Analysis Of Clinical Outcome Of Liraglutide And Correlation Between Liraglutide Treatment Phenotype And GLP-1R, DPP-4 Gene Polymorphism In Overweight Type 2 Diabetes Patients

ObjectiveLiraglutide has the effects of reducing blood sugar,weight loss,cardiovascular protection and so on,but it has obvious individual differences in clinical treatment.Some patients have poor therapeutic effect and(or)obvious gastrointestinal adverse reaction(GIAR).Studies have shown that there is a correlation between glucagon-like peptide-1 receptor(GLP-1R),Dipeptidyl peptidase-4(DPP-4)single nucleotide polymorphism(SNP)and liraglutide related hypoglycemic and weight loss.This article aims to analyze the related factors that lead to liraglutide-related weight loss and GIAR,and further explore the relationship between DPP-4,GLP-1R gene polymorphisms and liraglutide treatment phenotype.Methods376 patients with overweight type 2 diabetes were included from June2017 to October 2019 undergoing liraglutide therapy Department of Endocrinology and Metabolism,the Second Affiliated Hospital of Chongqing Medical University.We Collect basic clinical data and follow up for 3 months to record the body weight and GIAR.152 patients with different weight loss and GIAR were selected to extract peripheral blood DNA.A total of 14 GLP-1R,DPP-4 SNP were searched in the database.PCR amplification and sequencing results were used to analyze the relationship between GLP-1R and DPP-4 gene polymorphisms and liraglutide treatment phenotype.Results(一)Clinical outcome(1)After 3 months of liraglutide treatment,the patient’s weight,BMI,and waist circumference(WC)decreased(P <0.01).55.1% of patients achieved effective weight loss(weight loss ≥ 5%),44.9% of patients weight loss <5%,and 49 people had no change in body weight.Logistic regression found that age(P <0.05,OR = 0.974)and basal WC(P <0.05,OR = 1.029)were independent factors influencing liraglutide-related effective weight loss.(2)The incidence of adverse reactions of liraglutide was 29.52%.The most common GIAR are nausea(42.3%),then appetite(38.7%),diarrhea(27.0%),and vomiting(14.4%).Except nausea symptoms,the remaining GIAR are mainly grade 1.Multivariate logistic regression found that sexwas an independent factor for liraglutide-related GIAR,and that GIAR in men were significantly lower than those in women(P <0.05 OR = 0.377).(二)Genetic polymorphism analysis(1)The frequency of GLP-1R rs3765467 A allele in GIAR group and non-response group of overweight type 2 diabetes patients was 28.6% VS15%(P <0.05).The ratio of GLP-1R rs2254336 T alleles was 59.5% vs45.5% in GIAR group and the non-response group(P <0.05).The frequency of DPP-4 rs12617336 C allele in the weight loss effective group and ineffective group was 4.2% VS 13.2%(P <0.05).Trend test results show that with the increase of rs12617336 C alleles,overweight type 2diabetes patients are less likely to obtain effective weight loss(P <0.05).With the rs2254336 T allele and rs3765467 A allele increased,patients with overweight type 2 diabetes using liraglutide were more likely to have GIAR(P <0.05).(2)Logistic regression results show that the contributions of DPP-4rs12617336、GLP-1R rs2254336、GLP-1R rs3765467 to the disease are consistent with the additive model and the dominant model.It is not easy for overweight type 2 diabetic patients with CC genotype at DPP-4rs12617336(additive model,P <0.05,OR = 0.277)and GC + CC genotype(dominant model,P <0.05,OR = 0.273)to get effective weight loss with liraglutide.Liraglutide related GIAR is more likely to occur in overweight type 2 diabetic patients with TT genotype at GLP-1R rs2254336(additivemodel,P <0.05,OR = 2.096)and AA + AT genotype(dominant model P<0.05,OR = 4.439),and AA genotype at GLP-1R rs3765467(additive model P <0.05,OR = 2.259)and GA + AA genotype(dominant model P<0.05,OR = 2.317).(3)After 3 months of liraglutide treatment,the weight loss of GG genotype at DPP-4 rs12617336 was significantly higher than(5.606 ±4.399)GC genotype(2.870 ± 2.67)and CC genotype(2)patients(P <0.05).(4)Gene interactionIn the gene-gene interaction analysis,there was no interaction between the three sites of DPP-4 rs12617336 、 GLP-1R rs2254336 and GLP-1R rs3765467 on liraglutide-related weight loss and GIAR(P≥0.05).conclusionsThe individual differences in weight loss and GIAR of liraglutide in the treatment of patients with overweight type 2 diabetes are not only related to the clinical characteristics of patients,but also related to the polymorphisms of DPP-4 and GLP-1R.