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The role of clinical response to metformin in patients newly diagnosed with type 2 diabetes: a monotherapy study

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Abstract

A major predicament in certain users of metformin, which is one of the most commonly used antihyperglycemic agents for type 2 diabetes (T2DM) treatment, is the lack of appropriate response to the drug. We evaluated the role of metformin response and OCT1 (organic cation transporter1) Met420del polymorphism in a monotherapy study (metformin therapy for 12 weeks) on patients newly diagnosed with T2DM. Based on the response to metformin, patients (n = 108) were divided into two groups: responders (n = 49) and non-responders (n = 59). HbA1c levels were determined by affinity technique. The OCT1-Met420del polymorphism was genotyped by PCR-based restriction fragment length polymorphism. There was a significant association between the variable response with HbA1c and fasting blood sugar (FBS) (Wilks’ λ = 0.905, p = 0.01). Responders had significantly lower HbA1c and FBS levels compared with non-responders (η 2 = 0.087, p = 0.004 for HbA1c and η 2 = 0.055, p = 0.022 for FBS). The interaction treatment–response increased the effect sizes from 32 to 58 % for HbA1c. Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) values were significantly lower in the responder group than in the non-responders (η 2 = 0.067, p = 0.01 for ALT and η 2 = 0.052, p = 0.025 for AST). This observational study showed that the variant OCT1-Met420del may be more effective on plasma glucose than HbA1c. The variable response could account for a significant proportion of the variance in HbA1c levels observed following treatment with metformin. Metformin shows a significantly greater effect on ALT and AST in responders than in non-responders.

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References

  1. Rizos CV, Elisaf MS (2013) Metformin and cancer. Eur J Pharmacol 705:96–108

    Article  CAS  PubMed  Google Scholar 

  2. Salpeter SR, Buckley NS, Kahn JA, Salpeter EE (2008) Meta analysis: metformin treatment in persons at risk for diabetes mellitus. Am J Med 121:149–157

    Article  CAS  PubMed  Google Scholar 

  3. Zinman B, Harris SB, Neuman J, Gerstein HC, Retnakaran RR, Raboud J et al (2010) Low-dose combination therapy with rosiglitazone and metformin to prevent type 2 diabetes mellitus (CANOE trial): a double-blind randomised controlled study. Lancet 376:103–111

    Article  CAS  PubMed  Google Scholar 

  4. Esteghamati A, Eskandari D, Mirmiranpour H, Noshad S, Mousavizadeh M, Hedayati M et al (2013) Effects of metformin on markers of oxidative stress and antioxidant reserve in patients with newly diagnosed type 2 diabetes: a randomized clinical trial. Clin Nutr 32:179–185

    Article  CAS  PubMed  Google Scholar 

  5. Gao Y, Yoon KH, Chuang L-M, Mohan V, Ning G, Shah S et al (2009) Efficacy and safety of exenatide in patients of Asian descent with type 2 diabetes inadequately controlled with metformin or metformin and a sulphonylurea. Diabetes Res Clin Pract 83:69–76

    Article  CAS  PubMed  Google Scholar 

  6. Burcelin R, Serino M, Chabo C, Blasco-Baque V, Amar J (2011) Gut microbiota and diabetes: from pathogenesis to therapeutic perspective. Acta Diabetol 48:257–273

    Article  PubMed  PubMed Central  Google Scholar 

  7. Chan JC, Deerochanawong C, Shera AS, Yoon K-H, Adam JM, Binh TV et al (2007) Role of metformin in the initiation of pharmacotherapy for type 2 diabetes: an Asian-Pacific perspective. Diabetes Res Clin Pract 75:255–266

    Article  CAS  PubMed  Google Scholar 

  8. Aljada A, Mousa SA (2012) Metformin and neoplasia: implications and indications. Pharmacol Ther 133:108–115

    Article  CAS  PubMed  Google Scholar 

  9. Ota S, Horigome K, Ishii T, Nakai M, Hayashi K, Kawamura T et al (2009) Metformin suppresses glucose-6-phosphatase expression by a complex I inhibition and AMPK activation-independent mechanism. Biochem Biophys Res Commun 388:311–316

    Article  CAS  PubMed  Google Scholar 

  10. Viollet B, Guigas B, Garcia NS, Leclerc J, Foretz M, Andreelli F (2012) Cellular and molecular mechanisms of metformin: an overview. Clin Sci 122:253–270

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Takane H, Shikata E, Otsubo K, Higuchi S, Ieiri I (2008) Polymorphism in human organic cation transporters and metformin action. Pharmacogenomics 9:415–422

    Article  CAS  PubMed  Google Scholar 

  12. Kerb R (2006) Implications of genetic polymorphisms in drug transporters for pharmacotherapy. Cancer Lett 234:4–33

    Article  CAS  PubMed  Google Scholar 

  13. DiStefano JK, Watanabe RM (2010) Pharmacogenetics of anti-diabetes drugs. Pharmaceuticals 3:2610–2646

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Holstein A, Seeringer A, Kovacs P (2011) Therapy with oral antidiabetic drugs: applied pharmacogenetics. Br J Diabetes Vasc Dis 11:10–16

    Article  CAS  Google Scholar 

  15. Shu Y, Sheardown SA, Brown C, Owen RP, Zhang S, Castro RA et al (2007) Effect of genetic variation in the organic cation transporter 1 (OCT1) on metformin action. J Clin Invest 117:1422–1431

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Nies AT, Koepsell H, Winter S, Burk O, Klein K, Kerb R et al (2009) Expression of organic cation transporters OCT1 (SLC22A1) and OCT3 (SLC22A3) is affected by genetic factors and cholestasis in human liver. Hepatology 50:1227–1240

    Article  CAS  PubMed  Google Scholar 

  17. Marchesini G, Brizi M, Bianchi G, Tomassetti S, Zoli M, Melchionda N (2001) Metformin in non-alcoholic steatohepatitis. Lancet 358:893–894

    Article  CAS  PubMed  Google Scholar 

  18. Schwimmer JB, Middleton MS, Deutsch R, Lavine JE (2005) A phase 2 clinical trial of metformin as a treatment for non-diabetic paediatric non-alcoholic steatohepatitis. Aliment Pharmacol Ther 21:871–879

    Article  CAS  PubMed  Google Scholar 

  19. Tiikkainen M, Hakkinen A-M, Korsheninnikova E, Nyman T, Makimattila S, Yki-Jarvinen H (2004) Effects of rosiglitazone and metformin on liver fat content, hepatic insulin resistance, insulin clearance, and gene expression in adipose tissue in patients with type 2 diabetes. Diabetes 53:2169–2176

    Article  CAS  PubMed  Google Scholar 

  20. Belcher G, Schernthaner G (2005) Changes in liver tests during 1-year treatment of patients with Type 2 diabetes with pioglitazone, metformin or gliclazide. Diabet Med 22:973–979

    Article  CAS  PubMed  Google Scholar 

  21. Bennet PH (1999) Impact of the new WHO classification and diagnostic criteria. Diabetes Obes Metab 1(Suppl 2):S1–S6

    Article  Google Scholar 

  22. Friedwald WT, Levy RI, Fredrickson DS (1972) Estimation of the concentration of low-density lipoprotein cholesterol in plasma, without use of the preparative ultracentrifuge. Clin Chem 18:499–502

    Google Scholar 

  23. Hoff-Olsena P, Mevag B, Staalstrøma E, Hovdea B, Egeland T, Olaisen B (1999) Extraction of DNA from decomposed human tissue: an evaluation of five extraction methods for short tandem repeat typing. Forensic Sci Int 105:171–183

    Article  Google Scholar 

  24. Pacanowski MA, Hopley CW, Aquilante CL (2008) Interindividual variability in oral antidiabetic drug disposition and response: the role of drug transporter polymorphisms. Expert Opin Drug Metab Toxicol 4:529–544

    Article  CAS  PubMed  Google Scholar 

  25. Zolk O (2012) Disposition of metformin: variability due to polymorphisms of organic cation transporters. Ann Med 44:119–129

    Article  CAS  PubMed  Google Scholar 

  26. Zhou K, Donnelly LA, Kimber CH, Donnan PT, Doney AS, Leese G et al (2009) Reduced-function SLC22A1 polymorphisms encoding organic cation transporter 1 and glycemic response to metformin: A GoDARTS study. Diabetes 58:1434–1439

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  27. Shikata E, Yamamoto R, Takane H, Shigemasa C, Ikeda T, Otsubo K et al (2007) Human organic cation transporter (OCT1 and OCT2) gene polymorphisms and therapeutic effects of metformin. J Hum Genet 52:117–122

    Article  CAS  PubMed  Google Scholar 

  28. Sherifali D, Nerenberg K, Pullenayegum E, Cheng JE, Gerstein HC (2010) The effect of oral antidiabetic agents on A1C levels. Diabetes Care 33:1859–1864

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Becker ML, Visser LE, van Schaik RH, Hofman A, Uitterlinden AG, Stricker BH (2009) Genetic variation in the organic cation transporter 1 is associated with metformin response in patients with diabetes mellitus. Pharmacogenomics J 9:242–247

    Article  CAS  PubMed  Google Scholar 

  30. Sissung TM, Troutman SM, Campbell TJ, Pressler HM, Sung H, Bates SE et al (2012) Transporter pharmacogenetics: transporter polymorphisms affect normal physiology, diseases, and pharmacotherapy. Discov Med 13:19–34

    PubMed  PubMed Central  Google Scholar 

  31. Orchard T, Temprosa M, Goldberg R, Haffner S, Ratner R, Marcovina S et al (2005) The effect of metformin and intensive lifestyle intervention on the metabolic syndrome: the diabetes prevention program randomized trial. Ann Intern Med 142:611–619

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  32. Sattar N, McConnachie A, Ford I, Gaw A, Cleland SJ, Forouhi NG et al (2007) Serial metabolic measurements and conversion to type 2 diabetes in the west of Scotland coronary prevention study. Diabetes 56:984–991

    Article  CAS  PubMed  Google Scholar 

  33. Matthews DR, Charbonnel BH, Hanefeld M, Brunetti P, Schernthaner G (2005) Long-term therapy with addition of pioglitazone to metformin compared with the addition of gliclazide to metformin in patients with type 2 diabetes: a randomized, comparative study. Diabetes Metab Res Rev 21:167–174

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

This research was funded with the support of Mazandaran University of Medical Sciences, Sari, Iran. The authors thank Dr. Ozra Akha and Dr. Saeed Abedian Kenari for contributions.

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The authors have not declared any conflict of interest.

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Correspondence to Abdolkarim Mahrooz.

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Mahrooz, A., Parsanasab, H., Hashemi-Soteh, M.B. et al. The role of clinical response to metformin in patients newly diagnosed with type 2 diabetes: a monotherapy study. Clin Exp Med 15, 159–165 (2015). https://doi.org/10.1007/s10238-014-0283-8

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  • DOI: https://doi.org/10.1007/s10238-014-0283-8

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