Improvement of Glycemic Control, Triglycerides, And

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Emerging Treatments and Technologies ORIGINAL ARTICLE

Improvement of Glycemic Control, Triglycerides, and HDL Cholesterol Levels With Muraglitazar, a Dual (␣/␥) Peroxisome Proliferator–Activated Receptor Activator, in Patients With Type 2 Diabetes Inadequately Controlled With Metformin Monotherapy A double-blind, randomized, pioglitazone-comparative study

1 6 DAVID M. KENDALL, MD MICHAEL O’MAHONY, MD respectively) were observed in the muragli- 2 7 CINDY J. RUBIN, MD KENNETH SALL, MD tazar and pioglitazone groups; at week 50, 2 8 PHARIS MOHIDEEN, MD GREG SLOAN, MD weight gain and edema were 2.5 and 1.5 kg, 3 9 JEAN-MARIE LEDEINE, MSC ANTHONY ROBERTS, MBBS respectively, and 11.8 and 8.9%, respectively. 2 2 RENE BELDER, MD RED IEDOREK MD At week 50, heart failure was reported in seven 4 F T. F , JORGE GROSS, MD 10 patients (ﬁve with muraglitazar and two with 5 RALPH A. DEFRONZO, MD PAUL NORWOOD, MD pioglitazone), and seven deaths occurred: three from sudden death, two from cerebrovascular accident, and one from pancreatic cancer in the muraglitazar group and one from OBJECTIVE — We sought to evaluate the effects of muraglitazar, a dual (␣/␥) peroxisome perforated duodenal ulcer in the pioglitazone proliferator–activated receptor (PPAR) activator within the new glitazar class, on hyperglycemia group. and lipid abnormalities. CONCLUSIONS — We found that 5 mg RESEARCH DESIGN AND METHODS — A double-blind, randomized, controlled muraglitazar resulted in greater improvements trial was performed in 1,159 patients with type 2 diabetes inadequately controlled with met- in A1C and lipid parameters than a submaxi- formin. Patients received once-daily doses of either 5 mg muraglitazar or 30 mg pioglitazone for mal dose of 30 mg pioglitazone when added to a total of 24 weeks in addition to open-label metformin. Patients were continued in a double- metformin. Weight gain and edema were more blind fashion for an additional 26 weeks. common when muraglitazar was compared with a submaximal dose of pioglitazone. RESULTS — Analyses were conducted at week 24 for HbA1c (A1C) and at week 12 for lipid parameters. Mean A1C at baseline was 8.12 and 8.13% in muraglitazar and pioglitazone groups, respectively. At week 24, muraglitazar reduced mean A1C to 6.98% (Ϫ1.14% from baseline), Diabetes Care 29:1016–1023, 2006 and pioglitazone reduced mean A1C to 7.28% (Ϫ0.85% from baseline; P Ͻ 0.0001, muraglitazar vs. pioglitazone). At week 12, muraglitazar and pioglitazone reduced mean plasma triglyceride litazars are a new class of oral an- (Ϫ28 vs. Ϫ14%), apolipoprotein B (Ϫ12 vs. Ϫ6%), and non-HDL cholesterol (Ϫ6 vs. Ϫ1%) and increased HDL cholesterol (19 vs. 14%), respectively (P Ͻ 0.0001 vs. pioglitazone for all tidiabetic agents that activate comparisons). At week 24, weight gain (1.4 and 0.6 kg, respectively) and edema (9.2 and 7.2%, G nuclear receptors known as perox- ●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●●● isome proliferator–activated receptors (PPARs). Three PPAR subtypes have been 1 2 From the International Diabetes Center and the University of Minnesota, Minneapolis, Minnesota; Bristol- characterized: PPAR␣,-␥, and -␤/␦. Upon Myers Squibb, Princeton, New Jersey; 3Bristol-Myers Squibb, Braine-l’Alleud, Belgium; the 4Centro De Pesquisa Em Diabetes, Rio Grande Do Sul, Brazil; 5Valley Research, Fresno, California; 6Corunna Medical ligand binding, each receptor subtype Services, Ontario, Canada; the 7Sall Research Medical Center, Bellﬂower, California; the 8Emerald Coast mediates distinct physiological effects on Research Group, Chipley, Florida; 9South Australian Endocrine Clinical Research, Keswick Adelaide, Aus- glucose homeostasis and lipid metabo- tralia; and the 10University of Texas Health Sciences Center at San Antonio, San Antonio, Texas. lism. Activation of PPAR␥ reduces insulin Address correspondence and reprint requests to Ralph A. DeFronzo, MD, Department of Medicine, resistance and improves glycemic control, Division of Diabetes, University of Texas Health Sciences Center at San Antonio, Building HSC-DTL, Room ␣ 3.380S, 7703 Floyd Curl Dr., San Antonio, TX 78229. E-mail: [email protected]. whereas activation of PPAR reduces Received for publication 22 June 2005 and accepted in revised form 31 January 2006. triglyceride levels and increases concen- Abbreviations: apo, apolipoprotein; CHF, congestive heart failure; CRP, C-reactive protein; CVD, car- trations of HDL cholesterol (1,2). Mura- diovascular disease; FFA, free fatty acid; FPG, fasting plasma glucose; HOMA-IR, homeostasis model assess- glitazar, a dual (␣/␥) PPAR activator in the ment of insulin resistance; LOCF, last observation carried forward; NYHA, New York Heart Association; ␣ ␥ PAI-1, plasminogen activator inhibitor type 1; PPAR, peroxisome proliferator–activated receptor. glitazar class, activates PPAR and - , A table elsewhere in this issue shows conventional and Syste`me International (SI) units and conversion thereby improving hyperglycemia and factors for many substances. lipid abnormalities (i.e., reducing triglyc- DOI: 10.2337/dc05-1146 erides and increasing HDL cholesterol) © 2006 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 simultaneously. marked “advertisement” in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. Type 2 diabetes is a complex disorder

1016 DIABETES CARE, VOLUME 29, NUMBER 5, MAY 2006 Kendall and Associates comprising multiple metabolic and vas- mmol/l). Women of childbearing poten- the time of protocol development and cular abnormalities, including insulin re- tial were required to use effective methods study initiation, 30 mg pioglitazone was sistance, dyslipidemia, and vascular of contraception. Patients taking stable the maximum dose approved for use in inflammation. Each of these abnormali- doses of statins for at least 6 weeks before combination with metformin. Because ties represents a major risk factor for the randomization were eligible for enroll- the maximally effective dose of piog- development of cardiovascular disease ment and continued therapy at their base- litazone is 45 mg/day, the clinical sig- (CVD) (3–5). Reducing the markedly in- line statin doses during weeks 1–12. After nificance of differences between creased risk for CVD in patients with type week 12, investigators were permitted to muraglitazar- and pioglitazone-treated 2 diabetes is believed to be dependent on add lipid-regulating therapy (except for groups, both with respect to efficacy effective management of multiple risk fac- the combination of a statin plus a fibrate) and safety parameters, should not be tors (3). The current randomized double- or adjust the dose of current therapy if overinterpreted. Double-blind study blind study was conducted to evaluate the clinically necessary. medication was administered before the effects of muraglitazar on glycemic and Exclusion criteria included symp- morning meal along with the open-label lipid parameters and to compare the effi- tomatic type 2 diabetes, defined as poly- dose of metformin taken twice daily for cacy and tolerability of muraglitazar with uria or polydipsia with Ͼ10% weight loss 24 weeks. Dose titration of double- that of pioglitazone—a PPAR␥ activa- in the preceding 3 months; history of di- blind medications or open-label met- tor—in patients with type 2 diabetes in- abetic ketoacidosis or hyperosmolar non- formin was not permitted. Patients who adequately controlled with metformin ketotic coma; designation of class III/IV completed the initial 24 week period monotherapy. heart failure according to New York Heart were eligible to continue into a 26-week Association (NYHA) criteria; and treat- double-blind extension. The same dou- RESEARCH DESIGN AND ment with niacin, ezetimibe, or bile-acid ble-blind treatment (plus open-label METHODS — The primary objective binding agents within 6 weeks, with fi- metformin) assigned during the initial of this study was to compare the change in brates within 8 weeks, or with probucol 24-week period was continued without HbA1c (A1C) levels achieved after 24 within 1 year of randomization. Patients change during the subsequent 26-week weeks of treatment when adding either 5 could not use other oral glucose-lowering extension. Patients were discontinued mg muraglitazar or 30 mg pioglitazone to therapy, with the exception of metformin, from the study for lack of glycemic con- metformin in patients with inadequately during the 6 weeks before screening. trol if FPG (measured twice within 3–5 controlled (A1C Ն7.0 to Յ10.0%) type 2 All patients gave written informed days) was Ͼ240 mg/dl at week 6, Ͼ220 diabetes on metformin monotherapy. consent to participate in the study, and mg/dl at week 8, or Ͼ200 mg/dl at Secondary end points assessed the per- the institutional review board of each par- weeks 12, 16, or 20. Additionally, pa- centage of change from baseline in fasting ticipating center approved its protocol. tients were discontinued from the study lipid levels (triglyceride, HDL cholesterol, Qualified investigators conducted the study if A1C was Ͼ8% at weeks 30 or 37. apolipoprotein B [apoB], non-HDL cho- in accordance with good clinical practice Safety was assessed via patient- lesterol) after 12 weeks (presented as av- and under the principles of the Declaration reported adverse events, clinical observa- erage values obtained from weeks 11 and of Helsinki, its amendments, and applicable tions, and regular monitoring of vital 12) of treatment. Other efficacy variables regulations and guidelines. signs, physical examinations, and labora- assessed at week 24 included the propor- This was a multicenter randomized tory findings. There was no formal adju- tion of patients achieving A1C Ͻ7.0, double-blind parallel-group active- dication of coronary heart disease death, Ͻ6.5, and Ͻ6.0%; change from baseline controlled trial designed to show the non- nonfatal myocardial infarction, stroke, or in fasting plasma glucose (FPG) and fast- inferiority of 5 mg muraglitazar added to other clinical end points. In addition, ing insulin; analysis of homeostasis model metformin versus 30 mg pioglitazone subjects were not followed for occurrence assessment of insulin resistance (HOMA- added to metformin by evaluating the of these clinical events if they had been IR); percentage change from baseline in change in A1C from baseline to week 24. discontinued because of lack of efficacy, free fatty acid (FFA) and LDL cholesterol; Patients were drawn from 234 centers lo- side effects, or other cause. and percentage change from baseline in cated in 13 countries. Patients who met high-sensitivity C-reactive protein (CRP) screening and inclusion criteria partici- Assays and plasminogen activator inhibitor type pated in a 2-week placebo lead-in phase. Blood and urine samples were obtained at 1 (PAI-1). Safety and tolerability informa- Patients remained on metformin at doses specified time points for laboratory eval- tion reported during the 24-week study (open-label, 500-mg tablets) equal to or uations. With the exception of urine preg- and from the 26-week extension (for a less than the baseline dose according to nancy tests, which were performed at total of 50 weeks on treatment) also was the following schedule: baseline met- local investigative sites, all scheduled lab- evaluated. formin doses of 1,500 to Ͻ2,000 mg/day oratory tests were performed and ana- Men and women aged 18–70 years were switched to 1,500 mg/day; baseline lyzed at central laboratories. with type 2 diabetes and inadequate gly- metformin doses of 2,000 to Ͻ2,500 mg/ Plasma A1C levels were determined cemic control who were taking stable day were switched to 2,000 mg/day; and using high-performance liquid chroma- doses of metformin (1,500–2,550 mg/ baseline metformin doses of 2,500–2,550 tography (Variant II hemoglobin testing day) for at least 6 weeks were eligible for mg/day were switched to 2,500 mg/day. system; BioRad, Hercules, CA), and study participation. Patients were re- At the end of the lead-in phase, patients plasma glucose, triglyceride, total choles- quired to have a fasting C-peptide con- were randomly assigned to one of two terol, HDL cholesterol, LDL cholesterol, centration Ն1.0 ng/ml (0.34 mmol/l), treatment groups: once-daily 5 mg mura- and FFA levels were determined using BMI Յ41 kg/m2, and mean serum triglyc- glitazar or 30 mg pioglitazone. This dose enzymatic colorimetic assays (reagents eride concentration Յ600 mg/dl (6.78 of pioglitazone was selected because at obtained from Roche Diagnostics, India-

DIABETES CARE, VOLUME 29, NUMBER 5, MAY 2006 1017 Muraglitazar and type 2 diabetes

Table 1—Patient demographics, baseline disease characteristics, and primary reason for performed on data collected from all ran- discontinuation domly assigned patients who received at least one dose of double-blind study med- Muraglitazar Pioglitazone ication. To be included in the efficacy analyses on change from baseline, pa- n 587 572 tients had to have valid baseline and post- Demographics baseline data. Patients were only included Age (years) 55.3 Ϯ 8.6 54.1 Ϯ 9.1 in the analyses of A1C and lipid variables Men (%) 45.8 49.0 if they received at least 6 weeks of double- Race blind treatment; analyses of FPG and fast- White/black/other (%) 89.6/8.3/2.0 89.9/7.0/3.1 ing insulin included only those patients Ethnicity who received at least 8 days of double- Hispanic/Latino (%) 15.0 18.7 blind therapy. HOMA-IR values were Non-Hispanic/Latino (%) 85.0 81.3 computed using the following equation: BMI (kg/m2) 32.0 Ϯ 4.6 32.0 Ϯ 4.6 (1/22.5) ϫ FPG ϫ fasting plasma insulin. Body weight (kg) 90.2 Ϯ 17.4 91.0 Ϯ 17.2 The methodology of last observation car- Diabetes duration (years) 6.0 Ϯ 5.0 5.8 Ϯ 5.1 ried forward (LOCF) was used for efficacy Mean metformin dose (mg/day) 1,854 1,851 parameters. Disease characteristics Muraglitazar was noninferior to pio- A1C (%) 8.12 8.13 glitazone if the upper limit of the two- Fasting plasma glucose (mg/dl) 179 178 sided 95% CI of the difference in A1C Fasting insulin (␮U/ml) 15 15 change from baseline to week 24 LOCF FFAs (mEq/l) 0.66 0.66 between the two treatment groups was Lipids Յ0.25%. If noninferiority was demon- Triglycerides (mg/dl) 206 203 strated and the upper limit of the two- HDL cholesterol (mg/dl) 46 46 sided 95% CI was Ͻ0, the superiority of ApoB (mg/dl) 101 101 muraglitazar was tested at a two-sided sig- Non-HDL cholesterol (mg/dl) 152 151 nificance level of 0.05 using the same LDL cholesterol (mg/dl) 113 113 ANCOVA model. High-sensitivity CRP (mg/l) 3.16 3.19 PAI-1 (ng/ml) 43.8 41.9 RESULTS Primary reason for discontinuation (week 24) Patient demographics and Total discontinuations 65 (11.1) 90 (15.7) disposition Lack of glycemic efficacy 18 (3.1) 36 (6.3) A total of 2,173 patients were screened, Consent withdrawn 16 (2.7) 30 (5.2) and 1,202 patients received placebo Adverse event 15 (2.6) 8 (1.4) study medication during the lead-in Lost to follow-up 7 (1.2) 7 (1.2) phase. Of these, 1,159 patients were ran- Poor compliance/noncompliance 4 (0.7) 4 (0.7) domly assigned to double-blind treat- No longer met inclusion criteria 2 (0.3) 4 (0.7) ment, 1,004 (87%) patients completed Pregnancy* 1 (0.2) 1 (0.2) the initial 24-week period, and 762 Death 2 (0.3) 0 (0.0)† (66%) patients completed the entire 50- Data are means ϮSD or n (%), unless otherwise indicated. *Both pregnancies resulted in normal healthy week period. Treatment groups were well births; †one subject in the pioglitazone group died (perforated duodenal ulcer) after discontinuing the study matched with respect to baseline demo- because of an adverse event (calculus urinary). graphic and disease characteristics (Table 1). Baseline A1C values were 8.12 and napolis, IN). Non-HDL cholesterol was Products, Los Angeles, CA), and PAI-1 con- 8.13% in the muraglitazar and pioglita- computed as the difference between total centrations were determined using an en- zone groups, respectively. Mean duration cholesterol and HDL cholesterol. zyme-linked immunosorbent assay (means Ϯ SD) of diagnosed diabetes was ApoB and high-sensitivity CRP levels (TintElize; Trinity BioTech, Bray, Ireland). 5.9 Ϯ 5.0 years. A similar percentage were determined using immunoturbidi- (ϳ25%, 143 patients in the muraglitazar metric assays. Plasma samples were com- Statistical analyses group and 143 patients in the pioglita- bined with either anti-human apoB All analyses for mean change or mean per- zone group) of patients were on concom- antiserum or anti-human high-sensitivity centage of change from baseline were ad- itant statin therapy at baseline and at CRP antibody. The intensity of the turbid- justed for baseline level using ANCOVA. week 24 (i.e., 149 patients in the mura- ity (which is proportional to the concen- Point estimates and 95% CIs were con- glitazar group and 150 patients in the pio- tration of antibody-antigen complexes) structed for within-group adjusted mean glitazone group), indicating that few was measured at 340 nm for apoB and (percentage) changes from baseline and patients added a lipid-lowering drug dur- 700 nm for high-sensitivity CRP. for the difference in mean (percentage) ing the course of the study. Hypertriglyc- Plasma insulin concentrations were change from baseline between the mura- eridemia, defined as blood triglyceride determined using an enzymatic immu- glitazar and pioglitazone treatment values Ն150 mg/dl, was observed at base- nosorbent assay (Immulite Diagnostic groups. Efficacy and safety analyses were line in 352 patients in the muraglitazar

1018 DIABETES CARE, VOLUME 29, NUMBER 5, MAY 2006 Kendall and Associates

(mean triglyceride was 265 mg/dl in both groups), muraglitazar therapy was associated with a signiﬁcantly greater reduction in triglyceride than pioglitazone therapy (Ϫ35 vs. Ϫ19%, P Ͻ 0.0001). At week 12, increases in HDL cholesterol were greater in the muraglitazar group (19% from baseline) versus the pioglitazone group (14% from baseline; P Ͻ 0.0001) (Fig. 2). Mean percentage changes in LDL cholesterol levels from baseline to week 12 were similar in both groups. Muragli- tazar and pioglitazone both reduced apoB (Ϫ12 and Ϫ6%, respectively) and non- HDL cholesterol (Ϫ6 and Ϫ1%) concentrations at week 12 (both P Ͻ 0.0001 for muraglitazar vs. pioglitazone) (Fig. 2). Initiation of or changes to the dosage of lipid-regulating medications was permitted after week 12; changes in lipid parameters (triglyceride, HDL cholesterol, apoB, non-HDL cholesterol, and LDL cholesterol) at week 24 were similar to those observed at week 12).

High-sensitivity CRP and PAI-1 After 24 weeks of therapy, high- sensitivity CRP was 2.4 mg/l (Ϫ30.2% from baseline) in the muraglitazar group Figure 1—A: Mean change from baseline in A1C (and 95% CI) over time. B: Distribution of and 2.7 mg/l (Ϫ23.6% from baseline) in patients reaching target A1C levels at week 24. Number of patients with available data: muragli- ϭ ϭ ϭ Ͻ ϭ the pioglitazone group (P 0.04). PAI-1 tazar, n 569; pioglitazone, n 550. *P 0.0001 vs. pioglitazone; †P 0.0004 vs. pioglita- Ϫ zone. was 30.7 ng/ml ( 30.4% from baseline) at week 24 in the muraglitazar group and 34.4 ng/ml (Ϫ21.5% from baseline) in the pioglitazone group (P ϭ 0.0002). group and in 335 patients in the pioglita- tively (P Ͻ 0.0001). Mean changes from zone group. baseline in fasting insulin levels were Ϫ5.0 ␮U/ml for muraglitazar-treated pa- Safety Glycemic parameters tients and Ϫ3.6 ␮U/ml for pioglitazone- The overall incidence of adverse events A1C. Muraglitazar and pioglitazone both treated patients (P Ͻ 0.0001). during the study during week 50 was sim- lowered A1C levels from baseline. The re- HOMA-IR. Baseline HOMA-IR was 6.6 ilar in the muraglitazar (72%) and piogli- duction in A1C was significantly greater ␮U/ml mmol/l in both groups. At week tazone (69%) groups. Serious adverse in the muraglitazar group than in the pio- 24, HOMA-IR was reduced to 3.3 ␮U/ml events were reported for 8.2% (n ϭ 48) of glitazone group (Fig. 1). At week 24, mmol/l (Ϫ48.6% from baseline) in the patients in the muraglitazar group and mean A1C levels were 6.98% (Ϫ1.14% muraglitazar-treated group and 4.1 5.8% (n ϭ 33) of patients in the pioglita- from baseline) with muraglitazar and (Ϫ37.1) in the pioglitazone-treated group zone group. Adverse events (excluding 7.28% (Ϫ0.85% from baseline) with pio- (P Ͻ 0.0001). edema) observed in Ն5% of patients in glitazone (difference Ϫ0.29%, 95% CI FFAs. Reductions in FFAs at week 12 the muraglitazar and pioglitazone groups Ϫ0.39 to Ϫ0.19, P Ͻ 0.0001). At week were significantly greater in the muragli- were nasopharyngitis (8.3 vs. 8.0%), hy- 24, a larger percentage of patients treated tazar group (Ϫ30% from baseline) than in pertension (8.0 and 7.3%), arthralgia (7.2 with muraglitazar achieved target A1C the pioglitazone group (Ϫ21% from base- and 7.0%), headache (5.6 and 5.6%), up- levels Ͻ7orϽ6.5% (60 and 34%, respec- line) (P Ͻ 0.0001). FFA levels at week 12 per respiratory tract infection (5.6 and tively) compared with patients treated were 0.47 and 0.53 mEq/l in the muragli- 6.8%), back pain (5.5 and 4.4%), and with pioglitazone (45 and 23%, respec- tazar and pioglitazone groups, respectively. pain in extremity (5.1 and 3.0%). tively) (Fig. 1). Body weight. Increases in body weight FPG and insulin concentrations. Re- Lipid parameters were observed in both groups at weeks 24 ductions in FPG and in insulin levels were At week 12, the mean percentage change and 50. The change (mean Ϯ SE) in body significantly greater in the muraglitazar from baseline in fasting triglyceride levels weight was greater in muraglitazar- group than in the pioglitazone group. Af- was greater with muraglitazar (Ϫ28%) treated patients (ϩ1.4 Ϯ 0.14 kg) com- ter 24 weeks of therapy, FPG values were than pioglitazone (Ϫ14%) (P Ͻ 0.0001) pared with those receiving pioglitazone reduced 44 and 33 mg/dl in the muragli- (Fig. 2). In the subset of patients with tri- (ϩ0.6 Ϯ 0.15 kg, P Ͻ 0.0001). At week tazar and pioglitazone groups, respec- glyceride levels Ն150 mg/dl at baseline 50 the increases in body weight were

DIABETES CARE, VOLUME 29, NUMBER 5, MAY 2006 1019 Muraglitazar and type 2 diabetes

peptide) levels (n ϭ 2) in the muraglitazar group and NYHA class I heart failure (n ϭ 1) and coronary artery disease (n ϭ 1) in the pioglitazone group. Cardiovascular events and deaths. A total of 22 patients (12 [2.0%] in the muraglitazar group and 10 [1.7%] in the pioglitazone group) had a coronary or cerebrovascular event reported as an adverse event during the 50-week period. Over the 50-week period, six deaths were reported in the muraglitazar group, and one death was reported in the pioglitazone group. Five of six deaths in the muraglitazar group were classified as cardiovascular or cerebrovascular events: three sudden deaths occurred in subjects with known histories of atherosclerosis and multiple cardiac risk factors, with two of the three having histories of heart failure, and two deaths from stroke occurred in subjects with multiple risk factors for cerebrovascular accident. The remaining death in the muraglitazar group was caused by pancreatic cancer. The one death in the pioglitazone group was caused by a perforated duodenal ulcer. In the muraglitazar group, investigators reported the relationship of study medication and five of the deaths as “not related,” whereas the death caused by pancreatic Figure 2—Mean percentage change from baseline in lipid parameters at weeks 12 and 24. HDL-C, HDL cholesterol; LDL-C, HDL cholesterol; TG, triglyceride. *P Ͻ 0.0001 vs. pioglitazone. cancer was reported as “not likely related.” Discontinuations. Of the 1,159 ran- ϩ2.5 Ϯ 1.8 and 1.5 Ϯ 1.8 kg, respec- pioglitazone group had their heart failure domized patients, 1,004 completed the tively (P Ͻ 0.0001). event reported as a serious adverse event. initial 24-week period, with 155 patients Edema. Edema-related adverse events at The events were reported as mild (n ϭ 1), discontinuing (65 in the muraglitazar week 24 were observed in 9.2% of pa- moderate (n ϭ 3), and very severe (n ϭ 1) group and 90 in the pioglitazone group) tients treated with muraglitazar and 7.2% in the muraglitazar group and mild (n ϭ (Table 1). At week 24, adverse events re- of patients treated with pioglitazone (P ϭ 1) and severe (n ϭ 1) in the pioglitazone sulted in study discontinuation in 15 0.33). At week 50, 11.8% of patients in group. Four of the five subjects in the mu- (2.6%) and 8 (1.4%) patients treated with the muraglitazar group and 8.9% of pa- raglitazar group were treated with diuret- muraglitazar and with pioglitazone, re- tients in the pioglitazone group reported ics, with resolution of the events within spectively. A total of 18 patients in the at least one edema-related event (P ϭ 5–16 days. One subject in the muragli- muraglitazar group and 36 patients in the 0.19). All edema-related adverse events tazar group who experienced heart failure pioglitazone group discontinued the were graded as either mild or moderate, had a serious adverse event of myocardial study because of lack of glycemic efficacy with the exception of one severe adverse infarction and died within a few hours. at week 24. A total of 762 (66%) patients event reported in each treatment group. The heart failure event of one subject in (muraglitazar group, n ϭ 396; pioglita- Two patients in the muraglitazar group the pioglitazone group resolved with zone group, n ϭ 366) completed the 50- and one patient in the pioglitazone group treatment in 9 days, and the event in the week treatment period. Reasons for discontinued from the study because of other subject resolved with treatment in discontinuation in the muraglitazar and edema-related adverse events. 96 days. One subject in the muraglitazar pioglitazone groups included lack of gly- Heart failure. At week 24, there were group continued in the study after the cemic efficacy (12 vs. 17%), withdrawal three cases of mild to moderate heart fail- heart failure event, whereas the five others of consent (8 and 9%), adverse events (5 ure reported in the muraglitazar group (three muraglitazar, two pioglitazone) and 3%), sponsor-related administrative and one case reported in the pioglitazone discontinued according to protocol de- reason/lost to follow-up (6 and 4%), and group. Between weeks 24 and 50, there sign. All seven patients had histories of protocol violation/compliance problem/ were two additional cases of heart failure cardiac disease, which included NYHA pregnancy/other (3 and 2%). reported in the muraglitazar group and class II heart failure (n ϭ 2), severe hyper- one additional case reported in the piogli- tension (n ϭ 1), and coronary artery dis- CONCLUSIONS — The current study tazone group. Of these subjects, four in ease with elevated NT-proBNP (NH2- is the first to compare the effect of mura- the muraglitazar group and one in the terminal prohormone brain natriuretic glitazar, a dual (␣/␥) PPAR activator in the

1020 DIABETES CARE, VOLUME 29, NUMBER 5, MAY 2006 Kendall and Associates new glitazar class, with pioglitazone, a patients with atherosclerosis (6). How- presence of edema in patients treated with PPAR␥ activator, on glycemic control and ever, it is unknown whether the effects of PPAR␥ therapy from the development of lipid abnormalities in individuals with muraglitazar to decrease high-sensitivity conjestive heart failure (CHF). Although type 2 diabetes inadequately controlled CRP and PAI-1, coupled with the lipid the development of edema is relatively with metformin monotherapy. Results of effects (i.e., decreases in triglycerides and common, the development of heart fail- this 24-week, double-blind trial showed increases in HDL cholesterol), will trans- ure is infrequent and is reported in 1–3% that muraglitazar lowered A1C levels to a late into a difference in CVD risk. The of patients receiving thiazolidinediones greater extent than pioglitazone therapy effects of PPAR␥ activation (7) and either alone or in combination with insu- (mean difference of Ϫ0.29%, P Ͻ PPAR␣ activation (8) in long-term trials lin (15,16,27). Prior studies suggest that 0.0001) when added to stable doses of should provide more insight into the po- PPAR␥ agonists can reduce peripheral metformin. In addition, the proportion of tential impact of dual PPAR activators on vascular resistance and improve cardiac patients achieving target A1C levels was CVD outcomes. output (28). A recent observational study significantly greater in the muraglitazar Weight gain has been widely ob- examined the characteristics of fluid re- treatment group (at week 24) than in the served in clinical trials involving thiazo- tention in a large cohort of patients with pioglitazone group for each of the A1C lidinediones (9–12), and the magnitude diabetes and impaired left ventricular goals evaluated (Ͻ7.0, Ͻ6.5, and of weight gain is generally correlated with function (29). Results of this study Ͻ6.0%; P Յ 0.0004 vs. pioglitazone). the degree of improvement in glycemic showed that pulmonary edema was much Muraglitazar’s insulin-sensitizing effects control (10–12). In addition to the more common in individuals treated with were demonstrated by reductions in weight gain associated with improved gly- a nonthiazolidinedione antidiabetic agent plasma insulin levels, decreases in cemic control, several other mechanisms than with a thiazolidinedione (80 vs. HOMA-IR values, and lower circulating may also contribute to weight gain, in- 11%, respectively) (29). In the current FFA levels. Between-group differences for cluding fluid retention and an increase in study, a small number of patients devel- all three parameters statistically favored overall adipogenesis. Stimulation of oped clinical heart failure: five mura- muraglitazar. PPAR␥ receptors on adipocytes initiates glitazar-treated patients and two Compared with pioglitazone, mura- cell division, leading to an increase in the pioglitazone-treated patients. Given this glitazar resulted in a statistically signifi- number of small fat cells in subcutaneous low incidence, it is difficult to attribute cant improvement in plasma triglyceride, fat depots (13). In addition, activation of any clinical significance to this observa- HDL cholesterol, apoB, and non-HDL PPAR␥ receptors induces numerous tion. Nonetheless, thiazolidinediones are cholesterol concentrations at week 12, genes involved in lipogenesis and the in- contraindicated in diabetic patients with which was time on treatment before any hibition of lipolysis (11,14). These effects class III–IV CHF, and in the present additional modifications in lipid-lowering lead to an increase in subcutaneous fat study, CHF occurred in asymptomatic in- therapies could be made. Muraglitazar re- mass and are responsible, in part, for the dividuals with either known histories of duced triglyceride concentrations to a larger reduction in plasma FFA concentration. class I or II CHF and/or with significant extent than pioglitazone, regardless of base- Hence, a reduction in plasma FFA con- risk factors for CHF. Therefore, all dia- line triglyceride levels. Muraglitazar and centration and an increase in body weight betic patients who are treated with a pioglitazone treatment was associated with reflects improved insulin action, which PPAR␥ activator should be monitored slight (3–4%) increases in LDL cholesterol. correlates with improvements in glycemic closely for evidence of edema and symp- However, muraglitazar resulted in signif- control (10,11). toms of CHF. icantly larger reductions in apoB levels Fluid retention leading to the devel- A total of 22 patients (12 muraglitazar than pioglitazone. Reductions in apoB opment of peripheral edema is a well- and 10 pioglitazone) experienced a coro- levels were accompanied by minimal ef- known effect of current PPAR␥ activators. nary or cerebral event during the 50-week fects on LDL cholesterol levels, suggesting Edema has been reported in up to 16% of period. A total of seven deaths occurred a shift in LDL cholesterol particle size patients treated with thiazolidinedione during the course of this study. Five of the from small dense LDL particles to larger, monotherapy (9,12,15–18). Both mura- deaths in the muragltiazar group ap- more buoyant ones. Specific measure- glitazar and pioglitazone therapy were as- peared to be associated with either cardio- ment of LDL cholesterol particle size and sociated with edema (11.8 and 8.9%, vascular or cerebrovascular events. A concentration was not performed. respectively, at week 50) in the present recent publication (30) suggested that It should be noted that the maximally study. PPAR␥ activators can cause fluid muraglitazar was associated with an in- effective dose of pioglitazone is 45 mg/ retention by promoting solute and water creased number of cardiovascular events. day. Therefore, caution should be used in retention in the renal collecting duct However, this analysis (30) did not take evaluating the clinical significance of the (19,20). PPAR␥ agonists also possess cal- into account the patient years of exposure differences in A1C and plasma lipid levels cium channel–blocking activity (21) and in the various study groups, and it com- between the muraglitazar (5 mg/day) and stimulate the release of nitric oxide (22), bined with placebo an active comparator pioglitazone (30 mg/day) groups in the both of which are associated with edema (pioglitazone) to constitute the control present study. formation in ϳ5–10% of individuals group. Based on the recently published Significant reductions in levels of (23,24). PPAR␥ agonists have also been PROactive study (7), which demonstrated high-sensitivity CRP and the prothrom- shown to cause vascular leak in animals that the combined end point of death/ botic plasma marker PAI-1 were observed (25). Finally, it has been suggested that myocardial infarction/stroke was signifi- in the muraglitazar-treated group. Inter- PPAR␥ agonists enhance insulin- cantly decreased in pioglitazone-treated ventions that decrease high-sensitivity mediated sodium reabsorption by the diabetic patients, it is essential that the CRP levels have been shown to reduce the kidney (26). calculation of event rates (i.e., cardiovas- risk of macrovascular complications in It is important to differentiate the cular events and cardiovascular deaths)

DIABETES CARE, VOLUME 29, NUMBER 5, MAY 2006 1021 Muraglitazar and type 2 diabetes be based on patient exposure years for 24:308–315, 2001 [erratum Diabetes Acknowledgments— This study was sup- each individual group (i.e., muraglitazar, Care 24:973, 2001] ported by a grant from the Bristol-Myers 10. Einhorn D, Rendell M, Rosenzweig J, pioglitazone, placebo). This is a major te- Squibb Pharmaceutical Research Institute, net of all cardiovascular outcome studies, Egan JW, Mathisen AL, Schneider RL, for Princeton, New Jersey. The Pioglitazone 027 Study Group: Pio- and an analysis using these factors is cur- The authors thank Lynn Brown, PhD, for her glitazone hydrochloride in combination rently in development. In summary, it is assistance in the preparation of this manuscript. with metformin in the treatment of type 2 difficult to conclude either that any car- diabetes mellitus: a randomized, placebo- diovascular risk or cardiovascular benefit controlled study. Clin Ther 22:1395–1409, of muraglitazar exists, given the small References 2000 number of events which accrued over a 1. Lee CH, Olson P, Evans RM: Minireview: 11. Bays H, Mandarino L, DeFronzo RA: Role relatively short period of time. In addi- lipid metabolism, metabolic diseases, and of the adipocyte, free fatty acids, and ec- topic fat in pathogenesis of type 2 diabetes tion, in the muraglitazar clinical trials peroxisome proliferator-activated receptors. Endocrinology 144:2201–2207, 2003 mellitus: peroxisomal proliferator-acti- programs, outcome events were not adju- 2. Kota BP, Huang TH-W, Roufogalis BD: vated receptor agonists provide a rational dicated, nor was there long-term fol- An overview on biological mechanisms of therapeutic approach. J Clin Endocrinol low-up of patients who discontinued PPARs. Pharmacol Res 51:85–94, 2005 Metab 89:463–478, 2004 therapy. Accurate assessment of benefit 3. American Diabetes Association: Stan- 12. 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Okuno A, Tamemoto H, Tobe K, Ueki K, approved dose of this agent. During de- 5. Krauss RM: Lipids and lipoproteins in pa- Mori Y, Iwamoto K, Umesono K, velopment of the study protocol, the max- tients with type 2 diabetes (Review). Dia- Akanuma Y, Fujiwara T, Horikoshi H, Yazaki Y, Kadowaki T: Troglitazone in- imum pioglitazone dose approved for use betes Care 27:1496–1504, 2004 6. Nissen SE, Tuzcu EM, Schoenhagen P, creases the number of small adipocytes in combination with metformin was 30 Crowe T, Sasiela WJ, Tsai J, Orazem J, without the change of white adipose tis- mg, which is the highest recommended Magorien RD, O’Shaughnessy C, Ganz P: sue mass in obese Zucker rats. J Clin Invest dose for initiating combination treatment Statin therapy, LDL cholesterol, C-reac- 101:1354–1361, 1998 with metformin in the current pioglita- tive protein, and coronary artery disease. 14. Patsouris D, Muller M, Kersten S: Peroxi- zone prescribing information (15). 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