Earlier triple therapy with pioglitazone in patients with type 2 diabetes

This study assessed the efficacy of add-on pioglitazone vs. placebo in patients with type 2 diabetes uncontrolled by metformin and a sulphonylurea or a glinide. This multicentre, double-blind, parallel-group study randomized 299 patients with type 2 diabetes to receive 30 mg/day pioglitazone or placebo for 3 months. After this time, patients continued with pioglitazone, either 30 mg [if glycated haemoglobin A1c (HbA₁c) [less-than or equal to]6.5%] or titrated up to 45 mg (if HbA₁c >6.5%), or placebo for a further 4 months. The primary efficacy end-point was improvement in HbA₁c (per cent change). Secondary end-points included changes in fasting plasma glucose (FPG), insulin, C-peptide, proinsulin and lipids. The proinsulin/insulin ratio and homeostasis model assessment of insulin resistance (HOMA-IR) and homeostasis model assessment of β-cell function (HOMA-B) were calculated. Pioglitazone add-on therapy to failing metformin and sulphonylurea or glinide combination therapy showed statistically more significant glycaemic control than placebo addition. The between-group difference after 7 months of triple therapy was 1.18% in HbA₁c and -2.56 mmol/l for FPG (p < 0.001). Almost half (44.4%) of the patients in the pioglitazone group who had a baseline HbA₁c level of <8.5% achieved the HbA₁c target of < 7.0% by final visit compared with 4.9% in the placebo group. When the baseline HbA₁c level was greater-than-or-equal 8.5%, 13% achieved the HbA₁c target of < 7.0% in the pioglitazone group and none in the placebo group. HOMA-IR, insulin, proinsulin and C-peptide decreased and HOMA-B increased in the pioglitazone group relative to the placebo group. In patients who were not well controlled with dual combination therapy, the early addition of pioglitazone improved HbA₁c, FPG and surrogate measures of β-cell function. Patients were more likely to reach target HbA₁c levels (< 7.0%) with pioglitazone treatment if their baseline HbA₁c levels were < 8.5%, highlighting the importance of early triple therapy.