Pharmacogenetics of novel glucose-lowering drugs – published online 16/02/2021

Wolfgang Rathmann, Brenda Bongaerts

Pharmacogenetics is still an emerging field, and there remains a lack of studies on the role of gene variants in treatment responses to novel glucose-lowering drugs (e.g. dipeptidyl peptidase-4 inhibitors [DPP-4i], glucagon-like peptide-1 receptor agonists [GLP-1 RA] and sodium–glucose cotransporter 2 inhibitors [SGLT2i]). In this issue, Rathmann and Bongaerts (https://doi.org/10.1007/s00125-021-05402-w) discuss gene variants related to metabolic responses to these novel agents, including glycaemic effects, diabetes-related metabolic traits and body-weight changes. For  example, some studies have indicated a reduced glycaemic response to DPP-4i in individuals carrying GLP1R variants. On the other hand, greater weight reductions with GLP-1 RA were reported in carriers of certain GLP1R variants. For type 2 diabetes risk genes, the authors highlight that the magnitude of HbA_1c reductions under DPP-4i therapy is dependent on genotype: HbA_1c reductions were larger in those carrying a CDKAL1 variant vs those carrying two copies of the common alleles, whilst it was smaller in individuals carrying a specific TCF7L2 variant (rs7903146 TT genotype). Meanwhile, studies on SGLT2i have focused on genes affecting renal glucose reabsorption (e.g. SLC5A2), but the few pieces of data available indicate no effects. The authors suggest that further identification of type 2 diabetes subtypes will be necessary before pharmacogenetic insights can be used for stratified prescription of novel glucose-lowering drugs.

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