30 60 90 120 150 180 Time ( min )

Fig. 25. Mean plasma glucose and plasma insulin responses to oral glucose before (•) and after (O) 1 week of metformin treatment in NIDDM patients. Plasma glucose concentrations decreased significantly. (Source: Fantus and Brosseau, 1986.)

diabetics. Despite the controversy about hyperinsulinaemia as an independent risk factor for coronary heart disease, there is no doubt of its relationship to other risk factors (Campbell, 1990). In contrast to sulphonylureas, the non-insulinotropic biguanides are therefore the drug of choice (together with acarbose) for the treatment of dietary failure in obese Type-II diabetes mellitus. Fasting and postprandial serum insulin after 3 months of metformin is significantly lower than after treatment with sulphonylureas (McAlpine et al., 1988).

A combination of biguanides with sulphonylurea can be useful in patients who have failed to respond to sulphonylureas alone. In "secondary failure", the combination of metformin and sulphonylurea responded in more than 50% of cases. Clarke et al. (1967) reported a clinical study where blood glucose dropped from 266 to 184 mg per 100 ml after 12 weeks and HbA] improved from 9.1 to 7.6%. Similar results were obtained by Haupt et al. (1989). In contrast, Debry et al. (1977) did not agree that the combination of biguanides and sulphonylureas was beneficial. No significant differences were seen in blood glucose levels in Type-II diabetics treated with metformin + sulphonylureas versus sulphonylureas alone, while serum insulin was higher after sulphonylurea treatment only. It has been reported that the choice between metformin and metformin + sulphonylureas does not depend on the age or sex of the subjects. The only factor of therapeutic importance is the degree of intensity of metabolic imbalance.

The mortality risk for hypoglycaemia caused by sulphonylureas is not significantly different from lactacidosis associated with metformin (Campbell, 1984).

The combination of metformin and insulin in Type-II diabetics increases the efficacy of insulin and reduces insulin resistance in obese patients. A considerable reduction in insulin doses has been achieved (Leblanc et al., 1987). Free serum insulin levels have been reduced from 51 to 41 units/ml-1 (Stowers, 1980). On mixed biguanide-insulin treatment, the atherogenic effect of hyperinsulinaemia and the number of hypoglycaemic reactions can be reduced.

The hypolipidaemic effect of metformin has not been elucidated satisfactorily. The reduction of serum triglycerides and to a smaller extent total plasma cholesterol, however, is very welcome in the treatment of the metabolic syndrome in Type-II diabetes. The inhibitory effect of metformin on fatty acid oxidation (Schonborn et al., 1975) has been regarded as pivotal in its mechanism of antidiabetic action, because of the interrelations between fatty acid and carbohydrate metabolism.

In conclusion, it can be stated, that biguanides, preferably metformin, have been shown in innumerable clinical trials to be highly effective as antihyper-glycaemic drugs. Together with acarbose, they may be the first-choice drug for the treatment of obese hyperinsulinaemic, insulin resistant Type-II diabetics with dietary failure. They help to correct most of the unwanted aspects of the metabolic syndrome, which is felt to contribute most to the high mortality rate of NIDDM patients with heart disease.

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