Drug products: Competact, Eucreas®, Glucophage, Glucophage SR, Janumet®, Jentadueto, Metformin Actavis, Metformin Aristo, Metformin Aurobindo, Metformin Bluefish, Metformin Ebb, Metformin EQL, Metformin EQL Pharma, Metformin Hexal, Metformin Hydrochloride, Metformin Meda, Metformin Medical Valley, Metformin Mylan, Metformin Orifarm, Metformin Sandoz, Metformin STADA, Metformin Teva, Metformin Vitabalans, Mitforgen, Sitagliptin/Metformin Glenmark, Sitagliptin/Metformin Krka, Sitagliptin/Metformin Medical Valley, Sitagliptin/Metformin Sandoz, Sitagliptin/Metformin Zentiva, Synjardy, Velmetia®, Vildagliptin/Metformin hydrochloride Accord, Vildagliptin/Metformin Krka, Vildagliptin/Metformin STADA, Xigduo
ATC code: A10BA02, A10BD05, A10BD07, A10BD08, A10BD11, A10BD15, A10BD20
Substances: metformin, metforminhydrochloride
Controlled clinical studies in patients with type 2 diabetes showed comparable antihyperglycemic effect of metformin in men and women. One of the studies found that women had a higher risk of hypoglycemia than men regardless of treatment in general. In an observational study, metformin treated men had a greater HbA1c-reduction than women. In contrast, women treated with metformin had a higher reduction of body weight than men.
A potentially higher risk of lactic acidosis in women treated with metformin than men has been suggested, but further evidence is needed.
Studies indicate that men in the early middle age have a higher prevalence of type 2 diabetes mellitus compared with women in the same age group . In Sweden, the age-standardized prevalence of pharmacologically and non-pharmacologically treated diabetes was 56% for men and 39% for women in 2012 .
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% . 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 pharmaceutical company .
In the UK Prospective Diabetes Study (UKPDS) that reported long-term metabolic effects of metformin and reduced cardiovascular risk with use, included both men and women (in total 1704 patients, 342 with metformin), although the results were not presented separately for men and women .
Controlled clinical studies in patients with type 2 diabetes show comparable antihyperglycemic effect of metformin in men and women . 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 .
In an observational German study in patients with diabetes, effects of treatment with lifestyle, metformin or sulfonylurea on glycemic control and body weight were investigated. Data for subgroups of men and women adjusted for age, diabetes duration, baseline HbA1c and observational treatment period were analyzed. Men had higher HbA1c-reductions after treatment with lifestyle and metformin, respectively, than women. In contrast, women had a higher reduction of body weight after lifestyle intervention (2909 men, 2878 women), metformin (1098 men, 1082 women) or sulfonylurea (493 men, 450 women) monotherapies than men. Highest weight reductions were seen in women treated with metformin (women -1.8±0.2 vs. men -1.2±0.2kg; p<0.05) . Similarly, in a RCT evaluating the patterns of weight change in patients with type 2 diabetes (623 men, 461 women), women treated with metformin had lost more weight than men at six months (-0.8 kg vs. -2.1 kg, respectively). However, this sex difference did not persist to the end of follow-up period (50 months) . In contrast, another study (935 men, 1986 women) reported no significant differences between races/ethnicities or men and women in weight loss in response to metformin .
A RCT investigated the effect of metformin for obesity in Spanish prepubertal and pubertal children (72 boys, 68 girls) with BMI z score (age and sex standardized body mass index) reduction as primary outcome. For one of the secondary outcome measures, boys had an increased ALR (adiponectin-leptin ratio) after metformin treatment versus placebo, but girls only showed a trend .
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 in general .
In a nested case-control study (109 120 men, 48 805 women), using Taiwan’s National Health Insurance Research Database from 2001 to 2014, interaction between patient’s sex and use of oral antidiabetic drugs was explored among patients with myocardial infarction in the US Food and Drug Administration Adverse Event Reporting System from 2004 to 2014. Men had a higher risk of metformin- and sulfonylureas-associated myocardial infarction than women (OR men 1.37 vs OR women 1.15) .
Reproductive health issues
Regarding teratogenic aspects, please consult Janusmed Drugs and Birth Defects (in Swedish, Janusmed fosterpåverkan).
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 .
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 on adiponectin levels in diabetes patients .
In a RCT with patients newly diagnosed with diabetes, the effects of metformin (22 men, 19 women) and pioglitazone (19 men, 31 women) on omentin and leptin concentrations were investigated. After three months, metformin decreased both omentin and leptin concentrations in women, and leptin concentrations only in men .
In a study on diabetes type 2 patients treated with either metformin or lifestyle (446 men, 329 women), metformin was associated with higher fasting active and total GLP-1 levels but without any correlation to a patient’s sex .
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 .
In patients (163 men, 105 women) with normal or mildly impaired renal function (glomerular filtration rate of > 60 mL/min/1.73 m2), the impact of continuation of metformin prior to elective coronary angiography on acute contrast nephropathy was examined. The ejection fraction and contrast volume were found to be independent predictors of contrast-induced nephropathy, while patient’s sex was not .
Date of litterature search: 2021-01-26
- Gale EA, Gillespie KM. Diabetes and gender. Diabetologia. 2001;44(1):3-15. PubMed
- Jansson SP, Fall K, Brus O, Magnuson A, Wändell P, Östgren CJ et al. Prevalence and incidence of diabetes mellitus: a nationwide population-based pharmaco-epidemiological study in Sweden. Diabet Med. 2015;32(10):1319-28. PubMed
- 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
- Glucophage (metformin). DailyMed [www]. U.S. National Library of Medicine. [updated 2018-05-31, cited 2021-01-26]. länk
- Effect of intensive blood-glucose control with metformin on complications in overweight patients with type 2 diabetes (UKPDS 34) UK Prospective Diabetes Study (UKPDS) Group. Lancet. 1998;352(9131):854-65. PubMed
- 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
- Schütt M, Zimmermann A, Hood R, Hummel M, Seufert J, Siegel E, Tytko A, Holl RW; DPV initiative; German BMBF Competence Network Diabetes Mellitus. Gender-specific Effects of Treatment with Lifestyle, Metformin or Sulfonylurea on Glycemic Control and Body Weight: A German Multicenter Analysis on 9 108 Patients. Exp Clin Endocrinol Diabetes. 2015;123(10):622-6. länk
- 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
- 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
- Pastor-Villaescusa B, Cañete MD, Caballero-Villarraso J, Hoyos R, Latorre M, Vázquez-Cobela R et al. Metformin for Obesity in Prepubertal and Pubertal Children: A Randomized Controlled Trial. Pediatrics. 2017;140(1). PubMed
- 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
- Wang SH, Chen WJ, Hsu LY, Chien KL, Wu CS. Use of Spontaneous Reporting Systems to Detect Host-Medication Interactions: Sex Differences in Oral Anti-Diabetic Drug-Associated Myocardial Infarction. J Am Heart Assoc. 2018;7(22):e008959. PubMed
- 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
- 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
- Esteghamati A, Noshad S, Rabizadeh S, Ghavami M, Zandieh A, Nakhjavani M. Comparative effects of metformin and pioglitazone on omentin and leptin concentrations in patients with newly diagnosed diabetes: a randomized clinical trial. Regul Pept. 2013;182:1-6. PubMed
- 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
- Oktay V, Calpar Çıralı İ, Sinan ÜY, Yıldız A, Ersanlı MK. Impact of continuation of metformin prior to elective coronary angiography on acute contrast nephropathy in patients with normal or mildly impaired renal functions. Anatol J Cardiol. 2017;18(5):334-339. PubMed
- Statistikdatabas för läkemedel. Stockholm: Socialstyrelsen. 2020 [cited 2021-03-10.] länk
Reviewed by: Carl-Olav Stiller
Approved by: Karin Schenck-Gustafsson