The renaissance of metformin in endocrine clinical practice

Introduction

The aim of this article is to present the viewpoint of the Polish Society for Endocrinology in light of international guidelines recommending an extended use of metformin in the clinic of gynaecological endocrinology (the consensus statements of the British and American Societies for Gynaecology of 2004), and in impaired glucose tolerance and Type 2 diabetes mellitus (the consensus statements of the European Association for the Study on Diabetes and the American Diabetes Association of 2006) [1-5]. The guideline material is very extensive and it is available on the Internet web sites given in the References. For this reasons I present here its most important premises [1-5].

Diabetes Type 2 therapy in adults aims at achieving HbA₁C < 6.5%. HbA₁C equal to or >7% points to the necessity of altering the therapy, hypoglycaemia should be avoided, and the norm for diabetic patients is HbA₁C < 6.1%.

First stage of therapy

This starts with simultaneous modification of the lifestyle and metformin administration. It is recommended not to wait for the results of lifestyle modification alone for the following reasons:

1. The majority of patients fail to comply with the dietary and physical activity recommendations after 1 year.

2. Obesity and the pre-diabetic period is accompanied by hyperinsulinemia and decreased susceptibility to insulin; at this stage, the patients develop significant complications (more than half of the patients with Type 2 diabetes develop cardiovascular complications); for these reasons, metformin therapy should be instituted at an earlier stage than that recommended so far.

Early institution of metformin is recommended in all the patients regardless of their body mass. This drug is recommended because of its:

1. Hypoglycaemic effect, a decrease in HbA₁C by 1.5–2%.

2. Decrease in body mass.

3. Lack of hypoglycaemia (hypoglycaemia exerts a negative effect on the symptoms of myocardial ischemia).

4. Proven positive effect on cardiovascular complications and death reduction.

5. Good tolerance.

6. High therapy compliance rate.

7. Low treatment costs.

Onset of therapy:

1. Initial dose: 500 mg, one or two times daily with a meal (breakfast and/or dinner).

2. After 5–7 days, if the gastrointestinal symptoms are absent, the initial dose is increased to 2×850 mg or 2×1000 mg.

3. If adverse effects occur, a periodic decrease in dose followed by a gradual increase of the daily dose to the maximally tolerated level is recommended.

4. Maximum dose is 3 g/day.

5. The dose should be increased to the highest level for 1–2 months and lifestyle modification should be constantly emphasised.

6. The prolonged-release drug form may be administered 1 × daily, which is often associated with a reduction of the adverse effects.

Second stage of therapy

1. If after 1–2 months, the maximum dose of metformin and lifestyle modification prove ineffective, insulin, glitazone or sulfonurea derivatives should be added.

2. The level of HbA₁C is an indicator of which therapeutic modality should be chosen (insulin has a more potent action than sulfonurea derivatives, which are more potent than glitazone).

Third stage of therapy

1. If the level of HbA₁C is below 8%, the addition of a third oral anti-diabetic drug should be considered, although it is potentially less favourable and more expensive.

2. Concomitant administration of glitazone (TZD) and insulin is not currently approved in the European Union countries.

3. However, the addition of TZD to metformin is recommended in view of an additional potential HbA₁C decrease by 0.3–0.8%, favourable effect of both therapies on insulin sensitivity, and the effect on various target tissues.

Selection criteria of an anti-hyperglycaemic drug with regard to increased hypoglycaemic efficacy established on the basis of HbA₁C reduction also prefer metformin.

1. Metformin and SM derivates decrease HbA₁C by 1.5%.

2. TZD (thiasolidinedione) decrease HbA₁C by 0.5–1.4%.

3. Alpha-glycosidase inhibitors (Glucobay) decrease HbA₁C by 0.5–0.8%.

4. Glinidine decreases HbA₁C by 1–1.5%.

5. Insulin decreases HbA₁C by 1.5–2.5%.

6. Lifestyle modification decreases HbA1C by 1–2%.

In the opinion of Polish Diabetes Association [6], which was also confirmed by the Polish Society for Endocrinology, the announced consensus algorithm arouses numerous controversies, as it does not consider many situations, e.g. the division of patients according to body mass (obese, normal weight or overweight), acarbose in therapy, and situations of deprivation of the B-cell pool in the islets of Langerhans already at the time of diabetes diagnosis. Moreover, it is dominated by the ‘American’ point of view, accepting a target level of HbA₁c below 7%.

Metformin in the prevention of diabetes

It should be stressed that the statement concerning the use of metformin in diabetes prevention was published in 2007. It was based on the DPP studies [7], which demonstrated the effectiveness of metformin in diabetes prevention compared with that of lifestyle modification in young and obese subjects.

Nathan et al. [8] presented the ADA consensus statement in which they recommend metformin in the preventive management of abnormal fasting glycaemia, disturbances in glucose tolerance and significant cardiovascular risk. This important statement answers a number of questions on the preventive use of metformin. Now we can expect registration for the indications of this drug in diabetes prevention.

In gynaecological endocrinology, the most common clinical conditions in which metformin administration should be considered in view of disturbed glucose tolerance and Type 2 diabetes are polycystic ovarian syndrome (PCOS) and the climacteric period [9].

Metformin and PCOS

It should be emphasised that in Poland as well as in other countries metformin has not been registered for diabetes prevention despite positive studies recommending this application. Thus a patient to whom such a therapy is administered should be informed about possible adverse reactions and written consent for the therapy should be obtained.

In PCOS, about 31% of obese patients develop disturbances in glucose tolerance and 16% of them suffer from Type 2 diabetes. At the same time, 10.3% of non-obese patients with PCOS reveal glucose intolerance and 1.5% of them reveal Type 2 diabetes. Hyperinsulinemia and insulin resistance of tissues, which are acknowledged as a significant etiopathogenic factor for this disease, may be conditioned by various factors [10].

The official British and American standpoints on the use of metformin in PCOS were published in 2004. The former recommends the administration of metformin in combination with clomiphene in women with PCOS and body mass index above 25.0 kg/m², who failed to ovulate after clomiphene therapy alone [11]. The American Gynaecological Society, in contrast, recommends metformin as an initial therapy in overweight or obese women with a diagnosis of PCOS [12]. Both statements point to a significant improvement in the menstruation cycles, which are accompanied by increased ovulation and increased number of pregnancies, which were reported on the basis of a mega-analysis in the Cochrane Library. In PCOS women, the number of miscarriages is generally known to be high, and one of the contributory factors is believed to be associated with a decreased expression of glycodelin due to hyperinsulinemia and its effect on endometrial function. Glycodelin is secreted by the endothelium and inhibits its immunological response to the embryo, affecting its implantation. The administration of metformin was shown to elevate the blood serum glycodelin level [13-15].

In view of the above data, when contra-indications have been excluded, we recommend the administration of metformin as a ‘gold standard’ to overweight or obese women with PCOS, together with lifestyle modification, i.e. implementation of a low-calorie and low-fat diet and increased physical activity. The recommended dose is 1500 mg/day, which can be increased maximally to 2000 mg/day. Moreover, it should be remembered that metformin is often associated with adverse reactions, especially if it is used incorrectly. For this reason, to minimise the adverse effects, the therapy should start from an initial dose of 500 mg daily with a meal for 10–14 days, and then increased by 500 mg every 10–14 days until the therapeutic dose of 1500 mg/day is reached. This dose should be maintained for 3 months. If the therapy proves effective, it should be continued; otherwise, the dose should be increased by a further 500 mg and the patient should be observed for 3 months [9],[10],[16].

In PCOS women who wish to become pregnant and the 3-month therapy with metformin alone proved ineffective, clomiphene should be instituted additionally according to the generally accepted scheme. The use of metformin during pregnancy is still an open question. Pregnant women with well-managed diabetes have babies with inborn defects significantly less often than those with unbalanced diabetes. The studies by Khattab et al. [15] in 2006 demonstrated that metformin therapy at a dose of 1000/2000 mg/day in 200 pregnant women with PCOS resulted in a significant reduction in the miscarriage rate and the administration of metformin throughout the whole pregnancy did not reveal any teratogenic effect. The findings of a meta-analysis published by Gilbert et al. [17] on the effect of metformin therapy on significant foetal defects are spectacular. The authors reported a 1.7% incidence of inborn defects in the study group of treated patients, whereas the untreated control group demonstrated a significantly higher incidence of inborn defects i.e. 7.2%. The findings prove the protective effect of the drug.

Introduction of the recommendation for the use of metformin in pregnancy is encouraging for patients with PCOS who often develop habitual abortion of hormonal etiology [16-18].

Ibanez et al.[19] demonstrated that 3-year administration of metformin at a dose of 850 mg/day to girls with low birth weights and early maturation negatively affecting their final growth slowed maturation and increased the final growth. The girls on metformin therapy also revealed decreased levels of insulin, leptin and IGF-1 and increased levels of sex hormone – binding globuline (SHBG) and IGF-1BP. Similar clinical trials involved girls with PCOS. The therapy was limited to a few months and only single trials were randomised and blind. The findings were ambiguous, from enthusiastic to extremely cautious. Bridger et al. [20] found in a carefully designed clinical trial that metformin administered to girls with PCOS decreased the level of testosterone, elevated high density lipoproteins (HDL) levels and did not have any effect on insulin resistance and body mass. The therapy merely ‘increased the probability’ of menses.

From everyday practice, we know that young women with PCOS are generally not interested in conception, but mostly care about improved appearance (due to the symptoms of hyperandrogenism and obesity) and restoration of regular menses. For this reason, when a woman with PCOS is seen in our office, we should evaluate the EBM risk factors for cardiovascular disease, i.e. waist circumference >80 cm, BP >130/80 mm HG, fasting blood sugar level >100 mg/dL, triglycerides level >500 mg/dL and HDL cholesterol <500 mg/dL, as well as smoking habit to instituting metformin as the first choice of therapy.

Metformin and the climacteric period

Another clinical situation in women, which requires precise recommendations as to the use of metformin, is the menopause. Women in the climacteric period gradually develop hyperinsulinemia and insulin resistance, which are caused by the decreased number of insulin receptors with ageing, and also by the redistribution of the adipose tissue. The visceral fat deposits (responsible for all the negative metabolic disturbances and the risk of cardiovascular disease) increase at the expense of gynoidal fat deposits in the region of the buttocks and thighs and the waist circumference of the majority of women consequently increases to over 80 cm. Sex hormones play a significant role in the re-distribution of fat by competitive binding of glycocorticoid and androgenic receptors in the visceral adipose tissue, which reveals their increased expression compared with tissue from other regions. The result is that 13% of post-menopausal women develop Type 2 diabetes mellitus and 35% have an impaired glucose tolerance [16],[19]. American results of studies on Type 2 diabetes prevention in 3243 subjects with impaired glucose tolerance revealed an extraordinary effect of metformin versus placebo and versus intensive lifestyle modification. Moreover, a significant reduction of visceral deposits of adipose tissue was reported [21].

The therapeutic management of obese post-menopausal women should be similar to the algorithm proposed for PCOS, and the therapeutic dose should correspond to the severity of impaired glucose tolerance and risk factors for cardiovascular disease [22]. In the case of obese women with disturbed lipid metabolism and/or hypertension in whom the 3-month metformin therapy was ineffective, the use of statins or fibrates should be considered in relation to the type of lipid changes as well as enzyme-converting inhibitors in case of hypertension [16].

When discussing the indications for the use of metformin, we should bear in mind the contra-indications, the major one being the lack of indications for its use, the others including:

• metformin hypersensitivity

• renal insufficiency

• liver impairment

• alcohol abuse

• circulatory insufficiency

• acute myocardial infarction

• respiratory insufficiency

• severe infection

• the use of intravenous contrast media

• perisurgical period

• lactic acidosis and ketoacidosis

• extensive burns

• dehydration and diabetic coma

When administering metformin we should remember adverse reactions, which include:

• gastrointestinal disturbances (diarrhoea, nausea, flatulence, stomach ache)

• anorexia

• unpleasant or metallic taste in the mouth

• metabolic acidosis

• decrease in blood vitamin B12 levels

• megaloblastic anaemia

• rash

• very uncommon hypoglycaemia.

Because of the impaired intestinal adsorption of vitamin B₁₂ and folic acid, their supplementation should be administered during prolonged metformin therapy. The prevalence of adverse reactions may be minimised by a gradual increase of the dose by 500 mg/day every 7 days and the use of the drug form with prolonged release, i.e. Glucophage MX.

We must remember, however, that in every case of metformin therapy a modification in lifestyle should also be introduced. It is known that compliance with the physician's advice is low and amounts to 20%. As far as physical activity is concerned, we recommend intensive daily walking for 30 minutes, dosed by the patient so that the pulse does not exceed 40–50% of the maximum pulse. At the same time, it should be remembered that physical exercise may pre-dispose to injuries, especially in patients with neuropathy. When advising patients on a diet according to American recommendations, it should be remembered that the fat content should not exceed 7% of its total caloric content. The loss of 4 kg in weight indicates a reduction of hyperglycaemia.

Finally, I hope that the above remarks will enable us to extend the recommendations for the use of metformin, which is an inexpensive, safe and effective drug, which you may find very useful in your everyday medical practice.

Questions

1. Why is metformin recommended?

Metformin is recommended for many reasons: because of hypoglycaemic effect, a decrease in HbA₁C by 1.5–2%, decrease in body mass, lack of hypoglycaemia, proven positive effect on cardiovascular complications and death reduction, good tolerance, high therapy compliance rate and low treatment costs.

1. What are the effects of metformin in PCOS?

Metformin improves the menstruation cycles, which are accompanied by increased ovulation and increased number of pregnancies, which were reported on the basis of a mega-analysis in the Cochrane Library. In PCOS women, the number of miscarriages is generally known to be high, and one of the contributory factors is believed to be associated with a decreased expression of glycodelin due to hyperinsulinemia and its effect on endometrial function. Glycodelin is secreted by the endothelium and inhibits its immunological response to the embryo, affecting its implantation. The administration of metformin was shown to elevate the blood serum glycodelin level.

1. What are the contra-indications for metformin therapy?

Contra-indications for metformin use are as follows: metformin hypersensitivity, renal insufficiency, liver impairment, alcohol abuse, circulatory insufficiency, acute myocardial infarction, respiratory insufficiency, severe infection, the use of intra-venous contrast media, perisurgical period, lactic acidosis and ketoacidosis, extensive burns and dehydration and diabetic coma.