Pioglitazone elicits long-term improvements in insulin sensitivity in patients with type 2 diabetes: comparisons with gliclazide-based regimens

Abstract

Aims/hypothesis: Recent studies have demonstrated that pioglitazone (PIO) has beneficial effects on insulin sensitivity compared with placebo in patients with type 2 diabetes. The effects of PIO and gliclazide (GLIC)-based therapy on insulin sensitivity have not previously been directly compared. This analysis aimed to compare the effects of 52 weeks of treatment with PIO (30-45 mg/day) and GLIC (80-320 mg/day), both titrated to maximum tolerable doses, as monotherapy or in combination with metformin (MET), on insulin sensitivity and lipid parameters known to be related to insulin sensitivity in patients with type 2 diabetes. Methods: We performed an analysis of 1,880 patients with inadequately controlled type 2 diabetes (HbA 1 c 7.5-11.0%) who were participants in two parallelgroup, double-blind, double-dummy, randomised, multicentre, clinical trials. Measures of insulin sensitivity and lipids were assessed. Results: The PIO-and GLIC-based regimens produced similar levels of glycaemic control (HbA 1 c). In both trials, insulin sensitivity as assessed using the homeostasis model assessment was improved in patients receiving PIO, but decreased in those receiving GLIC (mean change, baseline to endpoint: PIO 15.5, GLIC −15.6; p<0.001 and PIO+MET 18.9, GLIC+MET −5.3; p<0.001). Improvements in the atherogenic index of plasma (mean change: PIO −0.17, GLIC −0.08; p<0.001 and PIO+MET −0.17, GLIC+MET −0.02; p<0.001), triglycerides (mean change, mmol/l: PIO+MET −0.62, GLIC+MET −0.22; p< 0.001) and NEFA (mean change, mmol/l: PIO+MET −0.12, GLIC+MET−0.05; p<0.001) were greater in PIO-treated patients than in patients receiving GLIC. Conclusions/ interpretation: The PIO-based regimens resulted in improved insulin sensitivity and more favourable insulin sensitivity-related lipid profiles compared with the GLIC-based regimens. These benefits may be important in the management of cardiovascular risk in patients with type 2 diabetes.

Secondary prevention of macrovascular events in patients with type 2 diabetes in the PROactive Study (PROspective pioglitAzone Clinical Trial In macroVascular Events): a randomised controlled trial

“…Alternatively, pioglitazone might reduce the concentration of glucose in the blood to below a threshold at which insulin would be used. Finally, as previously suggested, pioglitazone could have a specific (β-cell sparing effect, manifest in other clinical studies by a reduction of circulating insulin, 15 and in animal studies by regranulation of the β cell. 16 We believe our results are generalisable to all patients with type 2 diabetes.…”

Pioglitazone treatment increases whole body fat but not total body water in patients with non-alcoholic steatohepatitis

“…However, there are several important differences in that study design and methods [24] when compared to our study. First, we believe that the small number of patients studied (n = 8) and short treatment duration (3 months) prevented the trend in weight gain (+0.9 kg) to become significant as it has been consistently reported with pioglitazone use by our group [21,22,33] and in the literature [9,34,35], in particular in studies lasting P6 months [11][12][13][14]16,36]. This is also true for other TZDs [9,10,15,37].…”

“…The mechanisms remain poorly understood. Weight gain most frequently develops within the first few months of treatment [11][12][13][14] and appears to plateau thereafter although there can be additional weight gain over time [15]. Occasionally, the use of thiazolidindiones is associated with lower extremity edema [15][16][17][18], although rarely with the development of congestive heart failure [19,20].…”

The backbone of oral glucose‐lowering therapy: time for a paradigm shift?

“…For patients failing on sulfonylurea therapy, the addition of pioglitazone offered significantly greater improvements in HbA 1c and FPG than continued sulfonylurea therapy plus placebo () [46] and improvements in glycemic control that were comparable to the addition of metformin [47]. The addition of rosiglitazone to glibenclamide achieved significantly greater improvements in glycemic control than uptitration of the sulfonylurea alone [48].…”

“…Encouragingly, these improvements appear to be maintained during long-term therapy, despite some weight gain [19,61]. Charbonnel et al [47] directly compared the effects of pioglitazone and the sulfonylurea gliclazide on insulin sensitivity in type 2 diabetes. Using the homeostasis model of assessment (HOMA) to provide an indirect measure of insulin sensitivity (HOMA-IR), they found that over 1 year pioglitazone was associated with an improvement in insulin sensitivity, whereas gliclazide therapy was associated with a decrease.…”