Low metformin dose and its therapeutic serum concentration in prediabetes

Edyta Sutkowska, Paulina Fortuna, Jerzy Wisniewski, Karolina Sutkowska, Pawel Hodurek, Andrzej Gamian, Bernadetta Kaluza, Edyta Sutkowska, Paulina Fortuna, Jerzy Wisniewski, Karolina Sutkowska, Pawel Hodurek, Andrzej Gamian, Bernadetta Kaluza

Abstract

This prospective study aimed to analyze whether the patients with pre-diabetes (pre-DM) reach the TC (therapeutic concentration) of the metformin during repeated, low, constant drug dose. The guidelines do not recommend any metformin dose for this group of patients. Based on the previous study after a dose of 1700 mg/day the patients seem to reach the therapeutic drug concentration, which guarantees the glycemic effect. Twenty patients with new-diagnosed pre-DM were treated with a 1500 mg/day regimen of the metformin for 15 weeks. The serum concentration of the drug was assessed by liquid chromatography-mass spectrometry technique at 6 and 15 week of the treatment. The correlation of the serum metformin concentration with BMI (body mass index) and patients' weight was also performed. The mean metformin concentration was: 4.65 μmol/L (± 2.41) and 5.41 μmol/L (± 3.44) (p = 0.27) after 6 and 15 weeks of the treatment respectively. There was a positive correlation between the serum concentration of the metformin and body weight (but not BMI) in the 15th week of the therapy (p = 0.04)- the higher body weight the higher concentration of the metformin. Patients with pre-diabetes can be successfully treated with a low dose of metformin, to reach the drug's therapeutic concentration. Body weight can impact the metformin serum concentration during long-term treatment what should be taken into consideration when choosing the dose because of its pleiotropic effect e.g. on the cardiovascular system via reduction of the oxidative stress and would be not connected with the drug's hypoglycemic effect.ClinicalTrials.gov number: NCT03398356; date of first registration: 01/07/2018.

Conflict of interest statement

The authors declare no competing interests.

Figures

Figure 1
Figure 1
The flow chart of the management of the patients.
Figure 2
Figure 2
Correlation between metformin concentration after 6 weeks of the treatment with BMI.
Figure 3
Figure 3
Correlation between metformin concentration after 6 weeks of the treatment with body weight.
Figure 4
Figure 4
Correlation between metformin concentration after 15 weeks of the treatment with BMI.
Figure 5
Figure 5
Correlation between metformin concentration after 15 weeks of the treatment with body weight.

References

    1. description of lifestyle intervention Diabetes Prevention Program (DPP) Research Group. The Diabetes Prevention Program (DPP) Diabetes Care. 2002;2:2165–2171. doi: 10.2337/diacare.25.12.2165.
    1. the Diabetes Prevention Program Outcomes Study Diabetes Prevention Program (DPP) Research Group. Long-term effects of lifestyle intervention or metformin on diabetes development and microvascular complications over 15-year follow-up. Lancet Diabetes Endocrinol. 2015;3:866–875. doi: 10.1016/S2213-8587(15)00291-0.
    1. Diabetes Prevention Program (DPP) Research Group. Long-term Effects of Metformin on Diabetes Prevention: Identification of Subgroups That Benefited Most in the Diabetes Prevention Program and Diabetes Prevention Program Outcomes Study. Diabetes Care42, 601–608. 10.2337/dc18-1970 (2019).
    1. an intent-to-treat analysis of the DPP/DPPOS Diabetes Prevention Program (DPP) Research Group. The 10-year cost-effectiveness of lifestyle intervention or metformin for diabetes prevention. Diabetes Care. 2012;35:723–730. doi: 10.2337/dc11-1468.
    1. Goldberg R, et al. Lifestyle and metformin treatment favorably influence lipoprotein subfraction distribution in the Diabetes Prevention Program. J. Clin. Endocrinol. Metab. 2013;98:3989–3998. doi: 10.1210/jc.2013-1452.
    1. Goldberg R, et al. Diabetes Prevention Program Research Group. Lifestyle and metformin interventions have a durable effect to lower CRP and tPA levels in the Diabetes Prevention Program except in those who develop diabetes. Diabetes Care. 2014;37:2253–2260. doi: 10.2337/dc13-2471.
    1. the Diabetes Prevention Program randomized trial Orchard, T. et al. Diabetes Prevention Program (DPP) Research Group. The effect of metformin and intensive lifestyle intervention on the metabolic syndrome. Ann. Intern. Med. 2005;142:611–619. doi: 10.7326/0003-4819-142-8-200504190-00009.
    1. Goldberg R, et al. Diabetes Prevention Program (DPP) Research Group. Effect of long-term metformin and lifestyle in the Diabetes Prevention Program and its outcome study on coronary artery calcium. Circulation. 2017;136:52–64. doi: 10.1161/CIRCULATIONAHA.116.025483.
    1. UK Prospective Diabetes Study (UKPDS) Group. Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34). Lancet.352, 854–865 (1998).
    1. Hong J, et al. SPREAD-DIMCAD Investigators. Effects of metformin versus glipizide on cardiovascular outcomes in patients with type 2 diabetes and coronary artery disease. Diabetes Care. 2013;36:1304–1311. doi: 10.2337/dc12-0719.
    1. Kooy A, et al. Long-term effects of metformin on metabolism and microvascular and macrovascular disease in patients with type 2 diabetes mellitus. Arch. Intern. Med. 2009;169:616–625. doi: 10.1001/archinternmed.2009.20.
    1. Metformin 500 mg. Available from: . Accessed 17 Feb 2020.
    1. Frid A, et al. Novel assay of metformin levels in patients with type 2 diabetes and varying levels of renal function. Diabetes Care. 2010;33:1291–1293. doi: 10.2337/dc09-1284.
    1. Kajbaf F, De Broe M, Lalau J. Therapeutic concentrations of metformin: a systematic review. Clin. Pharmacokinet. 2016;55:439–459. doi: 10.1007/s40262-015-0323-x.
    1. Graham G, et al. Clinical Pharmacokinetics of metformin. Clin. Pharmacokinet. 2011;50:81–98. doi: 10.2165/11534750-000000000-00000.
    1. Lalau J, et al. Role of metformin accumulation in metformin-associated lactic acidosis. Diabetes Care. 1995;18:779–784. doi: 10.2337/diacare.18.6.779.
    1. Lalau J, Lacroix C. Measurement of metformin concentration in erythrocytes: clinical implications. Diabetes Obes Metab. 2003;5:93–99. doi: 10.1046/j.1463-1326.2003.00241.x.
    1. The Task Force for diabetes, pre-diabetes, and cardiovascular diseases of the European Society of Cardiology (ESC) and the European Association for the Study of Diabetes (EASD). 2019 ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD. Eur. Heart. J.41, 255–323. 10.1093/eurheartj/ehz486 (2020).
    1. World Health Organization. Definition of an older or elderly person. . Accessed 17 Feb 2020.
    1. Metformin and metformin-containing medicines. EMA. . Accessed 17 Feb 2020.
    1. 2017 Guidelines on the management of diabetic patients. A position of Diabetes Poland. Clin. Diabetol.6(Suppl. A), 1 (2017).
    1. Azar J, Bassil M, Irani J, Badawi K, Sawan C, et al. Factors determining blood and urine concentrations of metformin among patients with type 2 diabetes: A Cross Sectional Study. J Biomed. Sci. 2018;4:14–19. doi: 10.4172/2254-609X.100093.
    1. Wiśniewski J, et al. A novel mass spectrometry-based method for simultaneous determination of asymmetric and symmetric dimethylarginine, l-arginine and l-citrulline optimized for LC-MS-TOF and LC-MS/MS. Biomed. Chromatogr. 2017;31(11):e3994. doi: 10.1002/bmc.3994.
    1. Knowler W, et al. Diabetes Prevention Program Research Group. Diabetes Prevention Program Research Group. Reduction in the incidence of type 2 diabetes with lifestyle intervention or metformin. N. Engl. J. Med. 2002;346:393–403. doi: 10.1056/NEJMoa012512.
    1. Stage T, et al. A twin study of the trough plasma steady-state concentration of metformin. Pharmacogenet. Genom. 2015;25:259–262. doi: 10.1097/FPC.0000000000000133.
    1. Christensen M, et al. The pharmacogenetics of metformin and its impact on plasma metformin steady-state levels and glycosylated hemoglobin A1c. Pharmacogenet. Genomics. 2011;21:837–850. doi: 10.1097/FPC.0b013e32834c0010.
    1. Duong J, et al. Population pharmacokinetics of metformin in healthy subjects and patients with type 2 diabetes mellitus: simulation of doses according to renal function. Clin. Pharmacokinet. 2013;52:373–384. doi: 10.1007/s40262-013-0046-9.
    1. Bardin C, et al. Population pharmacokinetics of metformin in obese and non-obese patients with type 2 diabetes mellitus. Eur. J. Clin. Pharmacol. 2012;68:961–968. doi: 10.1007/s00228-011-1207-0.
    1. Ghobadi C, et al. Application of a system approach to the bottom-up assessment of pharmacokinetics in obese patients: expected variations in clearance. Clin. Pharmacokinet. 2011;50:809–822. doi: 10.2165/11594420-000000000-00000.
    1. Ningrum V, Ikawati Z, Sadewa A, Ikhsan M. Patient-factors associated with metformin steady-state levels in type 2 diabetes mellitus with therapeutic dosage. J. Clin. Transl. Endocrinol. 2018;12:42–47. doi: 10.1016/j.jcte.2018.05.001.
    1. Chen M, et al. Pharmacokinetic analysis of bioequivalence trials: implications for sex-related issues in clinical pharmacology and biopharmaceutics. Clin. Pharmacol. Ther. 2000;68:510–521. doi: 10.1067/mcp.2000.111184.
    1. Freire A, Basit A, Choudhary R, Piong C, Merchant H. Does sex matter? The influence of gender on gastrointestinal physiology and drug delivery. Int. J. Pham. 2011;415:15–28. doi: 10.1016/j.ijpharm.2011.04.069.
    1. Soldin O, Mattison D. Sex differences in pharmacokinetics and pharmacodynamics. Clin. Pharmacokinet. 2009;48:143–157. doi: 10.2165/00003088-200948030-00001.

Source: PubMed

Спонсоры и соавторы

Заболевания

Медикаментозные вмешательства

Подписаться