(AH) Determinants of Higher Metformin Daily Dosage Among Type 2 Diabetic Patients: A Genetic Risk Score Analysis in The Rotterdam Study

Saturday, August 27, 2022

8:00 AM – 6:00 PM CEST

Location: Hall E South

Publication Number: 668

Presenting Author(s)

Soroush Mohammadi Jouabadi, PharmD, MSc
– erasmusmc, Rotterdam, Zuid-Holland, Netherlands

Co-Author(s)

Payam Peymani, PharmD
– Postdoctoral Fellow, The University of Manitoba, Winnipeg, Manitoba, Canada
Bruno H. Stricker
– Professor of Pharmacoepidemiology, Epidemiology department, Erasmus Medical Center, Rotterdam, The Netherlands, Rotterdam, Netherlands
Fariba Ahmadizar
– Assistant Professor, Molecular (Pharmaco) Epidemiology, Julius Center, UMC Utrecht, the Netherlands, Netherlands

Background: The glycemic response to metformin as the first-line treatment of type 2 diabetes mellitus (T2D) differs individually and between populations. Although dose-response variability is associated with several distinct mechanisms, there is a scarcity of research evaluating the effect of genetic variants on dose-response to metformin.

Objectives: The objective of this study was to examine whether a variety of single nucleotide polymorphisms (SNPs) corresponding to metformin response were associated with the changes in metformin dosage among a population of European ancestry. We further studied non-genetic factors associated with changes in metformin dosage.

Methods: We used the data from the Rotterdam Study (RS), a prospective population-based cohort study. In a longitudinal study, patients with T2D using metformin (according to pharmacy-based data) with available genetic data were included. Genotyping in the RS was performed using the Illumina 550K and 610K quad array and were imputed to the Haplotype Reference Consortium. We studied a total of 27 SNPs filtered by quality-control tests (SNPs excluded if: inter-SNP LD >0.5, MAF < 0.01, HWE P-value < 0.05). We composed a genetic risk score (GRS), calculated as unweighted mean-centered GRS based on risk allele frequency of SNPs corresponding to poor response to metformin in the literature.The association between GRS and metformin dosage as a time-varying outcome was investigated using linear mixed models and adjusted for potential confounders such as age, sex, and smoking. All data were analyzed using R version 3.1.

Results: Our study included 1,285 metformin users with a median follow-up of 4.9 years (mean age of 70.6 ± 10.3 years and 45.8% male, mean BMI 29.3 ± 4.74, median [IQR] GRS of 24 [13,33], and 66.8% ever smokers). Repeated measure analysis revealed that higher GRS were significantly associated with increasing metformin dosage (ß=0.008, 95%CI [0.0001, 0.0148]). Non-genetic risk factors associated with changes in the daily metformin dosage were eGFR (ß= -0.06, 95%CI [-0.08, -0.04]), age (ß= -0.29, 95%CI [-0.31, -0.27]), and female gender (ß= -0.05, 95%CI [-0.1, -0.01]). Further analysis showed an increasing trend in metformin dosage per increasing sequence of prescription regardless of GRS (ß=0.67, 95%CI [0.63, 0.72]).

Conclusions: Our findings highlight the complex interplay of genetic and clinical factors among the out-of-the-box factors associated with response to medications, i.e., metformin therapy. More studies are warranted given the nature of other unknown factors and in line with personalized medicine principles.