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CLINICAL RESEARCH

Pioglitazone Improves Myocardial Blood Flow and Glucose Utilization in Nondiabetic Patients With Combined Hyperlipidemia

A Randomized, Double-Blind, Placebo-Controlled Study

Rossi P. Naoumova, MD, PhD, FAHA, MRCP^_*, Heiko Kindler, MD, MRCP^_*, Lucia Leccisotti, MD^_*,, Marco Mongillo, MD, PhD^_*, Muhammad T. Khan, MD, FRCS^_*, Clare Neuwirth, RN^_*, Mary Seed, MA, DM, FRCPath, FREP, Paul Holvoet, PhD, FAHA, John Betteridge, PhD, MD, FAHA, FRCP^|| and Paolo G. Camici, MD, FESC, FACC, FAHA, FRCP^_*,#,_*

^_* Medical Research Council Clinical Sciences Centre, Imperial College, Hammersmith Hospital, London, United Kingdom
^# National Heart and Lung Institute, Imperial College, Hammersmith Hospital, London, United Kingdom
Institute of Nuclear Medicine, Catholic University of the Sacred Heart, Rome, Italy
Lipid Clinic, Charing Cross Hospital, London, United Kingdom
Department of Cardiovascular Diseases, Faculty of Medicine, Katholieke Universiteit Leuven, Leuven, Belgium
^|| Department of Medicine, University College London, University College Hospitals, London, United Kingdom. Supported in part by an unrestricted grant from Takeda Europe.

Manuscript received October 31, 2006; revised manuscript received July 6, 2007, accepted July 18, 2007.

^_* Reprint requests and correspondence: Prof. Paolo G. Camici, MRC Clinical Sciences Centre, Hammersmith Hospital, Du Cane Road, London W12 0NN, United Kingdom. (Email: paolo.camici{at}csc.mrc.ac.uk).

Objectives: This study's aim was to examine whether treatment with pioglitazone, added to conventional lipid-lowering therapy, would improve myocardial glucose utilization (MGU) and blood flow (MBF) in nondiabetic patients with familial combined hyperlipidemia (FCHL).

Background: Thiazolidinediones were found to improve insulin sensitivity and MGU in type 2 diabetes and MBF in Mexican Americans with insulin resistance. Familial combined hyperlipidemia is a complex genetic disorder conferring a high risk of premature coronary artery disease, characterized by high serum cholesterol and/or triglyceride, low high-density lipoprotein (HDL) cholesterol, and insulin resistance.

Methods: We undertook a randomized, double-blind, placebo-controlled study in 26 patients with FCHL, treated with pioglitazone or matching placebo 30 mg daily for 4 weeks, followed by 45 mg daily for 12 weeks. Positron emission tomography was used to measure MBF at rest and during adenosine-induced hyperemia and MGU during euglycemic hyperinsulinemic clamp at baseline and after treatment.

Results: Whereas no change was observed in the placebo group after treatment, patients receiving pioglitazone showed a significant increase in whole body glucose disposal (3.93 ± 1.59 mg/kg/min to 5.24 ± 1.65 mg/kg/min; p = 0.004) and MGU (0.62 ± 0.26 µmol/g/min to 0.81 ± 0.14 µmol/g/min; p = 0.0007), accompanied by a significant improvement in resting MBF (1.11 ± 0.20 ml/min/g to 1.25 ± 0.21 ml/min/g; p = 0.008). Furthermore, in the pioglitazone group HDL cholesterol (+28%; p = 0.003) and adiponectin (+156.2%; p = 0.0001) were increased and plasma insulin (–35%; p = 0.017) was reduced.

Conclusions: In patients with FCHL treated with conventional lipid-lowering therapy, the addition of pioglitazone led to significant improvements in MGU and MBF, with a favorable effect on blood lipid and metabolic parameters. (A study to investigate the effect of pioglitazone on whole body and myocardial glucose uptake and myocardial blood flow/coronary vasodilator reserve in patients with familial combined hyperlipidaemia; http://www.controlled-trials.com/mrct/trial/230761/ISRCTN78563659; ISRCTN78563659 [controlled-trials.com] )

Abbreviations and Acronyms   BMI = body mass index   CAD = coronary artery disease   CFR = coronary flow reserve   FCHL = familial combined hyperlipidemia   FDG = 2-[18F]fluoro-2-deoxy-D-glucose   H2 15O = oxygen-15–labeled water   HDL = high-density lipoprotein cholesterol   LDL = low-density lipoprotein cholesterol   M = whole body glucose disposal   MBF = myocardial blood flow   MGU = myocardial glucose utilization   PAI = plasminogen activator inhibitor   PET = positron emission tomography

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