The form matters – the benefits of metformin with sustained release

Authors: Dana Prídavková;  Udovít Šutarík;  Marián Mokáň
Authors‘ workplace: I. Interná klinika JLF UK a UN Martin
Published in: Forum Diab 2020; 142(3): 177-183


The oral route of administration is the most natural of all treatments. Sustained and controlled drug delivery allows a constant concentration in the circulation, while delayed release prolongs the duration of action without exposing the metabolism to a shock dose that may be associated with side effects. There are several drug modalities, of which the matrix form of the drug provides better patient compliance than immediate release (IR) drugs, eliminates repeated administration and minimizes fluctuations in levels. The use of a hydrophobic carrier in conjunction with a hydrophilic polymer generally effectively controls the initial rapid release of highly water-soluble drugs, including metformin hydrochloride. Metformin (MET) as the first-line antihyperglycemic drug in patients with type 2 diabetes mellitus (DM2T) is used by about 120 million individuals worldwide [1]. Its biological effect depends on several variables such as form, dose size, solubility, etc. Extended release (XR) MET formulas reduce side effects, improve patient compliance, and ultimately lead to better glycemic outcomes.


diabetes mellitus type 2 – metformin hydrochloride – prolonged release

  1. Viollet B, Guigas B, Sanz Garcia N et al. Cellular and molecular mechanisms of metformin: an overview. Clin Sci (Lond) 2012; 122(6): 253–270. Dostupné z DOI: <>.
  2. Bailey CJ, Day C. Traditional plant medicines as treatments for diabetes. Diabetes Care 1989; 12(8): 553–564. Dostupné z DOI: <>.
  3. Curd FH, Davey DG, Rose FL. Studies on synthetic antimalarial drugs. Some biguanide derivatives as new types of antimalarial substances with both therapeutic and causal prophylactic activity. Ann Trop Med Parasitol 1945; 39: 208–216.
  4. Wiernsperger NF, Bailey CJ. The antihyperglycaemic effect of metformin: therapeutic and cellular mechanisms. Drugs 1999; 58(Suppl 1): 31–39. Dostupné z DOI: <–199958001–00009>.
  5. Scarpello JH, Howlett HC. Metformin therapy and clinical uses. Diab Vasc Dis Res 2008; 5(3): 157–167. Dostupné z DOI: <>.
  6. Pasik C. Diabetes and the biguanides: the mystery of each. In: Pasik C (ed) Glucophage: serving diabetology for 40 years. Groupe Lipha: Lyon 1997.
  7. Garcia EY. Flumamine, a new synthetic analgesic and anti-flu drug. J Philippine Med Assoc 1950; 26(7): 287–293.
  8. Kolata GB. The phenformin ban: is the drug an imminent hazard? Science 1979; 203(4385): 1094–1096. Dostupné z DOI: <http://dx.doi.orG/10.1126/science.424735>.
  9. Karen I, Svačina Š, Lžičařová B et al. Bezpečnostní profil XR formy metforminu v porovnání se standardní formou u pacientů s diabetem mellitus 2. typu v ČR. Practicus (Praha) 2013; 12(2): 18–24. Dostupné z WWW: <>.
  10. Bouchoucha M, Uzzan B, Cohen R. Metformin and digestive disorders. Diabetes Metab 2011; 37(2): 90–96. Dostupné z DOI: <>.
  11. Bailey CJ. Metformin: historical overview. Diabetologia 2017; 60(9): 1566–1576. Dostupné z DOI: <–017–4318-z>.
  12. [American Diabetes Association]. 9. Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes—2020. Diabetes Care 2020; 43(Suppl 1): S98-S110. Dostupné z DOI: <>.
  13. Buse JB, Wexler DJ, Tsapas A et al. 2019 update to: Management of hyperglycaemia in type 2 diabetes, 2018. A consensus report by the American Diabetes Association (ADA) and the European Association for the Study of Diabetes (EASD). Diabetologia 2020; 63(2): 221–228. Dostupné z DOI: <–019–05039-w>.
  14. Tsapas A, Avgerinos I. Karagiannis T et al. Comparative Effectiveness of Glucose Lowering Drugs for Type 2 Diabetes a Systematic Review and Network Meta-analysis. Ann Intern Med 2020; 173(4): 278–286. Dostupné z DOI: <–0864>.
  15. Liang H., Ding X., Li L et al. Association of preadmission metformin use and mortality in patients with sepsis and diabetes mellitus: a systematic review and meta-analysis of cohort studies. Crit Care 2019; 23(1): 50. Dostupné z DOI: <https://10.1186/s13054–019–2346–4>.
  16. Bramante C, Ingraham N, Murray T, et al. Observational study of metformin and risk of mortality in patients hospitalized with Covid-19. medRxiv. 2020; 28. Dostupné z DOI: <>.
  17. Kumar Singh A., Singh R. Is metformin ahead in the race as a repurposed host-directed therapy for patients with diabetes and COVID-19? Diabetes Res Clin Pract 2020; 165. Dostupné z DOI: <>.
  18. Chen Y, Yang D, Cheng B et al. Clinical characteristics and outcomes of patients with diabetes and COVID-19 in association with glucose-lowering medication. Diabetes Care 2020; 43(7): 1399–1407. Dostupné z DOI: <–0660>.
  19. Luo P, Qiu L, Liu Y et al. Metformin treatment was associated with decreased mortality in COVID-19 patients with diabetes in a retrospective analysis. Am J Trop Med Hyg 2020; 103(1): 69–72. Dostupné z DOI: <–0375>.
  20. Muniyappa R, Gubbi S. COVID-19 pandemic, coronaviruses, and diabetes mellitus. Am J Physiol Endocrinol Metab 2020; 318(5): E736–E741. Dostupné z DOI: <>.
  21. Cameron AR, Morrison VL, Levin D et al. Anti-inflammatory effects of metformin irrespective of diabetes status. Circ Res 2016; 119(5): 652–665. Dostupné z DOI: <>.
  22. Penlioglou T, Papachristou S, Papanas N. COVID-19 and diabetes mellitus: may old anti-diabetic agents become the new philosopher‘s stone? Diabetes Ther 2020; 11(6): 1–3. Dostupné z DOI: <–020–00830–0>.
  23. Dujic T, Zhou K, Donnelly LA et al. Association of organic cation transporter 1 with intolerance to metformin in type 2 diabetes: a GoDARTS study. Diabetes 2015; 64(5): 1786–1793. Dostupné z DOI: <–1388>.
  24. Wang YW, He SJ, Feng X, et al. Metformin: a review of its potential indications. Drug Des Devel Ther 2017; 11: 2421–2429. Dostupné z DOI: <>.
  25. [American Diabetes Association]. 8. Pharmacologic Approaches to Glycemic Treatment: Standards of Medical Care in Diabetes-2018. Diabetes Care. 2018; 41(Suppl 1): S73-S85. Dostupné z DOI: <>.
  26. Richy FF, Sabidó-Espin M, Guedes S et al. Incidence of Lactic Acidosis in Patients With Type 2 Diabetes With and Without Renal Impairment Treated With Metformin: A Retrospective Cohort Study. Diabetes Care 2014; 37(8): 2291–2295. Dostupné z DOI: <–0464>.
  27. Hsu WH, Hsiao PJ, Lin PC et al. Effect of metformin on kidney function in patients with type 2 diabetes mellitus and moderate chronic kidney disease. Oncotarget 2018; 9(4): 5416–5423. Dostupné z DOI: <>.
  28. Corcoran C, Jacobs TF. Metformin. [Updated 2020 Apr 28]. In: StatPearls [Internet]. StatPearls Publishing: Treasure Island (FL) 2020. Dostupné z WWW: <>.
  29. Zhou K, Donnelly L, Yang J, et al. Heritability of variation in glycaemic response to metformin: a genome-wide complex trait analysis. Lancet Diabetes Endocrinol 2014; 2(6): 481–487. Dostupné z DOI: <–8587(14)70050–6>.
  30. Tkáč I. Farmakogenetické aspekty liečby orálnymi antidiabetikami. Vnitr Lek 2012; 58(7–8): 97–100.
  31. Malki MA, Pearson ER. Drug–drug–gene interactions and adverse drug reactions. Pharmacogenomics J 2020; 20(3): 355–366. Dostupné z DOI: <–019–0122–0>.
  32. Cubeddu LX, Bonisch H, Gothert M et al. Effects of metformin on intestinal 5-hydroxytryptamine (5-HT) release and on 5-HT 3 receptors. Naunyn-Schmiedebergs Arc Pharmacol 2000; 361(1): 85–91. Dostupné z DOI: <>.
  33. Yee SW, Lin L, Merski M et al. Prediction and validation of enzyme and transporter off-targets for metformin. J Pharmacokinet Pharmacodynam 2015; 42(5): 463–475. Dostupné z DOI: <–015–9436-y>.
  34. McCreight LJ, Bailey CJ, Pearson ER. Metformin and the gastrointestinal tract. Diabetologia 2016; 59(3–4): 426–435. Dostupné z DOI: <–015–3844–9>.
  35. Carter D, Howlett HCS, Wiernsperger N et al. Differential effects of metformin on bile salt absorption from the jejunum and ileum. Diab Obes Metabol 2003; 5(2): 120–125. Dostupné z DOI: <–1326.2003.00252.x>.
  36. Scarpello JHB, Hodgson E, Howlett HCS. Effect of metformin on bile salt circulation and intestinal motility in type 2 diabetes mellitus. Diab Med 1998; 158(8): 651–656. Dostupné z DOI: <–9136(199808)15:8<651::AID-DIA628>3.0.CO;2-A>.
  37. Graham GG, Punt J, Arora M et al. Clinical pharmacokinetics of metformin. Clin Pharmacokinet 2011; 50(2): 81–98. Dostupné z DOI: <–000000000–00000<.
  38. Nanjwade BS, Mhase SR, Manvi FV. Formulation of Extended-Release Metformin Hydrochloride Matrix Tablets. Trop J Pharm Res 2011; 10(4): 375–383. Dostupné z DOI: <>.
  39. Gruszka A. New insight into the mechanisms of the anti-hyperglycemic action of metformin. Br J Med Med Res 2015; 13(1): 1–9. Dostupné z DOI: <>.
  40. Bailey CJ, Wilcock C, Scarpello JH. Metformin and the intestine. Diabetologia 2008; 51(8): 1552–1553. Dostupné z DOI: <–008–1053–5>.
  41. Scheen AJ. Clinical pharmacokinetics of metformin. Clin Pharmacokinet 1996; 30(5): 359–371. Dostupné z DOI: <–199630050–00003>.
  42. Terada T, Inui K. Physiological and pharmacokinetic roles of H+/organic cation antiporters (MATE/SLC47A). Biochem Pharmacol 2008; 75(9): 1689–1696. Dostupné z DOI: <>.
  43. Tucker GT, Casey C, Phillips PJ et al. Metformin kinetics in healthy subjects and in patients with diabetes mellitus. Br J Clin Pharmacol 1981; 12(2): 235–246. Dostupné z DOI: <–2125.1981.tb01206.x>.
  44. Vladovičová B, Kormanová V, Vítková M et al. Technológia tabliet s riadeným uvoľňovaním s obsahom veľmi dobre rozpustných liečiv. Čes Slov Farm 2010; 58(4): 179–185.
  45. Jaimini M, Kothari A. Sustained release matrix type drug delivery system: a review. J Drug Deliv Ther 2012; 2(6): 142–148. Dostupné z DOI: <>.
  46. Singh B, Beg S, Khurana RK et al. Recent Advances in Self-Emulsifying Drug Delivery Systems (SEDDS). Crit Rev Ther Drug Carrier Syst 2014; 31(2): 121–185. Dostupné z DOI: <>.
  47. Derosa G, D‘Angelo A, Romano D et al. Effects of metformin extended release compared to immediate release formula on glycemic control and glycemic variability in patients with type 2 diabetes. Drug Des Devel Ther 2017; 11:1481–1488. Dostupné z DOI: <>.
  48. Donnelly LA, Morris AD, Pearson ER. Adherence in patients transferred from immediate release metformin to a sustained release formulation: a population-based study. Diabetes Obes Metab 2009; 11(4): 338–342. Dostupné z DOI: <–1326.2008.00973.x>.
  49. Levy J, Cobas RA, Gomes MB. Assessment of efficacy and tolerability of once-daily extended release metformin in patients with type 2 diabetes mellitus. Diabetol Metab Syndr 2010; 2: 16. Dostupné z DOI: <https://doi: 10.1186/1758–5996–2-16>
  50. Idkaidek N, Arafat T, Melhim M et al. Metformin IR versus XR Pharmacokinetics in Humans. J Bioequiv Availab 2011; 3: 233–235. Dostupné z DOI: <>.
Diabetology Endocrinology Internal medicine
Forgotten password

Don‘t have an account?  Create new account

Forgotten password

Enter the email address that you registered with. We will send you instructions on how to set a new password.


Don‘t have an account?  Create new account