Investigation of the vascular and pleiotropic effects of atorvastatin and pioglitazone in a population at high cardiovascular risk

Abstract

Key words: atherosclerosis, inflammation, intima-media thickness, PPARγ, statins. IntroductionAtherosclerosis is a complex process that progresses through various functional and morphological alterations in the vessel wall, cumulating in overt cardiovascular disease. Measurement of the intima-media thickness (IMT) of the common carotid artery (CCA) by ultrasound has been established as a reliable screening tool for atherosclerosis and has been shown to predict the risk for stroke and ischaemic heart disease.1 Further, increased arterial stiffness measured by applanation tonometry is predictive for stroke, myocardial infarction and other macrovascular complications.2 In addition to these vascular measurements, laboratory markers of lipid metabolism, inflammation, adhesion molecules and new laboratory markers characterise the metabolic syndrome. Recently, intact proinsulin and adiponectin have been established as criteria of the metabolic syndrome and as predictors of cardiovascular risk in this high-risk population. 3,4The most common intervention to contain the atherosclerotic process and to reduce cardiovascular risk is treatment with 3-hydroxy-3-methyl-glutaryl-CoA (HMG-CoA) reductase inhibitors, or statins. 5,6 Besides lowering of plasma lipids, treatment with statins has been shown to exert several pleiotropic effects, including a reduction in IMT and an improvement in arterial elasticity. 7,8 During recent years, increasing attention has been paid to the role of insulin resistance and the metabolic syndrome in the development of atherosclerosis and cardiovascular disease. Peroxisome proliferator-activated receptor (PPAR)γ agonists (thiazolidinediones), such as pioglitazone, are a class In a recent study, pioglitazone in addition to simvastatin treatment was shown to improve insulin resistance, to inhibit low-grade inflammation and to improve the overall cardiovascular risk profile even in non-diabetic patients with cardiovascular disease (CVD). 15,16 The aim of this study was to evaluate the effect of pioglitazone in addition to atorvastatin compared to atorvastatin alone on intimamedia thickness, vascular elasticity and several cardiovascular risk markers in a non-diabetic patient population at cardiovascular risk. MethodsThis study was a two-centre, prospective, double-blind, placebo-controlled trial, evaluating the effects of pioglitazone in addition to atorvastatin on IMT, arterial stiffness, endothelial function and several laboratory markers predictive for cardiovascular risk. The study was performed according to the Declaration of Helsinki and Good Clinical Practice, it was approved by the local ethical review board and all patients gave their written informed consent prior to study entry.Patients and study procedure Non-diabetic patients at increased cardiovascular risk, defined as those with an IMT greater than 0.8 mm and a previous medical history of myocardial infarction, coronary angiography with proven CVD, unstable angina pectoris, cervical or leg vessels with atherosclerotic alterations demon...

Synergistic anticancer effects of valproic acid, atorvastatin and pioglitazone in human malignant and murine cells

“…The combination of ATOR + PIO or other statins and thiazolidinediones has shown synergic interactions towards the treatment and prevention of cardiovascular illnesses and diabetes through diverse experimental models (Forst et al, , 2008Hanefeld et al, 2007). Our results showed that ATOR+PIO inhibited proliferation of lung mucoepidermoid carcinoma; other studies also reported the anticancer effect of HMG-CoA inhibitor and PPARγ agonist in lines of lung cancer (Li et al, 2010;Chen et al, 2012Chen et al, , 2013.…”

High-Sensitivity C-Reactive Protein Predicts Cardiovascular Risk in Diabetic and Nondiabetic Patients: Effects of Insulin-Sensitizing Treatment with Pioglitazone

“…Indeed, studies have demonstrated that pioglitazone therapy benefits individuals with elevated hs-CRP values. [46][47][48][49][50][51][52][53] 54 published data of 136 Japanese type 2 diabetes patients showing that pioglitazone treatment (30 mg daily for 3 months) significantly reduced hyperglycemia and hs-CRP relative to an untreated control group. In fact, a stratification into glycemic control responders [>1% of reduction in hemoglobin A1c (HbA1c)] and nonresponders revealed that CRP reduction with pioglitazone occurred independently of changes in parameters related to glucose metabolism.…”

“…57 Our own investigations examined insulinsensitizing effects on CRP levels compared to the impact of lipid-lowering and antihypertensive therapy in patients at increased macrovascular risk. 47,49,53 The PIOSTAT study demonstrated that nondiabetic patients with vascular insulin resistance and dyslipidemia treated with pioglitazone therapy experienced an overall reduction in chronic systemic inflammation, which was significantly more pronounced than with alternative simvastatin therapy. Giving both drugs in combination resulted in a synergistic effect on the inflammatory biomarker hs-CRP.…”

“…Again, the addition of pioglitazone to atorvastatin resulted in a significant further reduction of high-sensitivity C-reactive protein (p < 0.05). 49 The primary objective of the PIOace study was to investigate the effects of pioglitazone, ramipril, or their combination on low-grade inflammation in nondiabetic hypertensive individuals. Patients were treated with 30/45 mg pioglitazone (dose titration), 2.5/5 mg ramipril, or their combination for 12 weeks.…”

Laboratory Evaluation of a New Lateral-Flow-Based Point-of-Care Rapid Test for Assessment of Chronic Systemic Inflammation

“…This was not the case with other more commonly prescribed drugs for treatment of metabolic syndrome such as metformin or sulfonylurea drugs. [24][25][26][27] These findings indicate that a more individualized approach to diabetes therapy may provide a better way to improve the macrovascular prognosis and outcome for a given patient. Characterization of the individual risk situation of patients by means of hs-CRP and other biomarkers (e.g., adiponectin to assess the activity of the visceral adipose tissue and the related insulin resistance 28 or intact proinsulin to determine the degree of β-cell dysfunction 29 ) may allow for selection and monitoring of more individually tailored therapies.…”