Combined Oral Therapy for Type 2 Diabetes

Treatment of patients with type 2 diabetes mellitus was much discussed at the recent congress of the American Diabetes Association (ADA) in Orlando, Florida, June 4 - 8, 2004. It was clear that treatment with oral hypoglycaemic agents has an increasingly important role in the management of type 2 diabetes. This follows the direction already indicated by the results of the UKPDS study which led the authors to conclude “it is reasonable to start with oral agents” (but only, if a good control is achieved; otherwise insulin is necessary). Prominent within the discussion at Orlando was the principle of combination therapy that included up to three different oral agents (“triple therapy”). This is not surprising since, as previously suggested by Standl (Munich), combination therapy with low doses of different substances could result in improving diabetes control with fewer side effects than with a single agent therapy.

Successful combination oral therapy was reported by us already in 1958 (Mehnert and Seitz). The first combination was that of sulfonylurea and a biguanide, which at the time was tolbutamide and phenformin or buformin. These findings were confirmed by Beaser (Boston) and Beringer (Vienna) later that year. Since then, this combination (at present mostly glibenclamide or glimepiride and metformin) has been used world-wide. Moreover, publication of the UKPDS results did not offer any serious indication to alter this practice. With respect to vascular complications, including death, treatment of overweight patients with type 2 diabetes was best managed by metformin. There were, however, increased deaths in patients treated with metformin and sulfonylurea compared to the control group who were treated with sulfonylurea only. But this unexpected result has been questioned by the authors themselves (Turner) as the sulfonylurea treated group were small and other data from the same authors did not confirm the disadvantageous effect of the combined therapy. Thus, although the UKPDS data caused uncertainty about the use of the combination in Germany, American and British diabetes societies have never seen a cause to warn against the combination of sulfonylurea and metformin. It is therefore important that in the sequel of the UKPDS reported by Holman at the IDF congress in Paris last year, no increased risk for death was observed in patients treated with this combination. It is not surprising, therefore, that also in the recent ADA meeting the superceded UKPDS results concerning the potential increased mortality under a combined treatment with sulfonylurea and metformin were no longer a matter of interest.

This therapy is by no means the only oral antidiabetic combination in use. In general - as discussed in Orlando - all combinations of substances with different mechanisms are possible. Among these are combinations of insulinotropic and non-insulinotropic substances. Apart from the combination of sulfonylurea and metformin mentioned above, this applies particularly to the combined use of the insulinotropic glinides with metformin. Repaglinide as well as nateglinide combined with metformin are reported to decrease blood glucose levels very successfully. Glinides (as a kind of “endogenous fast-and-short-acting injection of insulin”) lower mainly postprandial, whereas metformin acts predominantly on fasting blood glucose levels. This ideal combination of two agents can cause an “over-additive” decrease in blood glucose levels (Moses, Horton). A combination of sulfonylurea and glinides is not very efficient as these two agents have nearly the same mechanism of action. Other favourable combinations of non-insulinotropic and insulinotropic agents are acarbose or glitazone with sulfonylurea or glinide. Even more remarkable, however, is the option of a combined treatment with two substances which aim specifically to target insulin resistance: glitazone and metformin. This kind of treatment was often the main focus of interest in Orlando, as well as the “triple therapy”, mentioned above, of glitazone, metformine and sulfonylurea, which is uncommon in Germany. Not infrequently, the administration of three oral agents is seen as a sell-out and as an urgent indication for the change to insulin treatment. The answer to this question should be determined by practical considerations, e.g. if an overweight patient has a good metabolic control with triple therapy it would not be evident to increase his obesity by the application of insulin.

To complete the picture, there is also the possibility of combining acarbose with insulinotropic or non-insulinotropic agents. Indeed, acarbose is considerably less commonly used in the USA than in European countries, especially Germany. This could change if the interesting protective influences of acarbose on the development of macroangiopathia are confirmed.

Finally patients with type 2 diabetes can be treated with a combination of oral antidiabetic agents and insulin. Remarkably, this treatment, developed mainly by Bachmann in Germany, is now becoming popular also in the USA (Riddle). A world-wide favourite is the combination of insulin and metformin (Yki-Järvinen), as this oral agent can work best against insulin resistance and obesity caused by insulin (the alternative, glitazone plus insulin, is - in contrast to the USA - not approved in Germany). Sulfonylurea can also form an effective therapy in combination with insulin as previously shown by Bachmann. The administration of oral agents together with a long-acting insulin analog (basal supported oral therapy or “BOT”) is also common and successful in Germany and many other countries.

Concluding, it is obvious that the trend towards a combined treatment of patients with type 2 diabetes is growing and cannot be halted. Diabetologists are following a development which has preceded them in other diseases such as hypertension: there too, there was a slow step by step progression until eventually the use of two or three agents became the gold standard therapy.

Hellmut Mehnert, Munich