Metformin

Additional information

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 [1]. In Sweden, the age-standardized prevalence of pharmacologically and non-pharmacologically treated diabetes was 56% for men and 39% for women in 2012 [2].

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% [3]. 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 [4].

Effects

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 [5].

Controlled clinical studies in patients with type 2 diabetes show comparable antihyperglycemic effect of metformin in men and women [4]. 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 [6].

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)  [7]. 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) [8]. 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 [9].

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 [10].

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 in general [11].

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) [12].

Reproductive health issues

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

Other information

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 [13].

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 [14].

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 [15].

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 [16].

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 [17].

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 [18].