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Pharmacogenetics of Glucose-Lowering Drug Treatment

A Systematic Review

  • Endocrine Disorders
  • Published:
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Abstract

Intensive blood glucose lowering can significantly reduce the risk of micro- and macrovascular complications in patients with diabetes mellitus. However, 30% of all treated patients do not achieve optimal blood glucose levels. Genetic factors may influence the response to glucose-lowering medication.

A search of MEDLINE-indexed literature published between January 1966 and July 2007 revealed 37 studies reporting data on genetic polymorphisms and response to glucose-lowering drugs.

Most studies involving cytochrome P450 (CYP) genes had small sample sizes (21 studies <50 subjects) and were among healthy volunteers. Multiple studies indicated that the CYP2C9 *3 allele (Ile359Leu polymorphism) was associated with decreased clearance of sulfonylurea drugs. Supporting this, one study reported an increased insulin secretion in CYP2C9*3 allele carriers when using the sulfonylurea agent glyburide. The CYP2C9*3 allele was also associated with a decreased clearance of meglitinides, whereas the CYP2C8*3 (Arg139Lys; Lys399Arg) variant increased the clearance of meglitinides.

Polymorphisms in genes encoding the inwardly rectifying potassium channel Kir6.2 (KCNJ11) and the insulin receptor substrate-1 (IRS1) were reported to be associated with an increased risk of (secondary) failure to respond to sulfonylurea therapy. A significant decrease in fasting plasma glucose and hemoglobin A1c (HbA1c) in response to rosiglitazone was seen in subjects carrying the Pro12Ala polymorphism of the peroxisome proliferator-activated receptor-γ (PPARG) gene. Conversely, carriers of this polymorphism also had a higher conversion to diabetes mellitus when treated with acarbose; this effect was also seen in adiponectin (ADIPOQ) gene polymorphism carriers.

Future studies with adequate sample sizes in which several SNPs in multiple candidate genes are genotyped in patients with diabetes should provide reliable information on genetic variants and response to glucose-lowering drugs.

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Acknowledgments

This study was supported by an unrestricted grant from Novo Nordisk BV and The Scientific Institute of Dutch Pharmacists (WinAP). Neither had influence over the design, conduct or interpretation of the results of the study.

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  1. Department of Pharmacoepidemiology and Pharmacotherapy, Utrecht Institute of Pharmaceutical Sciences (UIPS), Utrecht University, Sorbonnelaan 16, 3584, CA Utrecht, The Netherlands

    Özlem Bozkurt, Anthonius de Boer, Eibert R. Heerdink &  Olaf H. Klungel

  2. Julius Center for Health Sciences and Primary Care., University Medical Center Utrecht, Utrecht, The Netherlands

    Diederick E. Grobbee & Huib Burger

  3. Department of Epidemiology and department of Psychiatry, University Medical Center Groningen, Groningen, The Netherlands

    Huib Burger

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  1. Özlem Bozkurt
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Bozkurt, Ö., de Boer, A., Grobbee, D.E. et al. Pharmacogenetics of Glucose-Lowering Drug Treatment. Mol Diag Ther 11, 291–302 (2007). https://doi.org/10.1007/BF03256250

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