Metformin (GlucophageŽ)? Why has it become so popular?
Metformin was originally developed in 1957 and used worldwide before finally being introduced to the US in 1994. Metformin is approved by the FDA for treatment of type 2 diabetes. Metformin is a biguanide oral antihyperglycemic.
Metformin has many actions, the main being suppression of endogenous glucose production by the liver. Among oral antihyperglycemic medications it is unique, unlike the sulfonlyureas such as DiabineseŽ it does not cause hypoglycemia, weight gain, unfavorable alteration of lipids, nor increase insulin secretion.
Unlike thiazolidinediones such as AvandiaŽ metformin does not cause weight gain, fluid retention, or potential idiosyncratic hepatotoxicity. Instead, metformin improves the effectiveness of insulin while maintaining or even decreasing insulin levels. Metformin decreases both basal and postprandial glucose levels, without the danger of hypoglycemia. Glucophage promotes weight loss and favorable changes in the lipid profile.
Metformin's effects are beneficial to women with type 2 diabetes. Metformin's unique properties have already established it as the initial medication of choice for type 2 diabetes treatment and produced many studies advocating other possible indications:
1. Metformin may decrease the progression from IGT to type 2 diabetes. In a prospective RCT, 3,234 women with IGT were followed for an average of 2.8 years. With placebo treatment, 11% per year progressed to type 2 diabetes. With a weight loss and exercise program, 4.8% per year progressed (a 58% improvement vs. placebo). With Glucophage treatment, 7.8% per year progressed (a 31% improvement vs. placebo). Weight loss and exercise remain the best hedge against developing IGT or type 2 diabetes. The usefulness of Metformin treatment in women simply with PCOS to prevent the development of IGT or type 2 diabetes is unknown.
2. In women with PCOS, three randomized, placebo controlled trials found metformin plus Clomid to be more effective than Clomid alone in ovulation induction. Glucophage may also improve the quality of ovulation induced by recombinant FSH administration. Sustained metformin administration may establish regular menses in women with PCOS.
3. Metformin may decrease the miscarriage risk associated with PCOS. These findings are preliminary, based on two small studies. PCOS is not associated with the most incessant forms of recurrent miscarriage. One small study found metformin may also decrease the incidence of gestational diabetes in PCOS women. The safety of Glucophage's use in pregnancy has not been established.
4. Metformin's effectiveness as a treatment for hirsutism have been mixed.
Metformin is chemically related to phenformin, which was withdrawn from the US market in 1976 because of a high association with lactic acidosis. With normal metformin dosing and normal renal function, development of lactic acidosis is very rare. It is prudent to verify a normal serum creatinine level before starting Metformin and to stop metformin treatment before conditions of relative renal compromise such as the administration of IV iodinated contrast agents and during fluid restriction. Cationic medications, such as cimetidine, compete with metformin for renal clearance thus increasing the risk of lactic acidosis.
Metformin's other contraindications are liver dysfunction, excessive alcohol intake, severe illness. The main side effects of metformin are GI: diarrhea, nausea. These effects can be mitigated by taking Glucophage with food and slowly building up to the target dosage of 1,500 to 2,000 mg total per day.
Metformin Summary:
* PCOS is a syndrome, defined by unexplained hyperandrogenism and associated ovulatory dysfunction. Although not essential to its definition, PCOS will usually be accompanied by polycystic ovaries, and in about half the women, IR .
* IR is suggested clinically by central obesity and acanthosis nigricans. IR is a given with IGT or Type 2 Diabetes. Because of its high prevalence in PCOS, a strong case can be made for all women with PCOS to undergo an OGTT to detect IGT and Type 2 Diabetes. Unfortunately, proven practical means to screen for less advanced forms of IR are not established. Elevated fasting insulin levels and decreased fasting glucose insulin ratios (G/I < 4.5) are consistent with early IR, before beta cell exhaustion. With IGT or Type 2 Diabetes, the best intervention is weight loss and exercise. Metformin is generally the first choice among pharmacologic agents.
* For most women with PCOS trying to conceive, the first medication option to induce ovulation is still Clomid. However, metformin is arguably the first choice in women with IGT and certainly in women with type 2 diabetes. The combination of metformin and Clomid is effective. Weight loss and exercise promote ovulation.
* In women with PCOS not trying to conceive, menstrual irregularity is usually best treated with an estrogen-progestin contraceptive. In some women, it is possible that sustained metformin treatment may induce regular, ovulatory menstruation.
* In women with PCOS not trying to conceive, hirsutism treatment initially usually consists of an estrogen-progestin contraceptive, an anti-androgen such as spironolactone, and mechanical cosmetic treatment.
* Metformin is a very safe medication when used properly and given to healthy women. It is contraindicated in women with renal compromise, liver disease, and at risk for lactic acidosis. GI side effects are initially very common, but usually are not
