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Metformin

Classification: A

Drug products: Competact, Eucreas®, Glucophage, Glucophage SR, Glucophage SR 1000 mg prolonged, Janumet®, Metformin Actavis, Metformin Amneal, Metformin Aurobindo, Metformin Bluefish, Metformin Ebb, Metformin EQL Pharma, Metformin GEA, Metformin Hexal, Metformin Hydrochloride, Metformin Meda, Metformin Mylan, Metformin Orifarm, Metformin Sandoz, Metformin STADA, Metformin Teva, Metformin Vitabalans, Mitforgen, Synjardy

ATC code: A10BA02, A10BD05, A10BD07, A10BD08, A10BD20

Substances: metformin, metforminhydrochloride

Summary

The anti-hyperglycemic effect of metformin in type 2-diabetes mellitus is similar in men and women.
Some studies indicate that women have a higher risk of hypoglycemia during antidiabetic treatment than men.
It has been discussed whether women have a higher risk than men to develop lactacidosis, however the evidence is not conclusive.
 
In our opinion, the described differences do not motivate differentiated dosing or treatment in men and women.

Additional information

Pharmacokinetics and dosing

The bioavailability of fixed-dose combination tablets of pioglitazone and metformin was examined in young healthy subjects (61 men, 63 women). For either pioglitazone or metformin, exposure differences in AUC between men and women did not exceed 20% and there was considerable overlap in AUC values. When AUC was normalized for 70-kg body weight, sex differences in mean AUC values were less than 10% [2]. According to the drug label information, there are no sex differences in metformin pharmacokinetics in normal subjects (19 men, 16 women) and no sex differentiation has been recommended by the manufacturer [3].

Effects

Controlled clinical studies in patients with type 2 diabetes show comparable antihyperglycemic effect of metformin in men and women [3]. A clinical trial (36 men, 42 women) evaluated the sex-related differences in the cardiac metabolic response to diabetes treatment. Patients received metformin alone, metformin plus rosiglitazone, or metformin plus Lovaza/Omacor (Omega-3 fish oil). In metformin treated men, but not in women, whole body fatty acid clearance decreased, which was linked to increased plasma fatty acid levels, myocardial fatty acid utilization and oxidation, and lower myocardial glucose utilization. Myocardial glucose metabolism was unchanged in women [4].

Adverse effects

The ACCORD study (Action to Control Cardiovascular Risk in Diabetes) was a randomized, controlled trial designed to test the effect of intensive glucose control compared with standard control on cardiovascular outcomes in patients with type 2 diabetes. The study showed that women had a higher risk of hypoglycemia than men regardless of treatment [1].

Reproductive health issues

Regarding teratogenic aspects, please consult the Drugs and Birth Defects Database (in Swedish, Janusmed fosterpåverkan).

Other information

Studies report conflicting results whether there is a sex difference in weight loss in metformin treated patients or not. A randomized controlled trial (623 men, 461 women) evaluated the patterns of weight change in patients with type 2 diabetes over a mean follow-up period of 50 months. At six months, women on treatment with metformin lost more weight than men (-0.8 kg vs. -2.1 kg, respectively). This sex difference did not persist to the end of follow-up [5]. Another study (935 men, 1986 women) reported no significant differences between races/ethnicities or men and women in weight loss in response to metformin [6].

In a Chinese study (199 men, 89 women), metformin was found to increase plasma lactic acid levels in type 2 diabetes patients. Women on metformin had higher lactic acid levels than men. Lactic acid concentrations increased with higher estradiol levels but decreased with increased levels of testosterone. The levels of testosterone and estradiol in women were significantly lower than those in men. This sex difference leads to different plasma lactate levels. The authors of this study suggest that lactate concentrations should be monitored frequently in diabetes patients during metformin administration, especially in women with high estrogen levels, to avoid potential lactic acidosis [7].

In an Iranian randomized, clinical trial (38 men, 61 women) of newly diagnosed, medication-naïve type 2 diabetes patients, the effects of metformin on serum concentrations of vaspin and adiponectin were studied. After 3 months of metformin therapy, vaspin dropped significantly only in women. Metformin therapy did not change adiponectin concentrations in neither women nor men. Higher adiponectin concentrations are believed to confer protection against development of type 2 diabetes in healthy subjects. This study showed that metformin exerts little benefit ion adiponectin levels in diabetes patients [8].

A Taiwanese study (18 239 men, 16 099 women) examining the possible metformin effect on cancer, found a benefit of metformin in colorectal cancer in women but not in men [9].

Updated: 2019-02-26

Date of litterature search: 2014-04-24

References

  1. Miller ME, Bonds DE, Gerstein HC, Seaquist ER, Bergenstal RM, Calles-Escandon J et al. The effects of baseline characteristics, glycaemia treatment approach, and glycated haemoglobin concentration on the risk of severe hypoglycaemia: post hoc epidemiological analysis of the ACCORD study. BMJ. 2010;340:b5444. PubMed
  2. Karim A, Slater M, Bradford D, Schwartz L, Zhao Z, Cao C et al. Oral antidiabetic drugs: bioavailability assessment of fixed-dose combination tablets of pioglitazone and metformin Effect of body weight, gender, and race on systemic exposures of each drug. J Clin Pharmacol. 2007;47:37-47. PubMed
  3. Glucophage (metformin). DailyMed [www]. US National Library of Medicine. [updated 2013-04-01, cited 2014-04-24]. länk
  4. Lyons MR, Peterson LR, McGill JB, Herrero P, Coggan AR, Saeed IM et al. Impact of sex on the heart's metabolic and functional responses to diabetic therapies. Am J Physiol Heart Circ Physiol. 2013;305:H1584-91. PubMed
  5. Tuthill A, McKenna MJ, O'Shea D, McKenna TJ. Weight changes in type 2 diabetes and the impact of gender. Diabetes Obes Metab. 2008;10:726-32. PubMed
  6. West DS, Elaine Prewitt T, Bursac Z, Felix HC. Weight loss of black, white, and Hispanic men and women in the Diabetes Prevention Program. Obesity (Silver Spring). 2008;16:1413-20. PubMed
  7. Shen Y, Liu F, Li Q, Tang J, Zheng T, Lu F et al. The gonadal hormone regulates the plasma lactate levels in type 2 diabetes treated with and without metformin. Diabetes Technol Ther. 2012;14:469-74. PubMed
  8. Esteghamati A, Mousavizadeh M, Noshad S, Zandieh A, Zarei H, Nakhjavani M. Gender-dependent effects of metformin on vaspin and adiponectin in type 2 diabetes patients: a randomized clinical trial. Horm Metab Res. 2013;45:319-25. PubMed
  9. Lee MS, Hsu CC, Wahlqvist ML, Tsai HN, Chang YH, Huang YC. Type 2 diabetes increases and metformin reduces total, colorectal, liver and pancreatic cancer incidences in Taiwanese: a representative population prospective cohort study of 800,000 individuals. BMC Cancer. 2011;11:20. PubMed
  10. Läkemedelsstatistik. Stockholm: Socialstyrelsen. 2015 [cited 2016-04-05.] länk

Authors: Linnéa Karlsson Lind, Desirée Loikas

Reviewed by: Mia von Euler, Expertrådet för endokrinologiska och metabola sjukdomar

Approved by: Karin Schenck-Gustafsson