Pioglitazone and Rosiglitazone Have Different Effects on Serum Lipoprotein Particle Concentrations and Sizes in Patients With Type 2 Diabetes and Dyslipidemia MARK A. DEEG, MD 1 JOHN B. BUSE, MD 2 RONALD B. GOLDBERG, MD 3 DAVID M. KENDALL, MD 4 ANTHONY J. ZAGAR, MS 5 SCOTT J. JACOBER, DO 5 MEHMOOD A. KHAN, MD 6 ALFONZO T. PEREZ, MD 7 MENG H. TAN, MD 5 ON BEHALF OF THE GLAI STUDY INVESTIGATORS* OBJECTIVE — Associated with insulin resistance in type 2 diabetes are increased serum triglycerides, decreased HDL cholesterol, and a predominance of large VLDL, small LDL, and small HDL particles. The comparative effects of thiazolidinedione insulin sensitizers on serum lipoprotein particle concentrations and sizes in type 2 diabetes are not known. We studied the effects of pioglitazone (PIO) and rosiglitazone (ROSI) treatments on serum lipoprotein particle concentrations and sizes in type 2 diabetic patients with dyslipidemia. RESEARCH DESIGN AND METHODS — This is a prospective, randomized, double- blind, multicenter, parallel-group study. After a 4-week placebo washout period, patients ran- domized to PIO (n = 369) were treated with 30 mg q.d. for 12 weeks followed by 45 mg q.d. for another 12 weeks, while patients randomized to ROSI (n = 366) were treated with 4 mg q.d. followed by 4 mg b.i.d. for the same intervals. Lipoprotein subclass particle concentrations and sizes were determined by proton nuclear magnetic resonance spectroscopy at baseline and end point (PIO [n = 333] and ROSI [n = 325] patients). RESULTS — PIO treatment increased total VLDL particle concentration less than ROSI treat- ment and decreased VLDL particle size more than ROSI. PIO treatment reduced total LDL particle concentration, whereas ROSI treatment increased it. Both treatments increased LDL particle size, with PIO treatment having a greater effect. Whereas PIO treatment increased total HDL particle concentration and size, ROSI treatment decreased them; both increased HDL cholesterol levels. CONCLUSIONS — PIO and ROSI treat- ments have different effects on serum lipopro- tein subclass particle concentrations and sizes in patients with type 2 diabetes and dyslipidemia. Diabetes Care 30:2458–2464, 2007 T wo core metabolic defects contrib- ute to the development of type 2 diabetes: insulin resistance and in- sulin insufficiency. Insulin resistance, present in most of these patients (1), is associated with a cluster of abnormalities that increase the risk for cardiovascular disease, including dyslipidemia (2,3) characterized by elevated triglycerides, decreased HDL cholesterol, and a pre- dominance of small LDL particles (4 –7). A major contributor to this hypertriglyc- eridemia is hepatic overproduction of tri- glyceride-rich VLDL and apolipoprotein (apo) B caused by insulin resistance and increased availability of free fatty acid substrate (8,9). Insulin suppresses large VLDL and apoB release in healthy hu- mans (10) but not in patients with type 2 diabetes, resulting in hypertriglyceride- mia (11). Decreased lipoprotein lipase activity in fat and skeletal muscle contrib- utes to the reduced clearance of triglycer- ide-rich lipoproteins (10,11). The exchange of triglycerides in the VLDL par- ticles with the cholesteryl esters in LDL and HDL particles (via the cholesteryl es- ter transfer protein system) leads to accu- mulation of small LDL and HDL particles, respectively (12). The mean particle size of VLDL increases and the LDL and HDL particle sizes decrease as insulin resis- tance worsens in nondiabetic subjects and type 2 diabetic patients (7). By targeting insulin resistance, the thiazolidinedione (TZD) class of oral an- tihyperglycemic medications (OAMs) can affect glucose and lipoprotein metabo- lism. Pioglitazone hydrochloride (PIO) (Actos; Takeda Pharmaceuticals North America, Lincolnshire, IL) and rosiglita- ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● From the 1 Department of Endocrinology and Metabolism, Veterans Affairs Hospital and Indiana University, Indianapolis, Indiana; the 2 Department of Endocrinology and General Medicine, University of North Caro- lina, Chapel Hill, North Carolina; the 3 Department of Endocrinology, Metabolism and Diabetes, University of Miami, Miami, Florida; the 4 International Diabetes Center, Park Nicollet Institute, Minneapolis, Minne- sota; 5 Lilly Research Laboratories, Eli Lilly and Company, Indianapolis, Indiana; 6 Takeda Pharmaceuticals North America, Lincolnshire, Illinois; and 7 Takeda Global Research and Development, Lincolnshire, Illinois. Address correspondence and reprint requests to Meng H. Tan, MD, Lilly Research Laboratory, Eli Lilly and Company, Indianapolis, IN 46285. E-mail: tan_meng@lilly.com. Received for publication 12 September 2006 and accepted in revised form 18 June 2007. Published ahead of print at http://care.diabetesjournals.org on 26 June 2007. DOI: 10.2337/dc06-1903. Clinical trial reg. no. NCT00331487, clinicaltrials.org. *A complete list of the GLAI Study Investigators can be found in the APPENDIX. D.M.K is currently affiliated with Amylin Pharmaceuticals, San Diego, California. M.A.D. has received honoraria from Takeda. J.B.B. has received consulting fees from Eli Lilly, LipoScience, Lilly, and Takeda. R.B.G. has received honoraria from Lilly, Takeda, Pfizer, Merck, Merck Schering Plough, KOS, Astra Zeneca, and Abbott; has received grant/research support from Novo Nordisk, Pfizer, Merck, KOS, Astra Zeneca, and Sankyo; and has received consulting fees from Lilly and Takeda, Pfizer, Merck, Merck Schering Plough, Astra Zeneca, and Abbott. Abbreviations: Apo, apolipoprotein; HOMA-IR, homeostasis model assessment of insulin resistance; IDL, intermediate-density lipoprotein; NMR, nuclear magnetic resonance; OAM, antihyperglycemic medi- cation; PIO, pioglitazone; ROSI, rosiglitazone; TZD, thiazolidinedione. A table elsewhere in this issue shows conventional and Syste `me International (SI) units and conversion factors for many substances. © 2007 by the American Diabetes Association. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Clinical Care/Education/Nutrition/Psychosocial Research O R I G I N A L A R T I C L E 2458 DIABETES CARE, VOLUME 30, NUMBER 10, OCTOBER 2007 Downloaded from http://diabetesjournals.org/care/article-pdf/30/10/2458/595706/zdc01007002458.pdf by guest on 27 September 2022