the PIOCOMB studyLiterature -
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.
Markolf Hanefeld, Andreas Pfützner, Thomas Forst, Iris Kleine and Winfried Fuchs GWT-TUD mbH, Dresden, Germany
Cardiovasc Diabetol. 2011;10:65
We 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.
In 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.
Results:Pioglitazone (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).
Addition 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.
Along with control of hyperglycemia, treatment of patients with type 2 diabetes is aimed to reduce the elevated risk of cardiovascular disease (CVD) by correcting dyslipidemia, hypertension, low grade inflammation, and abnormalities in blood coagulation. International guidelines recommend the combination of metformin with basal insulin if monotherapy with metformin does not reach the target . Combinations of insulin with pioglitazone and with metformin plus pioglitazone are considered as less validated therapies. So far efficacy and safety of pioglitazone in patients with stable treatment of basal insulin have not been assessed in comparative trials with metformin or metformin plus pioglitazone. Nevertheless, there are some reports on the effect of an add-on therapy with pioglitazone in patients with poorly controlled type 2 diabetes under intensified insulin therapy demonstrating that addition of pioglitazone significantly improved not only glycemic control but also had a positive effect on some major CV risk factors. Data from outcome studies suggest that metformin2 and pioglitazone3 can reduce CV events and progression of atherosclerosis. Insulin treatment, however, had no significant effect on cardiovascular outcome in the UKPDS2.
Due to the absence of outcome data for a combination treatment of OAD with insulin, evaluation of CV risk markers can be used as surrogate parameters. The matrix metalloproteinase 9 (MMP-9) is a known marker of inflammation produced by macrophages which contributes to vascular remodeling and transformation of stable to unstable plaques. Although MMP-9 seems to reflect an overall burden of vascular disease in type 2 diabetes patients4-9, it is still controversially discussed to use it as a reliable surrogate marker of CV risk to date10-12. Therefore, the primary outcome measure of this doubleblind, multi-centre, randomized, parallel three-arm trial was to investigate the effect of pioglitazone in comparison to metformin and the combination of both on MMP-9 together with a spectrum of established risk factors and biomarkers of inflammation during a 6-month therapy in type 2 diabetes patients pre-treated with insulin in order to use the generated data for evaluation of possible beneficial effects of comparator drugs as add-on treatment on cardiovascular risk. Secondary objectives were clinical results and adverse events/side effects.
Biomarkers of CV risk
Pioglitazone reduced MMP-9 by 54.1 ± 187.1 ng/mL, whereas metformin increased MMP-9 by 49.6 ± 336.2 ng/mL (p=0.0345). The combination of both decreased MMP-9 by 67.8 ± 231.4 ng/mL (p=0.0416, metformin vs combo, and p=0.8695, pioglitazone vs combo). After logarithmic transformation for stabilization of the observed high variances, exploratory p-values for the between-group comparison using the 3-group ANCOVA model reached significance for metformin vs pioglitazone (p=0.0043) and for metformin vs combo (p=0.0289).
Figure 2 illustrates the different effects of the three treatment regimens on MMP-9, insulin resistance and inflammation, indicating a clear superiority of pioglitazone with respect to biomarkers of inflammation, insulin resistance, and adiponectin.
Metabolic and hormonal parameters
Metformin or pioglitazone had only minor effects on HbA1C, whereas the combination reached significance within-group(-0.49%, p<0.0001), all versus baseline.
Mean insulin dosage was reduced by 7.3 units in the pioglitazone-group (p<0.0001) and by 6.0 units in the combo-group (p=0.0004), but was increased by 2.5 units in the metformin-group (p=0.1539). The between-group comparison on insulin dosage was significant for metformin vs pioglitazone (p<0.0001) and for metformin vs the combination (p=0.0005). A small but relevant increase in HDL-cholesterol was observed for both arms with pioglitazone. Between-group comparisons revealed a stronger increase in HDL for the combination vs metformin (p=0.0004) and the combination vs pioglitazone (p=0.0162). Only for the combination arm, a marked reduction of triglycerides was observed (p+0.0229). No such effects occurred with LDL-cholesterol.
In patients with long term type 2 diabetes and suboptimal stable insulin treatment, the addition of pioglitazone but not metformin reduced the level of inflammatory biomarkers such as MMP-9 and hs-CRP and increased insulin sensitivity and adiponectin. The combination of pioglitazone with metformin resulted in better HbA1C and lipid control without added effect on inflammation, fibrinolysis, and renal function. No serious side effects were observed in any regimen but pioglitazone treatment was associated with more edema and weight gain as expected. To compare risk benefit of individual add-on treatment with oral antidiabetic drugs to basal insulin, controlled clinical trials measuring cardiovascular endpoints are needed.
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