Diabetes: Is There a Future for Pharmacogenomics Guided Treatment?

Abstract

Diabetes is a disease defined on the basis of hyperglycemia. There are monogenic forms of diabetes where defining the genetic cause has a dramatic impact on treatment-with patients being able to transition from insulin to sulfonylureas. However, the majority of diabetes is type 2 diabetes. This review outlines the robust evidence accrued to date for pharmacogenetics of metformin, sulfonylureas, thiazolidinediones, and dipeptidyl peptidase-4 inhibitors but highlights that these variants will only be of clinical utility when the genotype is already known at the point of prescribing. The future of pharmacogenetics in diabetes and other common complex disease relies on a paradigm shift-that of preemptive panel genotyping and use of clinical decision support tools to assimilate this genetic information with other clinical phenotypic data and to present this information simply to the prescriber. Given the recent dramatic fall in genotyping costs, this future is not far off.

Figure 1

A framework for evaluating PGx in type 2 diabetes. PGx, pharmacogenetics; SGLT2i, sodium glucose transporter 2 inhibitor.

Figure 2

The future of pharmacogenetics in type 2 diabetes—incorporating genotype into a clinical decision support tool. A primary care physician starts to prescribe a new treatment for a patient whose glycemic control is above target. A clinical decision support tool built into the prescribing tool queries simple clinical and laboratory measures, actionable genotypes, and other biomarkers. The output is a probability of likely response and likely adverse drug reaction (ADR). The physician can use this to guide a discussion with their patient about the best drug to initiate to maximize benefit and minimize harm. BMI, body mass index; HbA1c, glycated hemoglobin A1c; SU, sulfonylurea; WGS, whole‐genome sequence.

Figure 3

The combined effect of reduced function SLC22A1 genotypes and organic cation transporter 1 (OCT1) interacting drugs on likelihood of metformin intolerance. The reference is those individuals with 1 or 0 risk alleles (RAs) who are not treated with a potential interacting drug (+ drug). Carriage of more than one RA or the use of interacting drugs are associated with intolerance. There is an additive effect in those with more than one RA who are also treated with interacting drugs having the greatest risk of intolerance.

Figure 4

The future role of pharmacogenetics in type 2 diabetes—a summary of the robust and clinically relevant drug–gene interactions that will be of likely clinical utility but only when a preemptive genotyping approach is adopted. CYP, cytochrome P450; DPP‐4, dipeptidyl peptidase‐4; HbA1c, hemoglobin A1c; OR, odds ratio; OCT1, organic cation transporter 1; PMAT, plasma membrane monoamine transporter; SU, sulfonylurea; T2DM, type 2 diabetes mellitus; TZDs, thiazolidinediones.