Double-blind, randomized, multicentre, and active comparator controlled investigation of the effect of Pioglitazone, Metformin, and the combination of both on cardiovascular risk in patients with type 2 diabetes receiving stable basal insulin therapy: the PIOCOMB study

Abstract

BackgroundWe analyzed specific effects of an add-on therapy with pioglitazone compared to metformin and their combination in patients with basal insulin treatment on biomarkers of CV risk.MethodsIn this double-blind, randomized, multicentre, active comparator controlled trial, 121 patients with type 2 diabetes were enrolled. Inclusions: treatment with basal insulin, HbA1C 6.5% - 8.5%, age 30 - 75 years. After glargine therapy over 2 weeks for titration towards FBG ≤ 7.8 mmol/L, patients received either (A) bid 850 mg metformin (n = 42), (B) bid 15 mg pioglitazone (n = 40), or (C) 30 mg pioglitazone plus 1.7 g metformin (n = 39) over 6 months. Matrix Metal Proteinase 9 (MMP-9) was primary objective, together with biomarkers of CV risk.ResultsPioglitazone (B) reduced MMP-9 versus baseline by 54.1 + 187.1 ng/mL, with metformin (A) it was increased by 49.6 + 336.2 ng/mL (p = 0.0345; B vs. A), and with the combination of both (C) it was decreased by 67.8 + 231.4 ng/mL (A vs. C: p = 0.0416; B vs. C: p = 0.8695). After logarithmic transformation due to high variances the exploratory results showed significance for A vs. B (p = 0.0043) and for A vs. C (p = 0.0289).Insulin dosage was reduced by 7.3 units in group B (p < 0.0001), by 6.0 units in C (p = 0.0004), but was increased by 2.5 units (p = 0.1539) in A at follow up. Reduction in hs-CRP was significant within treatment groups for B (p = 0.0098) and C (p < 0.0001), and between the groups for A vs. C (p = 0.0124). All three single regimens reduced PAI-1. Adiponectin was significantly elevated in B and C (p < 0.0001) and between-groups. HbA1C was only significantly decreased in the combination group. No significant effects were observed for NFkB and PGFα. peripheral edema were seen in 11.9% vs. 40.0% vs. 20.5%, and weight change was -0.7 kg vs. +4.3 kg vs. +2.7 kg (A vs. B vs. C).ConclusionsAddition of pioglitazone but not of metformin reduces MMP-9, hs-CRP and increased insulin sensitivity and adiponectin in this study. The combination of both had no additional effect on inflammation. Pioglitazone is suggested to be a rational add-on therapy to basal insulin in patients with high CV risk.

Effect of Circular ANRIL on the Inflammatory Response of Vascular Endothelial Cells in a Rat Model of Coronary Atherosclerosis

“…Previous studies have shown that IL-1 could promote AS, and IL-6 levels are independently associated with subclinical AS [24, 25]. Markolf et al showed that both hs-CRP and MMP-9 are markers of inflammation released from macrophages, which contribute to unstable plaques and vascular remodeling [26]. …”

Transient Receptor Potential Channels as Drug Targets: From the Science of Basic Research to the Art of Medicine

“…Indeed, markers of chronic low-grade inflammation (e.g., C-reactive protein [CRP]) are persistently high in patients with T2DM. Many antidiabetic drugs used in the management of patients with T2DM (e.g., the PPARg agonists rosiglitazone and pioglitazone) possess anti-inflammatory activity and reduce CRP (Hanefeld et al, 2011). In fact, blood glucose decreases in tandem with CRP after pioglitazone treatment.…”

Faster drug approval: challenges for safety

“…Numerous studies of pioglitazone have not led to drastic decisions by the regulatory agencies because no clear evidence has demonstrated negative cardiovascular effects [78,84].…”