2-Year effects of pioglitazone add-on to sulfonylurea or metformin on oral glucose tolerance in patients with Type 2 diabetes☆
Introduction
Insulin resistance and progressive pancreatic beta-cell secretory dysfunction are characteristic features of Type 2 diabetes that lead to reduced glucose uptake and utilization and increased hepatic glucose production [1]. Over time, glycemic control in patients deteriorates, as evidenced by increasing glycosylated hemoglobin (HbA1c) and fasting plasma glucose (FPG) levels [2], [3], [4].
As a consequence of insulin resistance and loss of glycemic control, patients with Type 2 diabetes are at increased risk of macrovascular and microvascular disease, including coronary heart disease, stroke, retinopathy, nephropathy and neuropathy [5], [6], [7]. Observational analyses have demonstrated that exposure to even modest degrees of hyperglycemia increase vascular risks as well as overall mortality [5]. Maintaining strict glycemic control is now recognized as a major therapeutic goal in the management of Type 2 diabetes [8], because even modest reductions in HbA1c are associated with significant decreases in the risk of microvascular complications [5].
HbA1c levels provide an integrated measure of glucose exposure and reflect FPG and postprandial plasma glucose levels. However, postprandial glucose concentrations are currently considered more reflective of the overall glycemic state than fasting glucose levels. Most patients with Type 2 diabetes experience excessive increases in post-meal plasma glucose concentrations as compared with normal subjects [9]. Moreover, 2-h post-load hyperglycemia has been associated with both micro- and macrovascular disease [6], [10], [11], [12], [13]. It has further been demonstrated that post-load plasma glucose concentrations in patients with Type 2 diabetes frequently remain elevated above baseline for a prolonged period, such that patients spend around two-thirds of the day in the postprandial state. Postprandial glucose tolerance, in addition to HbA1c and FPG, is an important parameter for the assessment of the overall potential of novel glucose-lowering agents and combination therapies in providing glycemic control. In clinical trials, postprandial glucose excursions are commonly approximated using the oral glucose tolerance test (OGTT). The OGTT is used in the primary diagnosis of diabetes mellitus as well as in study protocols in a modified form for the assessment of insulin sensitivity and provides a validated analysis tool for postprandial glucose tolerance.
Several groups of oral pharmacological agents are available for the management of Type 2 diabetes. While all of them act to lower blood glucose concentrations and provide glycemic control to a certain extent, they do so through different mechanisms of action. Oral glucose-lowering drugs include insulin secretagogues (sulfonylureas and glinides), metformin that decreases basal hepatic glucose production and secondarily acts to decrease peripheral insulin resistance, inhibitors of carbohydrate uptake in the intestine (acarbose) and the thiazolidinediones (glitazones) that act as insulin sensitizers (pioglitazone and rosiglitazone). Pioglitazone offers significant improvements in glycemic control, as assessed by HbA1c levels, and efficacy has been demonstrated in both short- and long-term mono- or combination therapy [14], [15], [16], [17], [18], [19].
Here, we report the results of post load glycemic control in two large-scale, 2-year clinical trials involving pioglitazone therapy in patients with Type 2 diabetes as assessed by OGTT. Study 1 provides results from a comparison of add-on treatment with either pioglitazone or gliclazide to failing metformin therapy, whereas in study 2 effects of the addition of pioglitazone versus metformin to failing sulfonylurea therapy on post-load glucose excursions were compared.
Section snippets
Patients
Male and female patients with Type 2 diabetes, age 35–75 years, who were inadequately controlled on either metformin or sulfonylurea monotherapy (HbA1c ≥7.5% and <11.0% and fasting C-peptide ≥1.5 ng/mL) were eligible for inclusion. For at least 3 months prior to enrolment, patients have been treated with either metformin (study 1) or a sulfonylurea (study 2) at ≥50% of the maximum recommended dose or the maximum tolerated dose. Exclusion criteria included: Type I diabetes, ketoacidosis,
Patient disposition and baseline characteristics
A total of 1269 adult patients received treatment with either pioglitazone plus metformin (N = 317) versus gliclazide plus metformin (N = 313), or pioglitazone plus sulfonylurea (N = 319) versus metformin plus sulfonylurea (N = 320). Across the two studies over 70% of patients in each group completed 2 years of treatment. The most common reasons for early discontinuation were adverse events and lack of efficacy. In study 1, similar numbers of patients withdrew due to adverse events (7% in the
Discussion
In two 2-year studies, combination treatment with pioglitazone added to failing metformin medication was compared with add-on treatment with gliclazide or pioglitazone was added to failing sulfonylurea therapy and compared with metformin addition. In addition to the examination of HbA1c and FPG, the effects of these combination therapies on the incremental glucose AUC were assessed by 3-h OGTTs in a subgroup of patients to measure post-load glucose and insulin excursions.
Pioglitazone, when
Conflict of interest
J.S. has received honoraria from Takeda Europe and Takeda Germany for speaking at meetings and participation in advisory boards and has received funding from Takeda for attendance at scientific meetings. R.U. is an employee of Takeda.
Acknowledgements
This work was supported by Takeda Europe Research and Development Centre Ltd. (London, UK) and Eli Lilly and Company (Indianapolis, IN).
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2011, Trends in Pharmacological SciencesCitation Excerpt :Table 2 summarizes the effects of adding TZD to metformin therapy in T2DM and clearly shows further lowering of FPG and peripheral insulin resistance [98–103]. There is also evidence that combined metfomin–TZD regimens are superior to the effect of adding sulfonylurea drugs to metformin therapy [104,105]. Furthermore, addition of rosiglitazone to sulfonylureas in T2DM not only improved FPG and insulin resistance (Table 2) [106–108], but also β-cell function [109,110] and adiponectin secretion [106,109] Pioglitazone–sulfonylurea combination also improve circulating triglycerides and HDL [108,111].
Thiazolidinediones plus metformin association on body weight in patients with type 2 diabetes
2011, Diabetes Research and Clinical PracticeCitation Excerpt :There was no difference in the mean weight change in the pioglitazone plus metformin versus gliclazide plus metformin study (pioglitazone plus metformin +1.3 kg and gliclazide plus metformin +0.6 kg). Seufert and Urquhart [34] compared treatment with either pioglitazone (15–45 mg daily) plus metformin (850–2550 mg daily) versus gliclazide (80–320 mg daily) plus metformin (850–2550 mg daily). Both treatments resulted in sustained lowering of HbA1c and FPG levels over the 2-year study period.
Vertebral fractures in males with type 2 diabetes treated with rosiglitazone
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A preliminary report of this analysis was presented at the 64th Scientific Sessions of the American Diabetes Association (G. Edwards, et al., Diabetes 53 (Suppl. 2) (2004) A1223, 522-P) and at the 40th Annual Meeting of the European Association for the Study of Diabetes (G. Belcher, et al., Diabetologia 47 (Suppl. 1) (2004) A254, P702).