Dual PPAR α/γ Agonism Normalizes Lipoprotein Profile of Renal Dyslipidemia

Hindawi Publishing Corporation PPAR Research Volume 2013, Article ID 391628, 7 pages http://dx.doi.org/10.1155/2013/391628 Clinical Study Dual PPAR 𝛼/𝛾 Agonism Normalizes Lipoprotein Profile of Renal Dyslipidemia O. Samuelsson,1 P. O. Attman,1 I. Gause-Nilsson,2 M. K. Svensson,1 and P. Alaupovic3 1 Department of Nephrology, Sahlgrenska University Hospital, 41345 Göteborg, Sweden AstraZeneca Research & Development, 43183 Mölndal, Sweden 3 Lipid and Lipoprotein Laboratory, Oklahoma Medical Research Foundation, Oklahoma City, OK, USA 2 Correspondence should be addressed to O. Samuelsson; Received 11 September 2012; Accepted 27 February 2013 Academic Editor: Brian Finck Copyright © 2013 O. Samuelsson et al. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Chronic kidney disease (CKD) is characterised by specific lipoprotein abnormalities and insulin resistance. Dual activation of the peroxisome proliferators-activated receptors (PPAR) 𝛼 and 𝛾 can significantly improve insulin sensitivity. The aim of the study was to investigate the effects of a dual PPAR 𝛼/𝛾 agonist on lipoprotein abnormalities in patients with CKD. One mg of the dual PPAR 𝛼/𝛾 agonist tesaglitazar was given once daily during six weeks to CKD patients, and to healthy subjects. Plasma lipids, apolipoproteins (apo) and discrete lipoprotein subclasses were measured at baseline and end of treatment. In the CKD patients apoA-I increased significantly by 9%, and apoB decreased by 18%. There was an increase of apoC-III in HDL by 30%, and a parallel decrease of apoCIII in VLDL + LDL by 13%. Both the apoB-containing cholesterol-rich and the triglyceride-rich subclasses decreased significantly. With the exception of ApoC-III,all plasma lipids apolipoproteins and lipoprotein subclasses were reduced by treatment down to similar levels as the baseline levels of a healthy group of reference subjects. This study suggests that by improving insulin sensitivity a dual PPAR 𝛼/𝛾 agonist has the potential to normalise most of the lipoprotein abnormalities in patients with CKD. 1. Introduction Chronic renal insufficiency is characterized by specific lipoprotein abnormalities [1–3], insulin resistance, and accelerated cardiovascular disease (CVD) [4–6]. The renal dyslipidemia shares many features with the alterations of the lipoprotein metabolism found in patients with insulin resistance [7]. Hence, reduction of insulin resistance in chronic renal insufficiency could theoretically have positive effects on renal dyslipidemia and, consequently, also positive effects on CVD morbidity in patients with chronic kidney disease (CKD). It is well documented that patients with chronic renal insufficiency as well as patients with diabetes mellitus are at high cardiovascular risk and that the characteristic lipoprotein abnormalities play an important role in atherogenesis [8, 9]. In a post-hoc analysis of the VA-HIT study the peroxisome proliferators-activated receptor (PPAR) 𝛼 agonist gemfibrozil was shown to reduce cardiovascular morbidity in coronary patients with mild to moderate renal insufficiency [10]. Furthermore, in a post-hoc analysis of the PROactive trial the PPAR 𝛾-agonist pioglitazone significantly reduced cardiovascular morbidity in type 2 diabetic patients with reduced renal function and documented macrovascular disease [11]. Tesaglitazar is a dual PPAR 𝛼/𝛾 agonist previously in clinical development for the treatment of type 2 diabetes mellitus. It significantly improves insulin sensitivity [12]. However, the clinical development of tesaglitazar was discontinued when phase III studies indicated that the benefit-to-risk profile was unlikely to give patients a benefit over other currently available antidiabetic therapies [13–15]. The aim of the present analyses was to investigate the effects of a dual PPAR 𝛼/𝛾 agonist on lipoprotein abnormalities in patients with CKD and various degrees of renal impairment. 2. Methods 2.1. Study Design and Study Groups. The study was an openlabel study in two parallel groups. The primary aim of 2 PPAR Research Table 1: Baseline characteristics of patient and reference groups. Mean and standard deviation (in parenthesis). Age (years) Male/female (𝑛) Body mass index (kg/m2 ) S-creatinine (𝜇mol/L) Glomerular filtration rate (mL/min × 1.73 m2 BSA) Blood pressure (mm Hg) CKD patients Healthy reference group 54.9 (11.9) 17/6 27.1 (3.9) 201 (66) 55.6 (10.3) 13/4 25.0 (2.4) 71 (11) 43.2 (24.0) 94.6 (13.2) 140 (17)/81 (10) 135 (14)/81 (7) the study was to evaluate pharmacokinetics of tesaglitazar in patients with renal impairment [16]. A secondary, and prespecified, aim of the study was to analyze the pharmacodynamic effects on the lipoprotein metabolism in patients with nondiabetic, chronic kidney disease. One mg of tesaglitazar was given once daily during six weeks to patients with various degrees of renal impairment (renal impaired group) and to subjects with normal renal function (reference group). After completion of active drug treatment, the groups were followed for an additional three weeks. No dietary advice was given during the study and followup. The aim was to include eight patients in each of the three groups of varying severities of renal impairment: mild renal impairment (GFR 51–80 mL/min × 1.73 m2 BSA), moderate renal impairment (GFR 31–50 mL/min × 1.73 m2 BSA), and severe renal impairment (GFR 10–30 mL/min × 1.73 m2 BSA). Twenty-three patients were finally included (𝑛 = 7, 𝑛 = 8, and 𝑛 = 8, resp.). All patients were nondiabetic, and no one had nephrotic-range proteinuria. Patients treated with any kind of pharmacological therapy that could interfere with the lipoprotein metabolism were excluded. A group of 18 age- and sex-matched subjects with normal renal function was included as a reference group. One subject was withdrawn during the treatment period. Baseline characteristics of the groups are presented in Table 1. The study was conducted according to the Declaration of Helsinki and in accordance with the Guideline of Good Clinical Practice and was approved by independent ethics committee. Signed informed consent was received from all subjects. 2.2. Procedures. Blood samples to determine plasma lipids, apolipoproteins, lipoproteins, and their sizes were drawn in all subjects at start and after six weeks, that is, at the end of active treatment. Plasma lipids were also determined after three-week followup of study drug. In addition, fasting plasma insulin and blood glucose were measured. All samples were taken after an overnight fast. To plasma samples for the lipoprotein measurements were added preservatives containing thimerosal and a protease inhibitor, 𝜀-amino caproic acid, and they were immediately shipped by air to the Lipid and Lipoprotein Laboratory at the Oklahoma Medical Research Foundatio (...truncated)