Clinical efficacy of new thiazolidinediones and glinides in the treatment of type 2 diabetes mellitus

Summary:

A central finding of the UKPDS was that in type 2 diabetic patients, tight glycemic control with HbA1c targets as close to the normal range as possible must be achieved to further reduce diabetes related-complications, -mortality, and -cardiovascular disease, highlighting the need for new, optimized treatment strategies. With a focus on clinical efficacy, this paper discusses the results from the 20 major therapeutical trials published in the years 1997-1999, that evaluated the new insulinsensitizing thiazolidinediones Rosiglitazone and Pioglitazone and the new insulin-releasing potassium channel blockers Repaglinide and Nateglinide. While for Nateglinide, promising, but only preliminary data is available at current, Rosiglitazone, Pioglitazone, and Repaglinide have been shown appropriate for both mono- and combination therapy with current standard drug treatment of type 2 diabetes. Similar to the known, older antidiabetic drugs, the new agents discussed have comparable blood glucose lowering potentials with a dose-related capacity of 0.5 to 1.5% HbA1c reduction. These beneficial effects were both seen in drug-naive patients previously treated with diet only and in combination therapies where patients had previous antidiabetic standard drug treatment suggesting effectiveness of glitazones and glinides also in more advanced stages of the disease. Problems with adverse effects appeared minor although longe-range implications of weight gain, edema, lowering of hemoglobin, increase of total cholesterol for the glitazones, and hypoglycemia for glinides warrant further consideration. What becomes clear from the variety of most recent mono- and combination treatment studies with as much as five different classes of antidiabetic drugs is that individually tailored therapies that recognize quality of life parameters and target the predominant features of metabolic pathology (such as early postprandial versus fasting hyperglycemia, degree of insulin resistance, progressive loss of β-cell function) may become a feasible goal in the future.

glinides - insulin sensitizer - insulin secretagogues - hypoglycemia - insulin resistance - prandial glucose regulation - glycaemic control - combination therapy - repaglinide - nateglinide - rosiglitazone - pioglitazone - responder - glitazones

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1 *** p < 0.0001, ** p< 0.0003, * p < 0.05, ¹) p = 0.05, n.r.: not reported, SD are not given in this table for better readability._FPG: fasting plasma glucose

2 *** p < 0.0001, * p < 0.05, n.r.: not reported, SD are not given in this table for better readability. ¹) (SU permitted were glibenclamide, glipizide, and gliclazid), ²) (metformin at a maximal dose of 2.5 g/day in inadequately controlled diabetes), ³) (poorly controlled diabetes with metformin of any dose prior to enrolment), ⁴) (enrolment of patients with insulin dose of >30 Units/day)._FPG: fasting plasma glucose

3 *** p < 0.0001, ** p < 0.001, * p < 0.01, n.r.: not reported, SD are not given in this table for better readability. ¹) (titration period of 4 weeks by `one-meal, one tablet' principle, thereafter doses were increased to 1 mg/meal if FBG > 7.8 mmol), ²) (until week 8, doses were titrated according to FPG goals of 5-9 mmol/l. 36% of patients thereafter were treated with 4 mg and 76% with 8 mg Repaglinide), ³) (6-8 week dose titration from 0.5-4 mg), ⁴) (FPG only reported from home blood glucose measurements)._FPG: fasting plasma glucose

4 *** p < 0.001, ** p < 0.01 between treatment groups, * p < 0.05, ^a) p < 0.05 for comparison Trogl. + Repa. vs. Trogl. vs. Repa., and Repa. vs. Trogl. n.r.: not reported, PBO: placebo, SD are not given in this table for better readability. ¹) (titration period of 4-8 weeks with `one-meal, one tablet' principle, thereafter doses were stepwise increased to 4 mg/meal if FPG > 7.8 mmol), ²) (27 patients of the 83 included withdrew during randomizazion), ³) (forced titration from week 0 to week 4, fixed dose until week 14, thereafter titration to maximum dose)._FPG: fasting plasma glucose