FOR THE GLAL STUDY GROUPOBJECTIVE -The hypothesis that pioglitazone treatment is superior to gliclazide treatment in sustaining glycemic control for up to 2 years in patients with type 2 diabetes was tested.RESEARCH DESIGN AND METHODS -This was a randomized, multicenter, double-blind, double-dummy, parallel-group, 2-year study. Approximately 600 patients from 98 centers participated. Eligible patients had completed a previous 12-month study and consented to continue treatment for a further year. To avoid selection bias, all patients from all centers were included in the primary analysis (a comparison of the time-to-failure distributions of the two groups by using a log-rank test) regardless of whether they continued treatment for a 2nd year. By using repeated-measures ANOVA, time course of least square means of HbA 1c and homeostasis model of assessment (HOMA) indexes (HOMA-%S and HOMA-%B) were analyzed.RESULTS -A greater proportion of patients treated with pioglitazone maintained HbA 1c Ͻ8% over the 2-year period than those treated with gliclazide. A difference between the KaplanMeier curves was apparent as early as week 32 and widened at each time point thereafter, becoming statistically significant from week 52 onward. At week 104, 129 (47.8%) of 270 pioglitazone-treated patients and 110 (37.0%) of 297 gliclazide-treated patients maintained HbA 1c Ͻ8%. Compared with gliclazide treatment, pioglitazone treatment produced a larger decrease in HbA 1c , a larger increase in HOMA-%S, and a smaller increase in HOMA-%B during the 2nd year of treatment.CONCLUSIONS -Pioglitazone is superior to gliclazide in sustaining glycemic control in patients with type 2 diabetes during the 2nd year of treatment. Diabetes Care 28:544 -550, 2005T ype 2 diabetes, with its core defects of insulin resistance and relative insulin deficiency, is a progressive disease. Insulin resistance remains generally stable throughout the natural history of the disease, but there is a progressive loss of glycemic control due to the continuing loss of ␤-cell function. The U.K. Prospective Diabetes Study (1) showed that at diagnosis, patients have already lost ϳ50% of their ␤-cell function, which was further reduced to ϳ30% at 5 years.The standard approach at initial diagnosis for many patients with type 2 diabetes is a prescription of diet and physical activity to correct their hyperglycemia. When glycemic targets cannot be attained or maintained with this approach, an oral antihyperglycemic medication (OAM) is added to the lifestyle regimen. When monotherapy fails, treatment is changed to combination OAM therapy, OAMs plus insulin, or insulin therapy (2). Most patients initially respond to OAM monotherapy when they use it. However, with continued therapy, some patients can no longer achieve their glycemic target. The inability to maintain the glycemic target may indicate progression of disease rather than lack of response to a drug (3,4).Sulfonylureas, first introduced in the mid-1950s, are commonly used as monotherapy in patients with type 2 diabete...

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1 The activity of adenosine 5'-diphosphoribose (ADP-ribose), a ribosylated purine nucleotide, was investigated on the carbachol-contracted taenia coli, a tissue possessing PI-(A2) and P2y-purinoceptors and on the guinea-pig vas deferens which possesses P2x-purinoceptors. 2 In the vas deferens, where ATP (1 JAM-I mM) produced concentration-dependent contractions, ADP-ribose was without effect at concentrations up to 1 mM. 3 In the taenia coli, ADP-ribose (0.1 AM-I mM) produced concentration-dependent relaxations with a potency similar to that of adenosine, but less than that of ATP. The pD2 values for ADP-ribose, adenosine and ATP were 4.5 ± 0.07 (27), 4.4 ± 0.10 (9) and 5.5 ± 0.14 (21), respectively. The time-course of the relaxations elicited by ADP-ribose was found to be significantly longer than that for ATP and significantly shorter than that for adenosine.4 The PI-purinoceptor antagonist, 8-phenyltheophylline (5 JAM), produced parallel rightward shifts in the concentration-response curves of the relaxations of the taenia coli elicited by ADP-ribose and adenosine but not ATP. 5 Dipyridamole (0.3 JM), a purine nucleoside uptake inhibitor, potentiated the responses to adenosine and ADP-ribose in the taenia coli. These potentiations were sensitive to 8-phenyltheophylline (5 JM). 9 It is concluded that ADP-ribose has a mixed pharmacological profile, evoking both PI (A2)-purinoceptor-mediated responses and P2Y-purinoceptor-mediated responses, while being inert at P2X-purinoceptors. It is suggested that ADP-ribose may provide a useful starting point for the generation of structural analogues which have specific activity at the P2Y-purinoceptor.

Cardiovascular mortality and morbidity are increased in patients with type 2 diabetes. However, there are few data from clinical trials comparing cardiovascular effects of alternative oral anti-diabetic agents. Major cardiovascular outcomes during four one-year, double-blind trials in over 3700 patients with type 2 diabetes randomised to either a thiazolidinedione, pioglitazone, metformin or a sulphonylurea, gliclazide treatment have been combined. Mean blood pressure was slightly reduced by all treatments, with pioglitazone treatment resulting in the largest falls (approximately 1.5 mmHg). Hospitalisations for cardiac or cerebrovascular events were similar with the different treatments. Overall mortality was seven of 1857 for pioglitazone and 10 of 1856 for non-pioglitazone treatments, of which three and six were cardiac deaths, respectively. The incidence of congestive cardiac failure was similar with pioglitazone (12/1857) and non-pioglitazone (10/1856) treatments. The results show similar cardiovascular outcome for the three different treatments over a one-year period, but demonstrate interesting differences, which will require longer-term formal outcome studies to determine their significance.

A total of 3,713 patients with poorly controlled type 2 diabetes were enroled into four multicentre, double-blind studies and randomised to receive pioglitazone, sulphonylurea, metformin or a combination of two of these agents for up to 52 weeks. Data from patients with a lipid evaluation, at week 52, were pooled, and treatment groups were compared using analysis of covariance. Pioglitazone, alone or combined with metformin or sulphonylurea, resulted in mean decreases in triglycerides (-9 to -11%), total/HDL cholesterol ratio (-9 to -10%) and free fatty acid (-0.051 to -0.123 mmol/l) and mean increases in HDL cholesterol (17 to 20%). The sustained, favourable effects of pioglitazone on important components of diabetic dyslipidaemia may contribute to reduced cardiovascular disease risk, among patients with type 2 diabetes.