitors also have significant undesired side effects – including bone loss as well as increased risk of bone fractures, urosepsis, and ketoacidosis. Significant variability exists in response to these drugs in terms of both efficacy and safety, and there are not currently good ways to identify individuals likely to respond or experience side effects. Our current grant (R01118942) supports a genome-wide association study in the Old Order Amish population to identify genetic variants that predict individuals’ responses to canagliflozin (the most widely used SGLT2 inhibitor) at a dose of 300 mg/day for 5 days. The ongoing clinical trial measures pharmacodynamic end-points related to both the beneficial and adverse effects of SGLT2 inhibitors. The grant supports two specific aims: • Aim 1. To identify variants associated with a clinical efficacy biomarker (24 hr urinary glucose excretion) • Aim 2. To identify variants associated with predictive biomarkers for safety end-points – including, plasma glucagon, ketone bodies, cardiovascular biomarkers (uric acid and blood pressure) and biomarkers of bone health (serum phosphorus, plasma FGF23, plasma 1,25-dihydroxyvitamin D, and plasma PTH). The NIDDK-funded project is a step toward the long-term objective of identifying genetic biomarkers to predict an individual patient’s response to SGLT2 inhibitors. This type of Precision Medicine approach would be a transformational advance in the way diabetes drugs are prescribed – enabling physicians to prescribe optimal therapies for each individual patient based on predictors of clinical benefit and susceptibility to adverse effects. This administrative supplement application proposes to obtain additional data in our ongoing clinical trial with the objective of exploring whether vitamin D supplements might mitigate the canagliflozin-induced risk of bone fracture. The proposed exploratory proof of concept study focuses on bone-related biomarkers. Canagliflozin decreases plasma 1,25-dihydroxyvitamin D and increases plasma PTH – two endocrine changes, which are predicted to mediate an adverse effect on bone health. This administrative supplement would explore whether there are nutrient-drug interactions between vitamin D and canagliflozin. Specifically, vitamin D deficient patients would undergo the ongoing five-dose canagliflozin protocol twice – both before and after receiving vitamin D supplements. The primary outcome will test whether vitamin D supplements mitigate the canagliflozin-induced decrease in plasma 1,25-dihydroxyvitamin D and/or the increase in plasma PTH levels.

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