2-Year effects of pioglitazone add-on to sulfonylurea or metformin on oral glucose tolerance in patients with Type 2 diabetes

https://doi.org/10.1016/j.diabres.2007.11.014Get rights and content

Abstract

Aim

We report the effectiveness of the thiazolidinedione, pioglitazone, as add-on medication to metformin or sulfonylurea in reducing post-load serum glucose levels, as assessed by 3-h oral glucose tolerance testing (OGTT).

Methods

Adult patients with Type 2 diabetes took part in one of two large-scale, 2-year clinical trials. One study compared pioglitazone treatment as add-on to failing metformin therapy (N = 317) with add-on gliclazide treatment to metformin (N = 313). The other study compared combination therapy with pioglitazone added to existing failing sulfonylurea therapy (N = 319) with metformin treatment in addition to sulfonylurea (N = 320). HbA1c and fasting plasma glucose concentrations were measured at baseline and throughout the study and at the final visit at week 104. At selected centers (N = 299 patients), a 3-h OGTT was performed at baseline and at week 104.

Results

At week 104, mean HbA1c reduction from baseline was 0.89% for pioglitazone and 0.77% for gliclazide addition to metformin (p = 0.200) and 1.03% with pioglitazone and 1.16% with metformin addition to sulfonylurea (p = 0.173) in the total patient cohort. In the 299 patients who underwent OGTT, 2 years of treatment with pioglitazone, whether added to existing metformin or sulfonylurea medication, resulted in decreases in glucose excursions after an oral glucose load without increasing post-load serum insulin concentrations. In contrast, gliclazide in combination with metformin therapy caused increases in both post-load serum glucose and insulin excursions after 2 years, whereas metformin add-on to sulfonylurea did not have a significant effect on post-load serum glucose concentrations and resulted in an increase in insulin levels.

Conclusions

There were no significant differences in HbA1c levels between groups. However, 2-year treatment with pioglitazone as an add-on to either failing metformin or sulfonylurea therapy improved post-load glucose excursions without affecting insulin secretion. In contrast, glucose excursions were not improved by gliclazide or metformin add-on therapy, despite increases in post-load insulin levels. These data suggest that pioglitazone reduces peripheral insulin resistance via mechanisms different from those of metformin.

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).

References (31)

  • M.M. Gabir et al.

    Plasma glucose and prediction of microvascular disease and mortality. Evaluation of 1997 American Diabetes Association and 1999 World Health Organization criteria for diagnosis of diabetes

    Diabetes Care

    (2000)
  • S.W. Zarich

    Treating the diabetic patient: appropriate care for glycemic control and cardiovascular disease risk factors

    Rev. Cardiovasc. Med.

    (2003)
  • S. Del Prato

    In search of normoglycaemia in diabetes: controlling postprandial glucose

    Int. J. Obes.

    (2002)
  • F. de Vegt et al.

    Hyperglycaemia is associated with all-cause and cardiovascular mortality in the Hoorn population: the Hoorn Study

    Diabetologia

    (1999)
  • Glucose tolerance and mortality: comparison of WHO and American Diabetes Association diagnostic criteria

    Lancet

    (1999)
  • Cited by (26)

    • The role of metformin and thiazolidinediones in the regulation of hepatic glucose metabolism and its clinical impact

      2011, Trends in Pharmacological Sciences
      Citation 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 Practice
      Citation 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

      2009, Bone
      Citation Excerpt :

      On the contrary, there are only few information concerning the bone effects of thiazolidinediones in males with type 2 diabetes, with the data on bone fractures being scanty and mostly limited to clinical reports of increased rate of non-vertebral fractures [10]. Moreover, long-term use of thiazolidinediones has been found to double the fracture risk among women with type 2 diabetes, without a significant increase in risk of clinical fractures among men with type 2 diabetes [10–14]. However, the studies analyzed did not have bone as primary endpoint, did report only clinical fractures and only one of them evaluated the effects of rosiglitazone [11].

    View all citing articles on Scopus

    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).

    View full text