Diabetes mellitus is a metabolic problem caused by a defect in insulin secretion, in its action or in both. In type 2 diabetes mellitus the defect in the action generally predominates (insulin resistance) in obese patients, and the secretory defect in those of normal weight or slim. Diabetes mellitus 2 associated with obesity is most common in our area. In recent years the choice of drugs for the treatment of diabetes mellitus 2 is a pertinent and current issue, which has acquired great relevance due to several factors: the increase in pharmacological options that have appeared and the pressure of the pharmaceutical industry of these new drugs. Among the options available for glycemic control in diabetes mellitus 2, metformin is the only one which, up to now, has been shown to reduce the risk of morbility and total mortality in the first long-term clinical trial (10.7 years), with primary results, the UK Prospective Diabetes Study (UKPDS). Metformin has been on the Spanish market for more than 40 years, but its use has not been as high and is still not as high as it should be. On the other hand, its low cost means it is not commercially promoted.
The UKPDS1,2 shows that in obese patients with diabetes mellitus 2, the choice of metformin as a first line drug due to the failure of treatment by diet, provides more benefits than risks, when it is compared with conventional treatment, as well as intensive treatment with other drugs (sulphonylureas or insulin). It not only reduces the risk of microvascular complications but also macrovascular ones and mortality. This study is the first proof which demonstrates the reduction in the risk of cardiovascular disease in the pharmacological treatment of patients with diabetes mellitus 2. The number of patients which is required to treat during 10 years to prevent one event more than makes up for the problems found. The patients included are newly diagnosed obese patients with type 2 diabetes mellitus, not controlled by diet treatment, with characteristics similar to those who attend our clinics. Although the study is carried out in the hospital environment, similar results can be obtained in primary care, since it does not require superhuman efforts: the patients are seen every month for the first 3 months and then every 3 months, or more often if control objectives need to be obtained.
Fasting glucose is used in each visit to adjust the treatment and glycosylated haemoglobin A1 each year to evaluate the level of control. Self testing of glucose is only used in those patients to whom insulin has to be added to achieve the required control.
The systematic review and meta-analysis published in this issue, after an exhaustive review of the literature, updates the subject, adding new studies which point in the same direction as regards the benefits gained. Thus, it confirms that metformin is a first choice drug in patients with diabetes and overweight or obese. It also adds studies where they compare with other drugs for secondary results, the new drugs not surpassing metformin as regards these results, although they may not yet have had time to show more beneficial results as regards primary results or safety profile.
Likewise it confirms that published in a recent systematic review of the virtually zero risk of lactic acidosis.3,4 The fear of lactic acidosis has always been taken into account when taking decisions. We actually do not know the real incidence of lactic acidosis, fatal or non-fatal, associated with the use of metformin in patients with type 2 diabetes mellitus. In population studies rates of 2 to 9 cases of lactic acidosis per 100 000/year have been reported among patients treated with metformin, most of them occurring in patients with serious acute problems, such as renal failure, which in itself can cause lactic acidosis.
The risk attributable to metformin is answered if we know that 9 cases per 100 000/persons/year have been reported in patients with type 2 diabetes not treated with metformin. The results of this systematic review confirm that previously reported in descriptive studies: no cases of lactic acidosis are seen.
It is a superb review which greatly exceeds the quality criteria of the QUOROM checklist. They should have ended perfectly with a last paragraph which pointed out the questions still requiring answers which will direct the necessary lines of investigation required, although in the text some of them are hinted at. Basically they are:
1. The effectiveness of metformin in non-overweight patients.
2. Comparison of primary results as regards the new drugs.
3. The combination of metformin due to the failure of other drugs.
4. An interesting aspect which remains outside this review is the promising treatment combined with insulin5.It is not uncommon to find patients with diabetes mellitus 2 on treatment with insulin where it is difficult to achieve acceptable glycemic control and frequently enter a vicious circle: insulin causes greater weight gain, increases insulin resistance, does not improve control, leading to increasing the insulin dose, the patient continues gaining weight and control does not improve. The use of a drug directed against insulin resistance, metformin, could be useful in these patients. The lack of studies directed to evaluating this aspect of treatment, which hypothetically seems promising, of the patient with diabetes mellitus 2 is striking. There are a few localized studies, which are of different quality, short duration and with a small sample size, although all show the usefulness of adding metformin. It is one of the typical cases where lack of interest of the usual sponsors of clinical trials leads to a lack of scientific proof on a potentially useful and efficient treatment.
We think studies are necessary which might confirm these benefits in large populations and in the long term, studies which possibly may have to have several financial backers from the industry. In the 7 trials they studied only 232 patients and a maximum follow up time of 6 months, but it is worth mentioning that in all of them the results point in the same direction of benefit, therefore we think that, while other proof is gathered, the addition of metformin to the treatment of patients with diabetes mellitus 2 insufficiently controlled with insulin is a useful alternative, especially if overweight, and if there are no contraindications for its use.
5. Its behaviour in age sub-groups, dyslipemic, hypertensive and metabolic syndrome patients in the prevention of diabetes.
