Why does metformin work better in diabetics

Diabetes mellitus: higher dose recommended for metformin

The worldwide prevalence of type 2 diabetes is estimated at three to five percent of the population, and the trend is rising. The introduction of western lifestyles combined with a higher life expectancy in developing and emerging countries will turn this metabolic disease into a pandemic.

Non-drug basic therapy shows the best results

The actual causes of the complex metabolic disorder have not yet been clarified. Genetic determination, environmental influences and aging are equally and mutually involved. There is no prospect of causal therapy in the foreseeable future. The primary treatment approach for this disease is non-pharmacological measures such as diet change, blood sugar self-control, increased physical activity and smoking cessation.

The UKPD (United Kingdom Prospective Diabetes Study) study with more than 4000 newly diagnosed type 2 diabetics over ten years showed the clear connection between improved blood sugar control, measured by fasting blood sugar and HbA1CValues, and the occurrence of diabetic complications. The group with non-drug basic therapy showed the best result in terms of decreasing HbA1C-Values.

Optimizing the use of proven drugs

Treatment with oral antidiabetic drugs should only be initiated if, after twelve weeks of consistent exhaustion of all possibilities, the individual therapy goal is not achieved. If monotherapy fails, they are used in combination. If the metabolism cannot be satisfactory even then, insulin injection is added.

However, the initially successfully used antidiabetic drugs fail after a certain time. Weight gain due to insulinotropic oral antidiabetic drugs and insulin also has a negative effect on the metabolic situation. The values ​​that the European Policy Group set in 1999 as the limit marks for the surrogate parameters of type 2 diabetes are often missed in practice. In order to achieve these ambitious goals, in addition to the development of new active ingredients such as glinides, glitazones and insulin analogues, there is an attempt to optimize the use of known drugs that have been tried and tested for decades.

In the UKPD study, a group of 537 overweight diabetics were treated with metformin as monotherapy for a median of ten years. Although there was no significant difference in blood sugar levels in comparison with other drug monotherapy treatments, an improvement in prognosis was found in the metformin group alone. In addition to the significant improvement in all diabetic endpoints, all-cause mortality, diabetes-related deaths and the number of myocardial infarctions decreased. The reduction in morbidity and mortality was much more pronounced than with sulphonylureas and insulin.

Effective maximum at 2000 mg per day

In evaluating these results, it should be noted that patients in the metformin group were treated with a dose of 1700 to 2250 mg per day. There is much to suggest that the success of metformin treatment depends on a sufficiently high dose. This was determined in several dose-finding studies. In a dose-response study with parallel groups, 451 patients with a fasting blood sugar level above 10 mmol / l were randomized to treatment with metformin in daily doses of 500 to 2500 mg for 11 weeks.

From a dose of 1000 mg, there were statistically significant reductions in fasting blood sugar compared to placebo, with the effect being most pronounced at 2000 mg and 2500 mg daily. The HbA decreased from 1500 mg1C by more than 1.5 percent. The best effect on HbA1C- and fasting blood sugar values ​​were achieved with 2000 mg metformin. At higher doses, no further lowering of the values ​​could be observed, so that 2000 mg is recommended as the maximum daily dose.

Gastrointestinal side effects not dose-dependent

Most of the adverse drug reactions from metformin affect the digestive tract and lead to discontinuation of therapy in approximately five percent of patients. A metallic taste, nausea, vomiting and diarrhea occur especially at the beginning of metformin intake, which is caused by an increased release of serotonin in the intestine and an increase in the concentration of bile salts.

These side effects can be minimized by gradually increasing the dosage with an initial dose of 500 mg and taking it directly after a meal. Persistent diarrhea, impaired kidney function, pregnancy and breastfeeding are contraindications for metformin treatment.

Note contraindications

The most feared side effect of metformin is lactic acidosis, the mortality rate of which is still 50 percent today. The initial symptoms are uncharacteristic and insidious: tiredness, nausea, vomiting, diarrhea, abdominal pain. With increasing acidosis, hyperventilation, restlessness and clouding of consciousness occur.

In intensive care medicine, the focus is on bicarbonate hemodialysis and the restoration of kidney function. The incidence of lactic acidosis with metformin, however, is very low; it is stated to be three to nine cases per 100,000 patient-years. The main cause seems to be the failure to observe the contraindication renal insufficiency.

Concomitant use of non-steroidal anti-inflammatory drugs can lead to lactic acidosis by restricting the excretion of metformin. Cimetidine also inhibits the renal elimination of metformin by competitive inhibition of tubular secretion. The intravenous administration of a contrast medium can lead to impaired kidney function or even kidney failure, so that there is a risk of lactic acidosis due to the accumulation of metformin. For this reason, a 48-hour metformin grace period before and after the administration of contrast medium is required in Germany. If these instructions for use are followed correctly and kidney function is monitored, the risk of metformin treatment is low.

Box text: Contraindications for metformin

  • renal dysfunction
  • severe liver damage
  • Use of intravenous contrast media
  • major surgical interventions
  • Heart failure
  • acute heart attack
  • Past lactic acidosis
  • Alcohol abuse in the past


Prof. Dr. Guntram Schernthaner, Vienna, Dr. John Scarpello, Stoke on Trent, Prof. Dr. Christoph Rosak, Frankfurt a. Main, Symposium "Dose-Optimized Treatment of Type 2 Diabetes: Strategies for Mono- and Combination Therapy" at the 37th Annual Meeting of the German Diabetes Society, Dresden, May 8, 2002, organized by Merck KGaA, Darmstadt.