Therapeutic potential of metformin in normal glucose tolerant persons with metabolic syndrome

Abstract

With an increasing prevalence of metabolic syndrome (MS) early detection and timely management of cardiometabolic risk factors are crucial to prevent complications such as type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD). There are no defined treatments for MS apart from addressing each of its components such as insulin resistance, hyperinsulinaemia, obesity, dyslipidaemia, hypertension and hyperglycaemia. The mechanism responsible for diabetes prevention is related to improved insulin sensitivity and reduced hyperinsulinaemia. Metformin has been established as a first-line therapy in patients with T2DM because it counteracts hyperinsulinaemia and hyperglycaemia and reduces cardiometabolic risk. Although the cardiovascular benefits with metformin are clearly demonstrated in diabetic and prediabetic patients, the efficacy of metformin in reducing cardiometabolic risk factors in persons with MS and normal glucose tolerance (NGT) remains inconclusive. This review focuses on the evidence base considering the therapeutic potential of metformin in NGT persons with MS representing a high-risk population for development of T2DM and CVD.

Keywords:

• Metformin
• metabolic syndrome
• normal glucose tolerance
• type 2 diabetes mellitus
• cardiovascular disease

Introduction

Metabolic syndrome (MS) is defined as a constellation of cardiometabolic risk factors, mainly insulin resistance, central (visceral) obesity, dyslipidaemia, raised arterial blood pressure and dysregulated glucose homeostasis that have been associated with an increased risk of type 2 diabetes mellitus (T2DM) and cardiovascular disease (CVD) [1–3]. Patients with T2DM without a previous myocardial infarction (MI) have as high a risk of having a MI as patients with no diabetes and with a previous MI [4]. Patients with T2DM without prior CVD have a similar cardiovascular event rate to patients with no diabetes with previous CVD, showing that T2DM is a coronary heart disease risk equivalent [5].

With an increasing global burden of T2DM and CVD, the prevention of these diseases is becoming a strategic aim of health systems all over the world, the main part of which is treatment of the MS. There is no definitive therapy for MS except reduction of the cardiometabolic risk factors such as visceral obesity, dyslipidaemia, arterial hypertension and hyperglycaemia [2]. The question of the underlying cause of MS is still subject of debate. Some consider that the metabolic antecedent is insulin resistance and others believe that it is obesity. Hyperinsulinaemia due to insulin resistance is considered the earliest stage of development of T2DM and a factor unifying the cardiovascular (CV) cluster of MS. It is regarded as a metabolic antecedent rather than consequence of obesity. In subjects with hyperinsulinaemia, weight gain could be a result of insulin overproduction, and dietary and pharmacologic strategies that reduce hyperinsulinaemia could promote weight loss [6].

Metformin has been established as a first-line therapy in guidelines for treatment of T2DM because it targets insulin resistance and hyperinsulinaemia and fulfills the treatment goals: good glycaemic control and a reduction of cardiometabolic risk [7,8]. It is the only antidiabetic medication that has been shown to improve prognosis of T2DM patients as a primary end-point in a randomised controlled trial [9,10]. Metformin is one of the main therapeutic options in polycystic ovary syndrome (PCOS), whose landmarks are insulin resistance and hyperinsulinaemia defining higher incidence of MS and increased CV risk [11–15]. Studies have shown that metformin can reduce the incidence of T2DM and CVD risk factors in individuals with impaired fasting blood glucose and impaired glucose tolerance [16–21]. Having in mind the role of metformin for diabetes prevention, the American Association of Clinical Endocrinologists has endorsed metformin use for the treatment of high-risk individuals with impaired glucose tolerance and impaired fasting blood glucose [2]. The American Diabetes Association has recommended metformin for prevention of T2DM in persons with prediabetes, especially for those with BMI ≥35 kg/m², those aged <60 years, women with prior gestational diabetes mellitus (GDM), and/or those with rising glycated hemoglobin (HbA_1c) despite lifestyle intervention [22]. Metformin has been shown to reduce the development of T2DM over 15 years. The subjects that benefitted the most are those with higher baseline fasting glucose or HbA_1c and women with a history of GDM [21]. Considering the protective cardiometabolic effects of metformin beyond glycaemic control, research and clinical interest have focused at its effect in persons with normal glucose tolerance (NGT) and MS, who are at a high-risk of T2DM and CVD [6,18,23–33].

This review attempts to summarise the accumulated evidence about the therapeutic potential of metformin in NGT persons with MS representing a high-risk population for development of T2DM and CVD, in order to assist clinicians in making their own decision if metformin could be considered an effective treatment for MS.

Effect of metformin on insulin resistance and hyperinsulinaemia

Insulin resistance and compensatory hyperinsulinaemia have been shown to be associated with an increased risk of developing T2DM and CVD [34–37] since Gerald Reaven proposed the concept of “syndrome X” in 1988. He hypothesised that target tissue resistance to insulin action is a key feature for the development of T2DM and CVD [34]. In the first official definition for the MS of the World Health Organisation [35], insulin resistance is a necessary requirement for diagnosis and should be determined with the “gold standard” hyperinsulinaemic euglycaemic clamp technique or with its surrogate measure HOMA-IR (homeostasis model assessment of insulin resistance) [35]. The best indicator of insulin resistance in non-diabetic individuals is fasting hyperinsulinaemia. It is considered a necessary requirement of the MS defined as insulin resistance syndrome according to the European Group for the Study of Insulin Resistance [36].

Hyperglycaemia in T2DM results from impaired insulin secretion and insulin resistance. Insulin resistance or decreased insulin sensitivity is defined as a subnormal tissue response to normal insulin concentrations. That is why, it may affect various metabolic actions of insulin in different tissues. However, from a clinical perspective, insulin resistance is defined in terms of subnormal glucose response to a particular insulin concentration, i.e. a condition in which the body needs higher levels of insulin to keep blood glucose at a normal level [37,38]. As insulin resistance is considered the leading cause of T2DM in most cases, the resulting compensatory hyperinsulinaemia is seen as the earliest stage for T2DM development [37]. Prevention of T2DM requires treatment targeted at both insulin secretion and insulin resistance. Treatment of insulin resistance is promising as a strategy to prevent the development of T2DM and CVD in high-risk subjects. Thus, agents that ameliorate insulin resistance and reduce hyperinsulinaemia, such as metformin, may provide a therapeutic option of the MS and could prevent T2DM and CVD [2].

Metformin has been shown to reduce hyperinsulinaemia and hyperglycaemia by improving hepatic and peripheral insulin sensitivity. Metformin suppresses hepatic gluconeogenesis and hepatic glucose production and also increases glucose uptake and glucose utilisation in peripheral tissues such as muscle and adipose tissue [10].

In an open-label prospective one-year observational clinical study in persons with MS, NGT and hyperinsulinaemia [33], metformin at a dose of 2.55 ± 0.2 g/daily restored the physiological insulin secretion by decreasing fasting and post-glucose load (PGL) hyperinsulinaemia in the oral glucose tolerance test (OGTT). The effect of metformin on hyperinsulinaemia increased over the time of observation. The decrease in fasting serum insulin and 3-h PGL serum insulin was significant at 6 and 9 months and, at 1 year, it was most pronounced. There was significant effect of metformin on 1-h and 2-h PGL serum insulin at 3, 6 and 9 months, and at 1 year this effect was most expressed. Physiologically, glucose stimulated insulin secretion during OGTT consists of a transient first phase at 30-60 min when it is increased 5–6 fold, followed by a sustained second phase at 60–120 min when it is increased 2–3 fold and a decline afterwards so as to reach the baseline level at 180 min. According to the immunoradiometric assay of serum insulin (Insulin IRMA kit, Immunotech, Beckman Coulter), the values of serum insulin during OGTT in healthy subjects are as follows: 8.8 ± 3.1 mIU/L at 0 min, 44.4 ± 14.1 mIU/L at 60 min, 17.6 ± 7.2 mIU/L at 120 min. At the end of the 1-year study period, the basal insulin secretion and dynamics of insulin release during OGTT were similar to the physiological insulin secretion on fasting and after glucose load [33]. In contrast to these findings, for the same period of 1 year, in upper-body obese impaired glucose tolerant and NGT persons with risk factors for T2DM from the Diabetes Prevention Program (DPP) study, there was no significant effect of metformin at a dose of 850 mg twice daily on fasting and 2-h PGL serum insulin [18]. Atabek and Pirgon [27] performed a double-blind placebo-controlled study to determine whether metformin treatment for 6 months is effective in reducing body weight and hyperinsulinaemia and also in ameliorating insulin sensitivity indices in obese adolescents (age range 9–17 years) with hyperinsulinaemia. They were divided into two groups (metformin group, receiving 500 mg metformin twice daily) and (placebo group, receiving placebo twice daily) plus individually tailored diet, exercise and behavioural therapy. After metformin, there was a significant decline in fasting insulin (from 19.2 ± 10.4 to 11.1 ± 6.1 μmol/mL, p < 0.001) and 2-h PGL insulin levels (from 103.7 ± 73.8 to 49.8 ± 30.9 μmol/mL, p < 0.001) [27]. In obese women with a hyperinsulinaemic PCOS, metformin 500 mg was applied three times daily for 9 months. There was a statistically significant decrease in fasting insulinaemia (22.18 ± 5.76 vs. 17.19 ± 6.67 μmol/mL, p < 0.01), 1-h PGL insulinaemia (179.18 ± 88.96 vs. 136.38 ± 75.43 μmol/mL, p = 0.04) and 2-h PGL insulinaemia (163.23 ± 89.2 vs. 88.46 ± 61.5 μmol/mL, p = 0.04) [11]. A significant decrease in fasting and 2-h PGL insulin levels was observed in obese women with PCOS after 2 years of metformin treatment without caloric restriction [13]. In a prospective, double-blind, randomised, placebo-controlled study in women with insulin resistance and PCOS, there was a significant reduction in serum fasting insulin only with metformin [14]. After metformin treatment in PCOS insulin resistant women, the 2-h PGL insulin levels were significantly reduced (p < 0.001), but not the fasting insulin levels [15].

Metformin: an antihyperglycaemic, but not hypoglycaemic agent

Studies have been confirmed the antihyperglycaemic, but not hypoglycaemic action of metformin. The DPP study reported a significant decrease in fasting plasma glucose (FPG) with no influence on 2-h PGL plasma glucose following 1 year of metformin treatment [18]. Andreadis et al. [28] also found that metformin, when added to the lifestyle recommendation, reduced FPG in overweight people, in persons with obesity, MS and NGT with risk factors for T2DM over a 1-year period [28]. In concordance to these data, Kamenova et al. [33] reported that the effect of metformin on FPG increased over the time of observation. FPG of 5.40 ± 0.53 mmol/L was significantly decreased at 3 months (5.07 ± 0.52 mmol/L; p = 0.029), at 6 months (5.04 ± 0.40 mmol/L; p = 0.002), at 9 months (4.88 ± 0.52 mmol/L; p < 0.001) and at 1 year (4.74 ± 0.50 mmol/L; p < 0.001). Metformin significantly reduced FPG within the normoglycaemic range at 3 months; this effect continued until the end of the observation and, at 1 year, it was most pronounced, without reaching hypoglycaemic values. At 1 year, it was significantly lower compared to that at 6 months (p = 0.036). The 1-hour and 2-hour plasma glucose levels were not changed [33]. The effect of metformin on FPG at 3 months in first-degree relatives of type 2 diabetics with NGT, MS and obesity was reported [25,29]. There was also a significant decrease in the FPG level in patients with MS taking metformin at a dose of 1 g daily for a period of 3 months but not in those on placebo [23]. Metformin treatment at a dose of 1.7 g/daily for a shorter period of 6 weeks did not show a significant effect on FPG [39]. The antihyperglycaemic, but not hypoglycaemic effect of metformin can be a consequence of its insulin sensitising action resulting in a reduction in high insulin and high blood glucose levels only, with no effect on insulin secretion.

Currently, the “gold standard” for evaluation of insulin sensitivity in humans is the hyperinsulinaemic euglycaemic clamp technique. However, this method is not suitable for routine clinical practice because it is expensive and requires special skills and expertise. Therefore, some surrogate measures of insulin sensitivity/insulin resistance are in common use, e.g. fasting glucose and insulin levels in HOMA-IR, Fasting Insulin Resistance Index (FIRI), Glucose/insulin ratio (G/I), and Quantitative insulin sensitivity check index (QUICKI) [40–44].

A valuable alternative to more sophisticated techniques in the evaluation of insulin sensitivity/insulin resistance in vivo is HOMA-IR. With this homeostasis model assessment of insulin resistance, high HOMA values denote low insulin sensitivity (insulin resistance) [40,44]. HOMA-IR was strongly correlated with insulin sensitivity, as assessed by the glucose clamp technique in both non-diabetic and diabetic subjects (r=-0.83, p < 0.01, and r=-0.92, p < 0.0001, respectively) [40]. There was significant correlation (r=-0.82, p < 0.0001)) between HOMA-IR and total glucose disposal rate in the glucose clamp technique, with no substantial differences between men and women, younger and older subjects, non-obese and obese subjects, non-diabetic and diabetic subjects and normotensive and hypertensive subjects [44]. In a one-year prospective clinical study, the effect of metformin on HOMA-IR, as well as on hyperinsulinaemia, increased over the time of observation. The decrease in HOMA-IR was significant at 6 and 9 months, and at 1 year, it was most pronounced, declining from a value of 5.74 to 2.58 (p < 0.001), indicating reduced insulin resistance [33]. Metformin reduced the insulin resistance compared with placebo (HOMA-IR from 3.39 to 2.5 vs.3.42 to 3.37, p = 0.01) in persons with MS after 3 months at a dose of 1 g daily [3]. At the same dose of metformin applied for 6 months, HOMA-IR decreased from 4.95 ± 3.34 to 2.6 ± 1.6 (p < 0.001) in obese adolescents [27]. Metformin treatment at a dose of 1.7 g daily for a period of 6 weeks did not have a significant effect on HOMA-IR [39]. In patients with heart failure and insulin resistance, as defined by FIRI ≥ 2.7, metformin 2 g/daily reduced insulin resistance (from 5.8 ± 3.8 to 4.0 ± 2.5, p < 0.001) for a period of 3 months [31]. In women with PCOS, there was a significant correlation of insulin sensitivity index from the frequently sampled intravenous glucose tolerance test with fasting G/I (r = 0.73, p < 0.0001) and 2-h G/I (r = 0.74, p < 0.001). As a screening test for insulin resistance in women with PCOS, a cut-off value of the fasting G/I of less than 4.5 was set [42]. Metformin improved insulin sensitivity in subjects with NGT, hyperinsulinaemia and MS expressed by increasing fasting G/I, 1-h, 2-h and 3-h PGL G/I. Fasting G/I increased from 5.33 to 7.86 at 9 months (p = 0.003) and to 8.71 at 1 year (p < 0.001). The 2-h G/I of 2.44 reached the values of 3.93 at 6 months (p = 0.01), 5.32 at 9 months (p < 0.001) and 4.73 at 1 year (p < 0.001), showing improved insulin action after glucose stimulus [33].

QUICKI is a novel, simple, accurate and reproducible method for determining insulin sensitivity in humans that may be a useful tool in investigations that study the role of insulin resistance in the pathophysiology of socially important problems such as obesity, CVD and T2DM. QUICKI calculated using the average data from two fasting blood samples obtained at −10 and 0 min of the glucose clamp study showed that glucose-clamp–derived estimates of insulin sensitivity (Si _clamp) were highly correlated for non-obese, obese and diabetic subjects (r = 0.78). When the correlations between QUICKI and Si _clamp were calculated for each group separately, the correlation coefficient was r = 0.49 for non-obese subjects (p < 0.01), r = 0.89 for obese subjects (p < 2 × 10 ⁻⁵), and r = 0.70 for diabetic subjects (p < 4 × 10⁻³) [43]. QUICKI increased significantly at 3, 6, 9 months and at 1 year of metformin treatment from 0.30 to 0.34 (p < 0.001), suggestive of increased insulin sensitivity [33]. Similarly to these data, metformin at a dose of 1 g daily increased QUICKI from 0.31 ± 0.02 to 0.34 ± 0.03 (p < 0.001) for six months in obese hyperinsulinaemic adolescents, having in mind that metformin was added to an individual diet and physical activity [27]. An overview of some studies showing reduction of insulin resistance and hyperinsulinaemia associated with metformin treatment is presented in Table 1. Studies in different populations from different regions of the world have demonstrated that metformin can improve the insulin action, independently of the duration of the study and the dose of metformin used.

Table 1. Overview of studies showing reduction of insulin resistance and hyperinsulinaemia by metformin treatment.

Location	Population	Duration	Treatment	Concluding remarks
Europe Bulgaria [33]	Persons with MS, NGT, hyperinsulinaemia	1 year	Metformin 2.55 g/d	Decrease fasting insulin, 1-h, 2-h, 3-h PGL insulin, HOMA-IR Increase fasting G/I, 1-h, 2-h, 3-h G/I, QUICKI
Europe Turkey [27]	Obese adolescents 9-17 years old hyperinsulinaemic	6 months	Metformin 1 g/d vs. placebo with LSM	Decrease fasting and 2-h PGL insulin, HOMA-IR Increase QUICKI
Europe N.Macedonia [11]	Obese PCOS Hyperinsulinaemic women	9 months	Metformin 1.5 g/d	Decrease fasting insulin, 1-h and 2-h PGL insulin
Europe Italy [23]	Persons with MS	3 months	Metformin 1 g/d vs. placebo	Decrease HOMA-IR
Europe UK [31]	Persons with heart failure and IR	4 months	Metformin 2 g/d	Decrease FIRI
America Argentina [14]	PCOS women with IR	4 months	Metformin 1.5 g/d vs. placebo with LSM	Decrease fasting insulin and HOMA-IR
Asia India [15]	PCOS women with IR	6 months	Metformin 2 g/d	Decrease 2-h PGL insulin

MS, metabolic syndrome; NGT, normal glucose tolerance; PGL, post glucose load; HOMA-IR, homeostasis model assessment of insulin resistance; G/I, glucose/insulin ratio; QUICKI, quantitative insulin sensitivity check index; LSM, lifestyle modification; PCOS, polycystic ovary syndrome; FIRI, fasting insulin resistance index; IR, insulin resistance.

Effect of metformin on obesity and visceral obesity

The International Diabetes Federation introduced central obesity measured with waist circumference as a prerequisite for MS to be diagnosed [45]. Indeed, the main complaint of persons with MS is the increase in body weight. Some report gain of a lot of weight within a short period of time (up to 1 year), whereas others, a gradual increase in body weight over a longer period. People usually think that their weight does not correspond to the food intake and physical activity. Even in individuals with genetic predisposition to T2DM, some environmental factors like diet and physical activity could influence the development of T2DM. Consequently, the change in lifestyle aimed at a reduction in body weight is the first and most important step for diabetes prevention [2,16,17]. However, lifestyle changes, such as hypocaloric diet and increased physical activity, in persons with MS often have an unsatisfactory or temporary effect on body weight. In these cases, the addition of medical treatment to the lifestyle modification is a helpful alternative [6,26]. The DPP/DPP Outcomes Study showed that the effect of metformin on body weight reduction was kept constant over time, which could explain some of the diabetes prevention effects of metformin [16,17,19,21]. In the DPP, the 1.7 kg weight reduction with metformin vs. 0.3 kg weight increase with placebo alone explained 64% of its beneficial effect on diabetes risk [46,47]. Metformin significantly improved other parameters of adiposity (body mass index, waist circumference and waist-hip ratio) as well, and fasting insulin and proinsulin compared with placebo [46,47]. Adjustment for weight, fasting insulin, proinsulin and other metabolic factors combined explained 81% of the beneficial effect of metformin on the risk of diabetes [46,47]. Improvements in FPG and estimated insulin sensitivity with metformin may be attributed to a combination of weight loss and other direct effects on the liver and, perhaps other tissues [47].

At least 6 months were needed for the expression of a significant effect of metformin on body weight, body mass index (BMI) and waist circumference in a prospective one year observational clinical study [32]. BMI (32.3 ± 5.2 kg/m²) was significantly reduced at 6 months (29.9 ± 4.8 kg/m²; p = 0.012), at 9 months (29.0 ± 4.8 kg/m²; p = 0.001) and at 1 year (28.4 ± 5.0 kg/m²; p < 0.001). The reduction in body weight, BMI and waist circumference continued to the end of the observation and it was not more pronounced compared to the 6^th month [32]. A significant decrease in BMI was observed at 6 months of metformin treatment from 28.5 ± 3.4 to 26.7 ± 4.0 kg/m² (p < 0.001) in obese hyperinsulinaemic adolescents, when metformin was given in combination with an individual diet and physical activity [27]. No significant change in BMI was observed in obese women with PCOS after two years of metformin treatment [13]. Metformin treatment for a period of 36.1 months without controlled diet resulted in a reduction in BMI (-1.09 ± 3.41 kg/m², p = 0.0117) especially in women with PCOS and MS at the beginning of treatment compared with those without MS (p = 0.0369) [12]. Lifestyle modification and 1500 mg of metformin or placebo for 4 months in insulin resistant women with PCOS resulted in similar weight improvements [14]. A significant reduction in waist circumference was only observed with metformin [14]. In a similar population of insulin resistant PCOS women, after six months of metformin treatment, there was a significant reduction in BMI (p = 0.047), but not in waist-hip ratio [15]. The waist circumference (102.8 ± 14.3 cm) was significantly reduced at 6 months (95.3 ± 12.2 cm, p = 0.004), at 9 months (92.6 ± 12.7 cm, p < 0.001) and at 1 year (90.9 ± 12.5 cm, p < 0.001) of metformin treatment in NGT persons with MS [32]. There was no significant difference in the volume of visceral fat and the indices of fat distribution measured by computed tomography scan between subjects who received placebo or metformin applied for a shorter period of 3 months [24].

Following metformin treatment, the mean body weight reduction at 6 months of 7.7 kg and at 1 year of 12.1 kg was greater than that described in DPP by both lifestyle intervention and metformin [32]. The average weight loss at 6 months was 2.1 and 5.6 kg in metformin and lifestyle intervention group and made the lifestyle intervention superior compared to metformin [16]. However, the intensive diet and 150 min physical exercise per week led to a mean body weight reduction of 6.8 kg in the first year [16]. Metformin in combination with carbohydrate-modified hypocaloric diet resulted in a body weight loss of 7.5 kg at 6 months and 10.7 kg at 1 year in non-diabetic women with hyperinsulinaemia [6]. The possible explanations for the difference in the anthropometric outcomes in various studies can be attributed to the differences in the baseline characteristics of the patients (age, ethnicity, type of the disease), duration of the treatment and the dose of metformin, and the treatment approach (metformin alone or in combibnation with lifestyle modification).

A relationship between insulin reduction and body weight loss was described [6]. The body weight reduction was more pronounced, the higher the initial body weight, BMI, waist circumference, fasting and 2-h PGL serum insulin and HOMA-IR were. The maximal weight loss at 3 months was 12 kg and at 6 months 20 kg in a 30-year-old man with an initial body weight of 117 kg [32]. The highest reduction in body weight at 1 year of metformin treatment was by 22 kilograms in a man with an initial body weight of 121 kg and by 21 kilograms in an 18-year-old woman with an initial body weight of 140 kg [32]. The effect of metformin therapy was most pronounced in individuals aged under 60 years and in those with higher values of BMI [16,48]. Even after 10 years of metformin treatment, the reduction in body weight was maintained and the incidence of diabetes was reduced by 18% in comparison to the placebo group [17]. These studies show that metformin is effective in reducing body weight. Lifestyle modification is effective in doing the same. It is logical to combine lifestyle modification with metformin, which would limit the duration of treatment and would improve the patient’s self-motivation.

Effect of metformin on dyslipidaemia and blood pressure

Long-term studies in PCOS women show favourable effects of metformin on serum lipids and blood pressure. For example, after a mean follow-up of 36.1 months with metformin treatment, there were improvements in high-density lipoprotein (HDL) cholesterol (+5.82 ± 11.02 mg/dL, p < 0.0001) and diastolic blood pressure (-2.69 ± 10.35 mmHg) [12]. The prevalence of MS decreased from 34.3% to 24.1% (p = 0.0495), having in mind the improvement in BMI as well [12]. There was a decrease in total cholesterol and an increase in HDL cholesterol after two years of metformin treatment [13]. The effect of metformin on total cholesterol was significant at 6 months (5.78 ± 0.76 vs. 5.11 ± 1.04 mmol/L, p < 0.009), on low-density lipoprotein (LDL) cholesterol and triglycerides at 9 months (3.61 ± 0.76 vs. 2.77 ± 0.68 mmol/L, p = 0.007 and 2.60 ± 1.74 vs. 1.55 ± 0.69 mmol/L, p = 0.004, respectively), and on HDL cholesterol at 1 year (1.10 ± 0.34 vs. 1.44 ± 0.28 mmol/L, p < 0.001). Systolic and diastolic blood pressure were significantly decreased at 9 months of metformin treatment (131 ± 18 vs. 121 ± 15 mmHg, p = 0.008 and 85 ± 11 vs. 78 ± 8 mmHg, p < 0.001, respectively) in NGT persons with MS [32]. Metformin significantly reduced total cholesterol, LDL cholesterol, Cholesterol:HDL cholesterol ratio and systolic blood pressure and significantly increased HDL cholesterol in double-blind randomised-controlled studies in women with PCOS and first-line relatives of type 2 diabetics with NGT and MS for a shorter period of 3 months [24,25,29]. Metformin treatment for a 1-year period significantly reduced systolic blood pressure, total and LDL cholesterol with no effect on body weight, HDL cholesterol and triglycerides in persons with normal and impaired glucose tolerance and impaired fasting blood glucose in a BIGPRO1 Trial [18]. In the Carmos study [28], metformin reduced the incidence of T2DM in overweight and obese non-diabetic adults, while also decreasing the rate of MS by improving the CVD risk factors. After 1 year of follow-up, the prevalence of T2DM in the metformin group was 1.1% and 8.1% in the non-metformin group (p = 0.012). The incidence of MS was decreased from 38.9% to 21.1% in the metformin group and from 36.2% to 32.8% in the non-metformin group (p = 0.035). The statistically significant decrease in the prevalence of MS in the metformin group was not correlated with waist circumference, triglyceride or blood pressure levels. The percentages of persons with low HDL cholesterol levels were decreased by 5.6% in the metformin group and by 3.0% in the non-metformin group (p = 0.046). HDL cholesterol was increased by 3.1 mg/dL from baseline in the metformin group vs. 1 mg/dL in the non-metformin group (p = 0.001) [28].

A 10-year analysis of effectiveness of three therapeutic regimens (metformin, lifestyle change and placebo) in the programme of diabetes prevention showed a significant reduction in systolic blood pressure, diastolic blood pressure, LDL cholesterol and triglycerides and a significant increase in HDL cholesterol in all treatment groups similarly [19]. There were fewer medications for dyslipidaemia and hypertension in the group with intensive lifestyle change [19]. At the beginning of an open-label one year prospective observational clinical study with application of metformin at a mean dose of 2.55 g/daily, 22 out of 52 persons with MS took antihypertensive drugs. At 1 year of metformin treatment, 12 persons had reduced the number of antihypertensive drugs and 8 had stopped them. At the end of the study, all 5 persons who were taking drugs for dyslipidaemia had discontinued their use [32]. These studies show that metformin is a valuable therapeutic alternative for MS because it does more than just tackle insulin resistance and obesity. Metformin counteracts other cardiovascular risk factors of MS such as dyslipidaemia and arterial hypertension.

Conclusions

Persons who have MS are at high risk of development of T2DM and CVD, which makes the treatment of cardiometabolic risk factors mandatory. Usually it requires taking a lot of medicaments. Studies show that treatment with metformin alone, without intensive diet and physical activity or added to lifestyle modification in NGT people with MS could reduce cardiometabolic risk factors such as visceral obesity, hyperinsulinaemia, insulin resistance, dyslipidaemia and arterial hypertension. They support the hypothesis that metformin could be applied for prevention of T2DM and CVD. This review hopes to provide clinicians with an overview of accumulated evidence to help them decide whether metformin could be considered effective in the treatment of MS. Future prospective population-based studies and randomised clinical trials especially concerning the dose of metformin and duration of treatment are needed.

Disclosure statement

No potential conflict of interest was reported by the author.