Effects Of GLP1R Gene Polymorphism On The Efficacy And Adverse Reactions Of GLP-1 Receptor Agonists In Chinese Patients With Type 2 Diabetes Mellitus

Background:Glucagon-like peptide-1 receptor agonists(GLR1RAs),also known as glucagon-like peptide-1(GLP-1)analogues,which enhance insulin secretion and inhibit glucagon secretion in a glucose-dependent manner,delay gastric emptiness,and suppress appetite by activating glucagon-like peptide-1 receptor(GLP1R),are novel therapeutic drugs for T2DM patients.GLP1RA is one of the first-line drugs for patients with type 2 diabetes mellitus(T2DM),especially for over-weight or fat patients,because of its significant hypoglycemic effect and low risk of hypoglycemia when used alone,as well as the effects of weight reduction,anti-hypertension and improvement of lipid profile.However,the clinical responses of T2DM patients to GLP1RAs vary among individuals.In terms of efficacy,some patients have poor blood glucose control;in terms of adverse drug reactions(ADRs),some patients have nausea,vomiting,diarrhea,abdominal distension and other gastrointestinal symptoms,both of which will lead to reduced patient compliance and increased medical costs.GLP1R gene polymorphism may be one of the important factors affecting drug efficacy and adverse reactions.However,there are few relevant studies in China,and no correction has been made for confounding factors such as gender,body weight and glycemic base value,which requires further study.Objectives:A prospective cohort study was conducted to explore the relationship between GLP1R rs10305420 and rs3765467 gene polymorphism and the efficacy of GLP1RAs and gastrointestinal ADRs in Chinese T2DM patients,so as to provide a basis for the selection of antidiabetic drugs guided by genes in clinical practice.Methods:The subjects of this study were inpatients diagnosed with T2DM and treated with GLP1RAs at the Department of Endocrinology of Shandong Provincial Qianfoshan Hospital,Shandong Provincial Hospital and Liaocheng People’s Hospital from January 2019 to December 2020.GLP1R rs10305420 and rs3765467 SNPs were genotyped by Sanger dideoxychain termination method using polymerase chain reaction(PCR).Chi-square test was used to verify whether the genotype frequency of these two loci complied with Hardy-Weinberg equilibrium and SHEsis analysis to verify whether complied with linkage disequilibrium.Power Analysis and Sample Size(PASS)software was used to calculate the total sample size.The basic information,lifestyle information,medical history,treatment medication and laboratory test results of the subjects were checked through the hospital information system.All the enrolled subjects were followed up for 12 weeks to see the efficacy and ADRs of GLP1RAs.The association between GLP1R gene polymorphism and GLP1RAs efficacy and ADRs was analyzed by univariate analysis,and confounding factors were corrected by stratified analysis and multiple linear regression analysis.Generalized multifactor dimensionality reduction(GMDR)was used to analyze the single gene polymorphism of GLP1R rs10305420,rs3765467,rs6923761,rs761386 and the correlation between gene-gene interaction and the efficacy of GLP1RAs.Results:A total of 176 patients were enrolled in this study.The genotype frequency of GLP1R rs10305420 and rs3765467 complied with Hardy-Weinberg equilibrium(χ2=3.172,P=0.191;χ2=0.210,P=0.951)but disobeyed linkage disequilibrium(r2=0.035).After 12 weeks of GLP1RAs treatment,GLP1R rs10305420 gene polymorphism had no significant effect on BMI and glucose level(P>0.05).However,GLP1R rs3 765467 GG patients had lower levels of FPG and HbAlc compared to GA/AA patients(FPG:6.9 ± 1.8 mmol/L vs.7.7 ± 1.5 mmol/L,P=0.015;HbA1c:6.9 ±1.0%vs.7.9 ± 1.0%,P<0.001)and a more significant decrease in HbA1c(ΔHbA1c:1.7 ± 2.4%vs.0.8 ± 1.8%,P=0.002).The control rate of HbAlc was also higher in GG patients(Control rate of HbAlc:50.9%vs.23.8%,P=0.002).In the stratified analysis,we performed subgroup analysis based on gender,baseline BMI and baseline HbAlc respectively.Patients with GLP1R rs3765467 mutant type had worse improvement of HbA1c and FPG in the subgroups of baseline BMI≥28 kg/m2(P=0.015),HbA1c<9%(P<0.001)or males(P=0.004),while wild type patients had better benefits after 12 weeks of treatment with GLP1RAs.In multiple linear regression analysis,GLP1R rs3765467 still had significantly association with GLP1RAs efficacy after adjusting for potential confounding factors,such as sex,age,sort of GLP1RAs,baseline,BMI,baseline,FPG,baseline and HbA1c.In terms of adverse reactions,no significant correlation was found between GLP1R rs10305420 and rs3765467 gene polymorphisms and gastrointestinal adverse reactions caused by GLP1RAs(P>0.05).The correlation between the gastrointestinal adverse reactions caused by exenatide and liraglutideband GLP1R rs10305420 and rs3765467 gene polymorphisms was analyzed by stratification,also with no statistically significant results.GMDR results showed rs3765467-rs761386 second-order interaction model ofΔBMI and rs3765467 first-order model of ΔHbA1c was statistically significant.Conclusions:GLP1R rs3765467 polymorphisms are associated with the blood glucose lowering effect in Chinese T2DM patients with GLP1RAs treatment.rs3765467 GG carriers benefit more compared with A allele carriers,especially in the subgroups of baseline BMI≥28 kg/m2，HbA1c<9%or male gender.However,GLP1RAs induced gastrointestinal ADRs were not associated with GLP1R rs10305420 or rs3765467 gene polymorphisms.