CLINICAL THERAPEUTICSVVOL.24, NO. 3,2002 Effects of Pioglitazone and Rosiglitazone on Blood Lipid Levels and Glycemic Control in Patients with Qpe 2 Diabetes Mellitus: A Retrospective Review of Randomly Selected Medical Records Patrick J. Boyle, MD,’ Allen Bennett King, MD,2 Leann Ohmsky, MD,3 Albert Marchetti, MD,4 Helen Lm, MS,4 Raf Magar, BS,4 and John Martin, MPH4 IDepartment of In ternal Medicine, School of Medicine, University of New Mexico, Albuquerque, New Mexico, 2Department of Family and Community Medicine, School of Medicine, University of California San Francisco, San Francisco, California, 3Section of Endocrinology, Metabolism, and Hypertension, School of Medicine, University of Oklahoma, Oklahoma City, Oklahoma, and 4Health Economics Research, Secaucus, New Jersey ABSTRACT Buckgrolmd: The antihyperglycemic effects of pioglitazone hydrochloride and rosigli- tazone maleate are well documented. The results of clinical trials and observational stud- ies have suggested, however, that there are individual differences in the effects of these drugs on blood lipid levels. Objective: The present study evaluated the effects of pioglitazone and rosiglitazone on blood lipid levels and glycemic control in patients with type 2 diabetes mellitus. Methods: This was a retrospective review of randomly selected medical records from 605 primary care practices in the United States in which adults with type 2 diabetes re- ceived pioglitazone or rosiglitazone between August 1, 1999, and August 3 1, 2000. The outcome measures were mean changes in serum concentrations of triglycerides (TG), to- tal cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), low-density lipopro- tein cholesterol (LDL-C), and glycosylated hemoglobin (HbAIJ values. Results: Treatment with pioglitazone was associated with a reduction in mean TG of 55.17 mg/dL, a reduction in TC of 8.45 mg/dL, an increase in HDL-C of 2.65 mg/dL, and a reduction in LDL-C of 5.05 mg/dL. Treatment with rosiglitazone was associated with a reduction in mean TG of 13.34 mg/dL, an increase in TC of 4.81 mg/dL, a reduc- tion in HDL-C of 0.12 mg/dL, and an increase in LDL-C of 3.56 mg/dL. With the ex- ception of HDL-C, the differences in mean changes in lipid parameters between treatment groups were statistically significant (P < 0.001, pioglitazone vs rosiglitazone). Reductions in HbA,, were statistically equivalent between treatments (1.04% pioglitazone, 1.18% rosiglitazone). Accepted for publication January 7,2002. Printed in the USA. Reproduction in whole or part is not permitted. 378 0149-2918/02/$19.00 P.J. BOYLE ET AL. Conclusions: Treatment with pioglita- tings, both in TZD-naive patients and zone was associated with greater benefi- those who required a switch from trogli- cial effects on blood lipid levels than tazone. Of particular interest were the sim- treatment with rosiglitazone, whereas ilarities and differences between the newer glycemic control was equivalent between drugs (ie, their relative tolerability and ef- the 2 treatments. fectiveness compared with troglitazone Key words: type 2 diabetes, thiazoli- and each other). Based on an August 2001 dinediones, blood lipids, glycemic con- search of the Internet and the contempo- trol, hyperglycemia, hyperlipidemia. (Clin rary medical literature indexed in PubMed, Ther. 2002:24:378-396) Ovid, and Ingenta, data from clinical tri- als and other studies have demonstrated no signs or symptoms of liver toxicity re- INTRODUCTION lated to pioglitazone,8*9 whereas 1 letter The thiazolidinediones (TZDs), a newer cited the only known case of elevation in class of antihyperglycemic agents, entered liver enzymes. lo Liver abnormalities in the US market with the approval of trogli- conjunction with rosiglitazone use have tazone in 1997. The glucose-lowering ef- been reported in only 3 patients.“-16 Al- fect of these drugs appears to be related to though close monitoring of liver function their ability to reduce insulin resistance in in patients receiving either pioglitazone liver, skeletal muscle, and adipose tissue, or rosiglitazone is still advised,8s11 con- thereby increasing the effectiveness of in- cerns that these agents may be associated sulin.1*2As a result, fasting and postpran- with the liver damage and dysfunction dial blood glucose concentrations and seen with troglitazone are diminishing in circulating insulin levels decrease, and he- light of their safety record to date.&16 patic glucose production may decline.2 Evidence supporting the antihyper- These pharmacologic actions are medi- glycemic effects of these newer com- ated through peroxisome proliferator- pounds continues to be reported.8~‘1~17-29 activated receptors that control genes in- In addition, an expanding pool of recently volved in adipocyte differentiation, fatty collected data reflects other metabolic and acid metabolism, and insulin regulation.3*4 biochemical changes effected by the Two TZDs, pioglitazone hydrochloride TZDS.*,“*‘~-~~In particular, a recent ret- and rosiglitazone maleate, are currently rospective assessment in TZD-naive pa- available in the United States for the treat- tients who had received pioglitazone, ment of type 2 diabetes mellitus. Trogli- rosiglitazone, or troglitazone for type 2 tazone was withdrawn from clinical use diabetes demonstrated improvements in on March 21, 2000, as a result of drug- glycosylated hemoglobin (I-IbA,,) values related idiosyncratic liver toxicity and he- as well as changes in serum concentra- patic failure5-7 that had led to 63 reported tions of triglycerides (TG), total cho- deaths by that time. lesterol (TC), high-density lipoprotein The withdrawal of troglitazone has cholesterol (HDL-C), and low-density prompted further investigation of this drug lipoprotein cholesterol (LDL-C).31 Simi- class, providing an opportunity to com- larly, clinical observations in patients pare and contrast the treatment effects of switched from troglitazone to either pi- the newer TZDs in routine clinical set- oglitazone or rosiglitazone demonstrated 379 CLINICAL THEFtAPEUTICS” treatment effects on blood lipid levels and from prescription and practice-volume HbA,,.30*32,33These observations are of data were invited to attend 1 of 9 orienta- particular interest because patients with tion sessions held across the United States type 2 diabetes are at risk for a myriad of between November and December 2000. vascular complications related to both hy- Physicians assessed their capacity to par- perglycemia and hyperlipidemia. Choos- ticipate, the quality of their medical ing interventions that modify several risk records, and the likelihood of having an factors simultaneously is particularly ap- equal distribution of patients taking the propriate in the current health care study drugs. Each investigator received a environment. nominal honorarium. Whether the 2 remaining TZDs have Participating physicians identified pa- equivalent potential to improve lipid tients with type 2 diabetes who had started parameters will be answered best by treatment with either pioglitazone or prospective head-to-head clinical trials. rosiglitazone between August 1,1999, and Pending the availability of such prospec- August 3 1,200O. Once patients were iden- tive research, the present article provides tified, their charts were collected, assigned comparative information based on a large, a confidential patient-specific identifier, nationwide retrospective evaluation of ordered by a random-number assignment patients with type 2 diabetes. The purpose to reduce potential selection bias, and ex- of this evaluation was to examine whether amined sequentially for inclusion criteria there were significant differences between (Table I). Chart selection was completed pioglitazone and rosiglitazone with re- when 5 qualified patients receiving pi- spect to their effects on blood lipid levels oglitazone and 5 qualified patients receiv- and glycemic control in patients with ing rosiglitazone were found or the prac- type 2 diabetes treated in a primary care tice population of patients with type 2 setting. diabetes was exhausted. In almost all in- stances, the practice population was ex- hausted in the process of identifying qual- MATERIALS AND METHODS ified patients (ie, those who met inclusion A retrospective chart review of data from criteria), which further reduced the likeli- 605 primary care practices nationwide hood of patient-selection bias. was conducted between November 2000 For qualifying patients, pretreatment and March 2001. Potential contributing and posttreatment (ie, baseline and follow- investigators were chosen based on their up) laboratory TG, TC, HDL-C, LDL-C, having a patient population that would be and HbA,, values were collected, as well likely to meet the study criteria. The in- as information on demographic character- tention was to identify physicians who istics and concomitant drug use. Primary had equal numbers of patients receiving outcome measures were mean changes pioglitazone and rosiglitazone sufficient in serum TG levels within each study- to contribute potentially qualified data to drug group (baseline vs follow-up) and the study and to ensure final sample sizes between study-drug groups (pioglitazone large enough for meaningful intragroup vs rosiglitazone). Secondary outcome and intergroup comparisons. To this end, measures were mean changes in TC, >I000 primary care physicians identified HDL-C, LDL-C, and HbA,, within each 380 P.J. BOYLE ET AL. Table I. Study inclusion and exclusion criteria. Inclusion criteria 1. Age 218