Genetic Variants Associated with Glycemic Response to Treatment with Dipeptidylpeptidase 4 Inhibitors

Űrgeová, Anna; Javorský, Martin; Klimčáková, Lucia; Židzik, Jozef; Salagovic, J; Hubáček, J.; Doubravová, Pavlina; Gotthardová, Ivana; Kvapil, Milan; Pelikánová, Terezie; Tkáč, Ivan; Stančáková, Alena

doi:10.2217/pgs-2019-0147

Cited by 19 publications

(17 citation statements)

References 33 publications

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“…Notably, we detected a drug‐by‐genotype effect whereby treatment with sitagliptin led to more significant glucose‐lowering in GG as compared with GA/AA individuals, suggesting that the metabolic advantage conferred by the variant is less important in the setting of higher endogenous GLP‐1 levels. This has been reported in two prior studies in which DPP‐4 inhibition lowered HbA1c less in GA/AA individuals than in GG individuals 6,7 . Thus, while the present study illustrates a metabolic advantage to this variant, it also shows that GG individuals benefit the most from the glucose‐lowering effects of DPP‐4 inhibition.…”

Section: Discussionsupporting

confidence: 83%

“…The GLP1R variant rs6923761 is a single nucleotide polymorphism with a G‐to‐A nucleic acid substitution 1 . In some studies, the variant was associated with lower baseline weight and triglycerides, 2–5 yet two reports demonstrated decreased responsiveness to DPP‐4 inhibition in individuals with the variant as measured by glycated haemoglobin (HbA1c) 6,7 . In vitro studies provide further conflicting information.…”

Section: Introductionmentioning

confidence: 99%

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Association of a glucagon‐like peptide‐1 receptor gene variant with glucose response to a mixed meal

Mashayekhi

Wilson

Kerman

et al. 2020

Diabetes Obesity Metabolism

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Dipeptidyl peptidase‐4 (DPP‐4) inhibitors increase endogenous glucagon‐like peptide‐1 (GLP‐1). We hypothesized that genetic variation in the gene encoding the GLP‐1 receptor (GLP1R) could affect the metabolic response to DPP‐4 inhibition. To evaluate the relationship between the GLP1R rs6923761 variant (G‐to‐A nucleic acid substitution) and metabolic responses, we performed mixed meal studies in individuals with type 2 diabetes mellitus and hypertension after 7‐day treatment with placebo and the DPP‐4 inhibitor sitagliptin. This analysis is a substudy of NCT02130687. The genotype frequency was 13:12:7 GG:GA:AA among individuals of European ancestry. Postprandial glucose excursion was significantly decreased in individuals carrying the rs6923761 variant (GA or AA) as compared with GG individuals during both placebo (P = 0.001) and sitagliptin treatment (P = 0.045), while intact GLP‐1 levels were similar among the genotype groups. In contrast, sitagliptin lowered postprandial glucose to a greater degree in GG as compared with GA/AA individuals (P = 0.035). The relationship between GLP1R rs6923761 genotype and therapies that modulate GLP‐1 signalling merits study in large populations.

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Section: Discussionsupporting

confidence: 83%

Section: Introductionmentioning

confidence: 99%

Association of a glucagon‐like peptide‐1 receptor gene variant with glucose response to a mixed meal

Mashayekhi

Wilson

Kerman

et al. 2020

Diabetes Obesity Metabolism

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“…Mashayekhi and colleagues also reported that subjects with one or two copies of the wild-type allele had increased postprandial glucose excursion as compared with Ser/Ser subjects while undergoing sitagliptin treatment [ 125 ]. Results of the study have been successfully replicated in a recent research which has proved an association between smaller glycemic responses to 6 month gliptin therapy in diabetic patients with a missense variant rs6923761 in the GLP1R gene [ 126 ].…”

Section: Genes Associated With Dpp4-inhibitors and Glp1 Receptor Amentioning

confidence: 99%

“…Also it was connected with therapeutic response to sulfonylurea treatment [ 146 , 147 ]. The association of the G-allele with smaller reduction in HbA1c level while DPP4I treatment has been demonstrated twice in independent studies [ 126 , 129 ].…”

Section: Genes Associated With Dpp4-inhibitors and Glp1 Receptor Amentioning

confidence: 99%

Pharmacogenetics of Type 2 Diabetes—Progress and Prospects

Nasykhova

Tonyan

Михайлова

et al. 2020

IJMS

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Type 2 diabetes mellitus (T2D) is a chronic metabolic disease resulting from insulin resistance and progressively reduced insulin secretion, which leads to impaired glucose utilization, dyslipidemia and hyperinsulinemia and progressive pancreatic beta cell dysfunction. The incidence of type 2 diabetes mellitus is increasing worldwide and nowadays T2D already became a global epidemic. The well-known interindividual variability of T2D drug actions such as biguanides, sulfonylureas/meglitinides, DPP-4 inhibitors/GLP1R agonists and SGLT-2 inhibitors may be caused, among other things, by genetic factors. Pharmacogenetic findings may aid in identifying new drug targets and obtaining in-depth knowledge of the causes of disease and its physiological processes, thereby, providing an opportunity to elaborate an algorithm for tailor or precision treatment. The aim of this article is to summarize recent progress and discoveries for T2D pharmacogenetics and to discuss the factors which limit the furthering accumulation of genetic variability knowledge in patient response to therapy that will allow improvement the personalized treatment of T2D.

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“…There are a few gene variants correlated to DPP4 inhibitor treatment. Two studies among Caucasian patients have shown that the GLP1R rs6923761 (Gly168Ser) variant is associated with a smaller reduction in HbA1c after gliptin therapy [93,94]. Genetic variation of GLP1R rs3765467 is associated with DPP4 inhibitor efficacy in Korean patients with T2D [95].…”

Section: Other Antidiabetic Agents and Associated Genesmentioning

confidence: 99%

Pharmacogenomic Studies of Current Antidiabetic Agents and Potential New Drug Targets for Precision Medicine of Diabetes

2020

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Diabetes is a major threat to people's health and has become a burden worldwide. Current drugs for diabetes have limitations, such as different drug responses among individuals, failure to achieve glycemic control, and adverse effects. Exploring more effective therapeutic strategies for patients with diabetes is crucial. Currently pharmacogenomics has provided potential for individualized drug therapy based on genetic and genomic information of patients, and has made precision medicine possible. Responses and adverse effects to antidiabetic drugs are significantly associated with gene polymorphisms in patients. Many new targets for diabetes also have been discovered and developed, and even entered clinical trial phases. This review summarizes pharmacogenomic evidence of some current antidiabetic agents applied in clinical settings, and highlights potential drugs with new targets for diabetes, which represent a more effective treatment in the future.

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Genetic Variants Associated with Glycemic Response to Treatment with Dipeptidylpeptidase 4 Inhibitors

Cited by 19 publications

References 33 publications

Association of a glucagon‐like peptide‐1 receptor gene variant with glucose response to a mixed meal

Association of a glucagon‐like peptide‐1 receptor gene variant with glucose response to a mixed meal

Pharmacogenetics of Type 2 Diabetes—Progress and Prospects

Pharmacogenomic Studies of Current Antidiabetic Agents and Potential New Drug Targets for Precision Medicine of Diabetes

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