- Email: [email protected]
γ agonist, improves apolipoprotein levels in non-diabetic subjects with insulin resistance
Atherosclerosis 197 (2008) 355–362
Tesaglitazar, a dual peroxisome proliferator-activated receptor ␣/␥ agonist, improves apolipoprotein levels in non-diabetic subjects with insulin resistance Herbert Schuster a,∗ , Bj¨orn Fagerberg b , Siˆon Edwards c , Tamas Halmos d , Jerzy Lopatynski e , Steen Stender f , Grethe Stoa Birketvedt g , Serena Tonstad h , Ingrid Gause-Nilsson i , j, ¨ Sigr´un Halld´orsd´ottir i , K. Peter Ohman for the SIR Investigators a
Humboldt University, Berlin, Germany Sahlgrenska University Hospital, G¨oteborg, Sweden c North Cardiff Medical Centre, Cardiff, Wales, UK d National Kor´ anyi Institute for Pulmonary Diseases, Budapest, Hungary Department of Primary Health Services and Family Medicine, Lublin Medical Academy, Lublin, Poland f Gentofte University Hospital, Hellerup, Denmark g Aker University Hospital, Oslo, Norway h Ullev˚ al University Hospital, Oslo, Norway i AstraZeneca R&D, M¨ olndal, Sweden j AstraZeneca R&D, Wilmington, DE, USA b
e
Received 4 March 2007; received in revised form 27 May 2007; accepted 29 May 2007 Available online 13 July 2007
Abstract Aim: To determine the effects of the peroxisome proliferator-activated receptor (PPAR) ␣/␥ agonist tesaglitazar on serum levels of apolipoprotein (apo) A-I, apoB, and apoCIII in non-diabetic insulin-resistant subjects. Methods: This randomized, double-blind, multicentre, placebo-controlled trial examined the effect of tesaglitazar (0.1, 0.25, 0.5, and 1 mg) once daily for 12 weeks on apolipoprotein levels in 390 abdominally obese subjects with hypertriglyceridaemia. Results: Tesaglitazar dose-dependently increased serum concentrations of apoA-I (p < 0.009) and decreased concentrations of apoB (p < 0.0001), the apoB/apoA-I ratio (p < 0.0001), and apoCIII (p < 0.0001). Similar improvements were observed in all subgroups of subjects, where individuals were grouped according to age, gender, baseline body mass index, serum triglycerides and high-density lipoprotein cholesterol levels. Low-density lipoprotein particle concentrations were also dose-dependently reduced by tesaglitazar (p < 0.0001). Conclusion: Although tesaglitazar is no longer in clinical development, these data indicate that dual PPAR␣/␥ agonism may be a useful pharmacological approach to improve the atherogenic dyslipidaemia associated with insulin resistance. © 2007 Elsevier Ireland Ltd. All rights reserved. Keywords: Apolipoprotein; Atherosclerosis; Dyslipidaemia; Hypertriglyceridaemia; Insulin resistance; Peroxisome proliferator-activated receptor
1. Introduction
∗ Corresponding author at: Infogen, Xantener Str. 10, 10707 Berlin, Germany. Tel.: +49 30 310 187 24; fax: +49 30 310 187 26. E-mail address: [email protected] (H. Schuster).
0021-9150/$ – see front matter © 2007 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.atherosclerosis.2007.05.029
The atherogenic dyslipidaemia associated with insulin resistance and type 2 diabetes typically involves high levels of triglycerides (TG), low levels of high-density lipoprotein cholesterol (HDL-C) and a predominance of small, dense
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low-density lipoprotein (sdLDL) particles [1]. Atherogenic risk is increasingly being quantified by determination of the apolipoprotein (apo) constituents of plasma lipoproteins. In particular, plasma concentrations of apoB and apoCIII, and the apoB/apoA-I ratio, are each indicators of cardiovascular disease (CVD) risk [2–6]. ApoB appears to be a stronger predictor of CVD risk than low-density lipoprotein cholesterol (LDL-C) [5,7]. The apoB/apoA-I ratio has also been shown to be a better predictor of coronary risk and myocardial infarction than LDL-C levels, and a better predictor of the risk of death from acute myocardial infarction than plasma concentrations of TG or total cholesterol [6,8]. These data, in addition to other clinical trial data that include populations with type 2 diabetes, suggest that an increased number of lipoprotein particles is a stronger determinant of atherogenicity than lipoprotein lipid content per se [9–11]. Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that regulate genes involved in lipoprotein metabolism, glycaemic control, and vascular inflammation [12]. Modulation of PPARs alters lipid and apolipoprotein levels in plasma. Activation of PPAR␣ can upregulate apoA-I and apoA-II while PPAR␥ activation can decrease apoB concentrations [12–14]. Both PPAR␣ and PPAR␥ agonists have antihypertriglyceridaemic properties; they reduce very-lowdensity lipoprotein (VLDL) production, leading to lower levels of TG, intermediate-density lipoprotein (IDL), and sdLDL, thereby lowering levels of their intrinsic apoB [15]. These features are desirable properties of antidiabetic agents. Tesaglitazar is a dual PPAR␣/␥ agonist that improved glucose and lipid parameters in subjects with insulin resistance [16] and patients with type 2 diabetes [17]. The clinical development of tesaglitazar was halted in May 2006 when the results of Phase III trials in patients with type 2 diabetes revealed that the benefit-risk profile was unlikely to provide an advantage over other currently available therapies. However, it remains of interest to fully define the beneficial effects of tesaglitazar, particularly for the purposes of guiding future research into the potential therapeutic roles of PPAR agonists, particularly dual agonists. The Study in Insulin Resistance (SIR) showed that tesaglitazar dose-dependently improved lipid measures in subjects with insulin resistance [16]. Tesaglitazar 1 mg reduced fasting TG by 37%, non-HDL-C by 15%, and increased HDL-C by 16% at the end of 12 weeks of treatment. There was also a dose-dependent increase in the proportion of subjects with larger, less atherogenic LDL particles (87% at 12 weeks for tesaglitazar 1 mg versus 40% at baseline). Here we report a prespecified analysis of the effect of tesaglitazar on serum levels of apoA-I, apoB, and apoCIII within the SIR population. Additionally, the effect of tesaglitazar on LDL particle concentration was examined.
2. Materials and methods The study design, protocol, and inclusion and exclusion criteria have been described elsewhere [16]. In summary, this was a multicentre, randomized, double-blind, placebocontrolled, five-arm, parallel-group, dose-finding study of tesaglitazar in non-diabetic subjects. The participants were outpatient men and women (the latter either surgically sterile or who had their last menstruation more than 12 months previously) over 30 years of age, who had abdominal obesity (waist-to-hip ratio was >0.9 for men and >0.85 for women) and hypertriglyceridaemia (fasting TG of >1.7 mmol/L). The combination of hypertriglyceridaemia and abdominal obesity indicates a high likelihood of insulin resistance [18,19]. The study included a 6-week, single-blind run-in period during which subjects took one placebo tablet each morning. At the end of this period, subjects were randomized to one of five daily treatments: placebo, or 0.1, 0.25, 0.5, or 1 mg of tesaglitazar, taken as a single tablet once each morning for 12 weeks. Subjects continued to take the treatment for up to 86 days and then entered a 14-day follow-up period during which they took neither placebo nor tesaglitazar. 2.1. Lipid, lipoprotein, and apolipoprotein analysis All blood samples were sent to the central laboratory (Quest Diagnostics, Heston, UK) for baseline analysis of serum HDL-C and serum TG, or for distribution (of frozen samples) to other laboratories for measurement of LDL particle and apolipoprotein concentrations. LDL particle concentration (nanomoles of lipoprotein particles per litre) was determined at baseline and after 12 weeks of tesaglitazar treatment using nuclear magnetic resonance spectroscopy (LipoScience Incorporated, Raleigh, USA). Venous blood samples for analysis of serum apoA-I, apoB, and apoCIII were drawn three times during the study: at the start of the run-in period (42 days before randomization), at baseline (day 0), and at the end of the 12-week randomized treatment period (day 84). Apolipoproteins were measured using immunoturbidimetric assay (Pacific Biometrics, California, USA). Results from the apoB and apoA-I measurements were used to calculate the apoB/apoA-I ratio. 2.2. Statistical analysis Data were analyzed on the basis of the intent-to-treat (ITT) principle, with the last observation carried forward. The ITT population comprised all subjects who took at least one dose of drug during the double-blind phase and for whom some efficacy data were obtained both at baseline and after randomization. Efficacy variables were log-transformed before statistical testing; end-of-treatment values are therefore geometric means. Changes in apolipoprotein concentrations from baseline were calculated for each group (placebo; 0.1, 0.25, 0.5, or
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1 mg of tesaglitazar) and analyzed in a linear model, using a fixed-effect analysis of covariance, with treatment and country as factors and baseline value as covariate. Confidence intervals (CI) were two-sided. Any trend to a dose–response relationship for changes in apolipoproteins was examined using the Jonckheere–Terpstra test; the null hypothesis of equal underlying distribution was tested versus the twosided alternative hypothesis of a trend at the 5% significance level (that changes in serum apolipoproteins were related to increasing doses of tesaglitazar). Mean changes were also calculated for subsets of subjects within each treatment group. Subjects were divided into subgroups according to sex and to the following baseline variables: <65 years of age or ≥65 years of age; body mass index (BMI) <30 kg/m2 or ≥30 kg/m2 ; baseline TG <2.3 mmol/L or ≥2.3 mmol/L (less than or at least 200 mg/dL); and baseline HDL-C <1.03 mmol/L or ≥1.03 mmol/L (less than or at least 40 mg/dL). The results for the subgroup analyses were analyzed separately and no formal comparison was made between subgroups. Throughout the study, confidence intervals and p-values were corrected using Dunnett’s method for multiple comparisons. Significance was assumed at p < 0.05.
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trend, p < 0.009). A statistically significant placebo-corrected increase from baseline in apoA-I (4%) was apparent only at the highest dose (1 mg) of tesaglitazar (Table 2). 3.2. ApoB concentrations A statistically significant trend towards decreasing apoB concentrations with increasing tesaglitazar dose was observed (p < 0.0001). Placebo-corrected reductions from baseline in serum apoB concentrations with tesaglitazar were only statistically significant at the 1-mg dose of tesaglitazar (12% placebo-corrected reduction from baseline; p < 0.0001) (Table 2). 3.3. ApoB/apoA-I ratio Changes in apoA-I and apoB resulted in significant reductions in the apoB/apoA-I ratio. There was a significant dose-dependent decrease in the apoB/apoA-I ratio with increasing tesaglitazar dose (p < 0.0001). Significant placebo-corrected reductions from baseline in the apoB/apoA-I ratio were observed at the two highest doses (0.5 and 1 mg) of tesaglitazar used (Table 2). 3.4. ApoCIII
3. Results A total of 397 individuals were randomized into the study: 137 to the placebo group, 62 to the tesaglitazar 0.1-mg group, 70 to the 0.25-mg group, 61 to the 0.5-mg group, and 67 to the 1-mg group. Seven of these 397 randomized subjects were excluded from the ITT population because they did not receive a drug treatment or had no efficacy data. There were more men than women in the study, but no important differences in baseline variables between any of the treatment groups were seen (Table 1). At baseline, subjects had a mean BMI of 31 kg/m2 (range 21–41 kg/m2 ) and mean serum TG levels of 3.0 ± 0.9 mmol/L. 3.1. ApoA-I concentrations There was a dose-dependent increase in apoA-I concentration with tesaglitazar (Jonckheere–Terpstra test for
There was a dose-dependent reduction in apoCIII following treatment with tesaglitazar (p < 0.0001 for trend). Placebo-corrected reductions in apoCIII from baseline were statistically significant (p < 0.0001) for tesaglitazar 0.25, 0.5, and 1 mg (Table 2). A maximal 25% placebo-corrected reduction from baseline was observed at the 1-mg dose of tesaglitazar (p < 0.0001). 3.5. LDL particle concentration The LDL particle concentration, measured by nuclear magnetic resonance, was dose-dependently reduced after 12 weeks of treatment with tesaglitazar 0.25–1 mg (Jonckheere–Terpstra test for trends, p < 0.0001). Placebocorrected reductions of 2% (p > 0.2), 9% (p = 0.007), 8% (p = 0.03), and 15% (p < 0.0001) were seen for the 0.1-, 0.25-, 0.5-, and 1-mg doses, respectively (Table 2).
Table 1 Baseline patient characteristics in the ITT population Placebo (n = 137)
Age (years) Men/women (n) BMI (kg/m2 ) Serum TG (mmol/L) Serum HDL-C (mmol/L)
50 (31–74) 107/30 31 (22–40) 3.0 (1.0) 1.12 (0.3)
Tesaglitazar 0.1 mg (n = 60)
0.25 mg (n = 70)
0.5 mg (n = 58)
1 mg (n = 65)
52 (34–72) 43/17 31 (21–41) 3.2 (1.1) 1.18 (0.3)
49 (31–74) 60/10 30 (24–40) 2.9 (1.0) 1.15 (0.3)
51 (31–76) 43/15 31 (24–40) 2.8 (0.7) 1.09 (0.2)
51 (29–77) 49/16 31 (23–39) 2.9 (0.9) 1.07 (0.2)
Values are means (range) for age and BMI, and means (S.D.) for TG and HDL-C. BMI: body mass index; HDL-C: high-density lipoprotein cholesterol; ITT: intent to treat; S.D.: standard deviation; TG: triglycerides.
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Table 2 Effect of tesaglitazar on concentrations of apolipoprotein and LDL particles in subjects with insulin resistance: mean values (S.D.) at baseline and 12 weeks Placebo (n = 135)
ApoA-I Baseline (g/L) 12 weeks (g/L) P-CC (%) 95% CI (%); p-value ApoB Baseline (g/L) 12 weeks (g/L) P-CC (%) 95% CI (%); p-value ApoB/apoA-I Baseline 12 weeks P-CC (%) 95% CI (%); p-value ApoCIII Baseline (g/L) 12 weeks (g/L) P-CC (%) 95% CI (%); p-value
0.1 mg (n = 58)
0.25 mg (n = 68)
0.5 mg (n = 56)
1 mg (n = 62)
1.31 (0.23) 1.36 (0.23)
1.39 (0.27) 1.42 (0.24) 0 −4, 4; >0.20
1.35 (0.25) 1.38 (0.22) 0 −4, 3; >0.20
1.30 (0.23) 1.39 (0.23) 3 −1, 7; >0.20
1.28 (0.17) 1.39 (0.19) 4 0, 8; 0.03
1.31 (0.22) 1.37 (0.26)
1.31 (0.22) 1.35 (0.23) −1 −6, 5; >0.20
1.33 (0.22) 1.33 (0.23) −4 −9, 1; 0.18
1.31 (0.21) 1.30 (0.24) −5 −10, 1; 0.12
1.27 (0.22) 1.18 (0.25) −12 −17, −7; <0.0001
1.02 (0.23) 1.03 (0.24)
0.96 (0.20) 0.97 (0.20) 0 −6, 6; >0.20
1.01 (0.22) 0.98 (0.22) −3 −9, 2; >0.20
1.03 (0.21) 0.97 (0.24) −7 −13, −2; 0.004
1.01 (0.23) 0.87 (0.23) −16 −20, −11; <0.0001
0.17 (0.05) 0.17 (0.05)
0.19 (0.06) 0.17 (0.06) −5 −12, 4; >0.20
0.17 (0.04) 0.15 (0.03) −13 −20, −6; <0.0001
0.16 (0.04) 0.13 (0.03) −18 −25, −11; <0.0001
0.17 (0.04) 0.13 (0.03) −25 −31, −19; <0.0001
Placebo (n = 134)
LDL particles Baseline (nmol/L) 12 weeks (nmol/L) P-CC (%) 95% CI (%); p-value
Tesaglitazar
1633 (384) 1707 (457)
Tesaglitazar 0.1 mg (n = 59)
0.25 mg (n = 68)
0.5 mg (n = 56)
1 mg (n = 61)
1588 (392) 1634 (368) −2 −9, 7; >0.20
1713 (402) 1578 (348) −9 −16, −2; 0.007
1633 (344) 1552 (343) −8 −16, −1; 0.03
1596 (356) 1429 (341) −15 −22, −8; <0.0001
Apo: apolipoprotein; CI: confidence intervals; LDL: low-density lipoprotein; P-CC: placebo-corrected change from baseline to 12 weeks; S.D.: standard deviation.
3.6. Apolipoprotein changes in subgroups
4. Discussion
ApoA-I, apoB, apoCIII, and the apoB/apoA-I ratio were dose-dependently improved with tesaglitazar treatment in all subgroups analyzed (data not shown). ApoA-I concentrations increased in all subgroups at the highest dose of tesaglitazar used, and there were no apparent differences between subgroups (Fig. 1A). ApoB concentrations and the apoB/apoA-I ratio were both consistently reduced from baseline in all subgroups at the 1-mg dose of tesaglitazar with the exception of gender (Figs. 1B and 2). A greater reduction in apoB concentrations (and consequently in the apoB/apoA-I ratio) occurred in women than in men at the highest dose (1 mg) of tesaglitazar used. ApoCIII was reduced in all subgroups analyzed at the highest dose of tesaglitazar (Fig. 1C). The only difference in a subgroup analysis of apoCIII concentrations was observed when comparing individuals with different baseline serum TG levels (<2.3 mmol/L versus ≥2.3 mmol/L). A tendency towards a greater reduction in placebo-corrected apoCIII concentrations from baseline was seen in individuals with high serum TG concentration at baseline.
Tesaglitazar, in previously published results from SIR, significantly improved the lipid profile of insulin-resistant subjects [16]. The current investigation extends these findings to include dose-dependent reductions in plasma levels of apoB and apoCIII, increased levels of apoA-I, and reductions in LDL particle concentration with 12 weeks of tesaglitazar treatment in these subjects. The study participants had both hypertriglyceridaemia and abdominal obesity, a combination of factors that indicates a high likelihood of insulin resistance [18,19]. Triglyceriderich lipoproteins are hydrolyzed to produce high levels of plasma free fatty acids (FFA), leading to insulin resistance and excessive deposition of visceral fat [20,21]. Insulin resistance at the level of adipose and hepatic tissue in turn contributes to an increased flux of FFA to the liver and the overproduction of TG-rich lipoproteins. TG concentrations are decreased by PPAR␣ agonism. Activation of PPAR␣ increases FFA catabolism, increases the expression of lipoprotein lipase and decreases apoCIII concentration, thereby lowering TG levels [22]. PPAR␣ agonists may also
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Fig. 1. (A–C) Placebo-corrected changes from baseline (95% confidence intervals) in serum concentrations of apolipoprotein (apo) A-I (A), apoB (B) and apoCIII (C) after 12 weeks of tesaglitazar 1 mg in different subgroups of individuals defined according to baseline characteristics of gender, age, body mass index (BMI), triglyceride (TG) and high-density lipoprotein (HDL).
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Fig. 2. Placebo-corrected changes from baseline (95% confidence intervals) in the apolipoprotein (apo) B/apoA-I ratio after 12 weeks of tesaglitazar 1 mg in different subgroups of individuals defined according to the baseline characteristics of gender, age, body mass index (BMI), triglyceride (TG) and high-density lipoprotein (HDL).
influence the assembly of VLDL particles and decrease the biosynthesis of TG in hepatocytes [23]. In addition, some studies suggest that fibrates lower insulin resistance [24,25], possibly through their modest FFA-lowering effects. This reduction in insulin resistance may contribute to the lowering of triglycerides, as may the improvement in insulin sensitivity that accompanies PPAR␥ treatment [22,23,26]. Tesaglitazar (0.25–1 mg) significantly reduced levels of apoCIII in the present investigation. Previously published results from both the SIR and Glucose and Lipid Assessment in Diabetes (GLAD) trials with tesaglitazar indicated a significant reduction in plasma VLDL concentrations [16,17]. ApoCIII inhibits the catabolism of triglyceride-rich lipoproteins and the corresponding delay in the clearance of VLDL from plasma contributes to its atherogenicity by promoting its uptake by cells involved in atherosclerosis [27,28]. Data from the Cholesterol And Recurrent Events (CARE) trial and information from other studies indicate that a high plasma concentration of apoCIII is a strong, significant predictor of coronary events in subjects with normal levels of LDL cholesterol [3,4,29]. Improvements in VLDL clearance may contribute to decreased atherogenicity and cardiovascular risk. Activation of PPAR␣ or of PPAR␥ has antiatherogenic properties at the level of reverse cholesterol transport [22,30,31]. In the current study, the significant increase in apoA-I levels with tesaglitazar at the highest dose is likely to have resulted from PPAR␣ modulation because the transcription of apoA-I and apoA-II is upregulated by activated PPAR␣ [22]. This increase in apoA-I and apoA-II forms the molecular basis for increased HDL with fibrate treatment. Studies performed in human macrophages in vitro showed that PPAR␣ activation also reduced intracellular cholesterol esterification, resulting in increased availability of free cholesterol for efflux [31]. In addition, both PPAR␣ and PPAR␥ activation has been shown to stimulate ATP bind-
ing cassette transporter A1-mediated cholesterol efflux in human macrophages [30]. These data indicate key potential roles for PPAR␣/␥ agonism in promoting reverse cholesterol transport. The current results showing tesaglitazar-mediated reductions in apoB concentration and the apoB/apoA-I ratio support and strengthen previous observations of reductions in non-HDL-C, VLDL-C, and the LDL-C/HDL-C ratio in the individuals examined here [16]. There is increasing support in the literature for the measurement of apolipoproteins (particularly apoB, apoA-I, and the apoB/apoA-I ratio) as markers of CVD risk and as measures of the efficacy of lipidlowering therapies [2,5–7,32]. The AMORIS study set out to compare concentrations of LDL-C and apoB as predictors of fatal acute myocardial infarction in 175,553 adults, followed up for 5.5 years [6]. It showed that both apoB and apoA-I were highly significant predictors across the population and that the apoB/apoA-I ratio not only had superior predictive power compared with LDL-C but that it was the strongest predictor of risk of fatal myocardial infarction [6]. The apoB/apoA-I ratio reflects the balance between atherogenic apoB-containing lipoprotein particles (LDL, VLDL, lipoprotein [a], and IDL) and the antiatherogenic HDL. It may therefore be a more comprehensive measure of lipoprotein profile than measurement of a single lipoprotein species. Additionally, the use of apolipoprotein concentrations to define coronary risk acknowledges the known association of particle number with increased atherogenic potential [9–11]. Thus, the ability of tesaglitazar to significantly reduce the apoB/apoA-I ratio in insulin-resistant subjects in the current study highlights the antiatherogenic potential of this dual PPAR␣/␥ agonist. The subgroup analyses performed here showed that in this patient population, whose selection was based on abdominal obesity and high TG (and thus with high likelihood of insulin resistance), the changes in apolipoproteins observed with the
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highest dose of tesaglitazar were independent of age, sex, BMI, or lipid levels at baseline. The dose-dependent reduction in LDL particle concentration with tesaglitazar treatment, reported here in insulin-resistant individuals, supports previous observations of a tesaglitazar-mediated increase in LDL particle size without a concomitant increase in LDL-C [16]. The presence of both small LDL and an increased LDL particle number are positively associated with an increased risk for CVD [1,9–11]. The placebo-controlled GLAD study also showed that tesaglitazar dose-dependently improved apoB and apoCIII levels and the apoB/apoA-I ratio and, at the 1-mg dose, dose-dependently improved TG, HDL-C, and LDL-C in patients with type 2 diabetes [17]. In conclusion, the current findings show that tesaglitazar dose-dependently reduced serum concentrations of apoB and apoCIII, increased serum concentrations of apoA-I, reduced the apoB/apoA-I ratio, and decreased LDL particle concentrations in insulin-resistant individuals. The development of tesaglitazar was discontinued because of reversible elevations in serum creatinine concentration with associated decreases in glomerular filtration rate that were observed in Phase III studies. Safety concerns have also led to the discontinuation of the clinical programmes of other dual PPAR␣/␥ agonists (e.g. muraglitazar, ragaglitazar, MK-0767, naveglitazar, and imiglitazar), but other PPAR modulators (e.g. metaglidasen, GSK-677954) are in development. The data presented here provide further evidence that dual PPAR␣/␥ agonism improves the atherogenic dyslipidaemic profile associated with insulin resistance and should help guide future research with PPAR agonists.
Acknowledgements We wish to thank Anna Palmer of PAREXEL MMS for providing medical writing support on behalf of AstraZeneca. This study was funded by AstraZeneca.
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H. Schuster et al. / Atherosclerosis 197 (2008) 355–362 levels in patients with primary hypertriglyceridemia. Diabetes Care 2005;28:1419–24. Mussoni L, Mannucci L, Sirtori C, et al. Effects of gemfibrozil on insulin sensitivity and on haemostatic variables in hypertriglyceridemic patients. Atherosclerosis 2000;148:397–406. Olefsky JM. Treatment of insulin resistance with peroxisome proliferator-activated receptor gamma agonists. J Clin Invest 2000;106:467–72. Fredenrich A. Role of apolipoprotein CIII in triglyceride-rich lipoprotein metabolism. Diabetes Metab 1998;24:490–5. Tomiyasu K, Walsh BW, Ikewaki K, Judge H, Sacks FM. Differential metabolism of human VLDL according to content of ApoE and ApoCIII. Arterioscler Thromb Vasc Biol 2001;21:1494–500.
[29] Gervaise N, Garrigue MA, Lasfargues G, Lecomte P. Triglycerides, apo C3 and Lp B:C3 and cardiovascular risk in type II diabetes. Diabetologia 2000;43:703–8. [30] Chinetti G, Lestavel S, Bocher V, et al. PPAR-alpha and PPARgamma activators induce cholesterol removal from human macrophage foam cells through stimulation of the ABCA1 pathway. Nat Med 2001;7:53–8. [31] Chinetti G, Lestavel S, Fruchart JC, Clavey V, Staels B. Peroxisome proliferator-activated receptor alpha reduces cholesterol esterification in macrophages. Circ Res 2003;92:212–7. [32] Miremadi S, Sniderman A, Frohlich J. Can measurement of serum apolipoprotein B replace the lipid profile monitoring of patients with lipoprotein disorders? Clin Chem 2002;48:484–8.
Tesaglitazar, a dual peroxisome proliferator-activated receptor ␣/␥ agonist, improves apolipoprotein levels in non-diabetic subjects with insulin resistance Herbert Schuster a,∗ , Bj¨orn Fagerberg b , Siˆon Edwards c , Tamas Halmos d , Jerzy Lopatynski e , Steen Stender f , Grethe Stoa Birketvedt g , Serena Tonstad h , Ingrid Gause-Nilsson i , j, ¨ Sigr´un Halld´orsd´ottir i , K. Peter Ohman for the SIR Investigators a
Humboldt University, Berlin, Germany Sahlgrenska University Hospital, G¨oteborg, Sweden c North Cardiff Medical Centre, Cardiff, Wales, UK d National Kor´ anyi Institute for Pulmonary Diseases, Budapest, Hungary Department of Primary Health Services and Family Medicine, Lublin Medical Academy, Lublin, Poland f Gentofte University Hospital, Hellerup, Denmark g Aker University Hospital, Oslo, Norway h Ullev˚ al University Hospital, Oslo, Norway i AstraZeneca R&D, M¨ olndal, Sweden j AstraZeneca R&D, Wilmington, DE, USA b
e
Received 4 March 2007; received in revised form 27 May 2007; accepted 29 May 2007 Available online 13 July 2007
Abstract Aim: To determine the effects of the peroxisome proliferator-activated receptor (PPAR) ␣/␥ agonist tesaglitazar on serum levels of apolipoprotein (apo) A-I, apoB, and apoCIII in non-diabetic insulin-resistant subjects. Methods: This randomized, double-blind, multicentre, placebo-controlled trial examined the effect of tesaglitazar (0.1, 0.25, 0.5, and 1 mg) once daily for 12 weeks on apolipoprotein levels in 390 abdominally obese subjects with hypertriglyceridaemia. Results: Tesaglitazar dose-dependently increased serum concentrations of apoA-I (p < 0.009) and decreased concentrations of apoB (p < 0.0001), the apoB/apoA-I ratio (p < 0.0001), and apoCIII (p < 0.0001). Similar improvements were observed in all subgroups of subjects, where individuals were grouped according to age, gender, baseline body mass index, serum triglycerides and high-density lipoprotein cholesterol levels. Low-density lipoprotein particle concentrations were also dose-dependently reduced by tesaglitazar (p < 0.0001). Conclusion: Although tesaglitazar is no longer in clinical development, these data indicate that dual PPAR␣/␥ agonism may be a useful pharmacological approach to improve the atherogenic dyslipidaemia associated with insulin resistance. © 2007 Elsevier Ireland Ltd. All rights reserved. Keywords: Apolipoprotein; Atherosclerosis; Dyslipidaemia; Hypertriglyceridaemia; Insulin resistance; Peroxisome proliferator-activated receptor
1. Introduction
∗ Corresponding author at: Infogen, Xantener Str. 10, 10707 Berlin, Germany. Tel.: +49 30 310 187 24; fax: +49 30 310 187 26. E-mail address: [email protected] (H. Schuster).
0021-9150/$ – see front matter © 2007 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.atherosclerosis.2007.05.029
The atherogenic dyslipidaemia associated with insulin resistance and type 2 diabetes typically involves high levels of triglycerides (TG), low levels of high-density lipoprotein cholesterol (HDL-C) and a predominance of small, dense
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low-density lipoprotein (sdLDL) particles [1]. Atherogenic risk is increasingly being quantified by determination of the apolipoprotein (apo) constituents of plasma lipoproteins. In particular, plasma concentrations of apoB and apoCIII, and the apoB/apoA-I ratio, are each indicators of cardiovascular disease (CVD) risk [2–6]. ApoB appears to be a stronger predictor of CVD risk than low-density lipoprotein cholesterol (LDL-C) [5,7]. The apoB/apoA-I ratio has also been shown to be a better predictor of coronary risk and myocardial infarction than LDL-C levels, and a better predictor of the risk of death from acute myocardial infarction than plasma concentrations of TG or total cholesterol [6,8]. These data, in addition to other clinical trial data that include populations with type 2 diabetes, suggest that an increased number of lipoprotein particles is a stronger determinant of atherogenicity than lipoprotein lipid content per se [9–11]. Peroxisome proliferator-activated receptors (PPARs) are ligand-activated transcription factors that regulate genes involved in lipoprotein metabolism, glycaemic control, and vascular inflammation [12]. Modulation of PPARs alters lipid and apolipoprotein levels in plasma. Activation of PPAR␣ can upregulate apoA-I and apoA-II while PPAR␥ activation can decrease apoB concentrations [12–14]. Both PPAR␣ and PPAR␥ agonists have antihypertriglyceridaemic properties; they reduce very-lowdensity lipoprotein (VLDL) production, leading to lower levels of TG, intermediate-density lipoprotein (IDL), and sdLDL, thereby lowering levels of their intrinsic apoB [15]. These features are desirable properties of antidiabetic agents. Tesaglitazar is a dual PPAR␣/␥ agonist that improved glucose and lipid parameters in subjects with insulin resistance [16] and patients with type 2 diabetes [17]. The clinical development of tesaglitazar was halted in May 2006 when the results of Phase III trials in patients with type 2 diabetes revealed that the benefit-risk profile was unlikely to provide an advantage over other currently available therapies. However, it remains of interest to fully define the beneficial effects of tesaglitazar, particularly for the purposes of guiding future research into the potential therapeutic roles of PPAR agonists, particularly dual agonists. The Study in Insulin Resistance (SIR) showed that tesaglitazar dose-dependently improved lipid measures in subjects with insulin resistance [16]. Tesaglitazar 1 mg reduced fasting TG by 37%, non-HDL-C by 15%, and increased HDL-C by 16% at the end of 12 weeks of treatment. There was also a dose-dependent increase in the proportion of subjects with larger, less atherogenic LDL particles (87% at 12 weeks for tesaglitazar 1 mg versus 40% at baseline). Here we report a prespecified analysis of the effect of tesaglitazar on serum levels of apoA-I, apoB, and apoCIII within the SIR population. Additionally, the effect of tesaglitazar on LDL particle concentration was examined.
2. Materials and methods The study design, protocol, and inclusion and exclusion criteria have been described elsewhere [16]. In summary, this was a multicentre, randomized, double-blind, placebocontrolled, five-arm, parallel-group, dose-finding study of tesaglitazar in non-diabetic subjects. The participants were outpatient men and women (the latter either surgically sterile or who had their last menstruation more than 12 months previously) over 30 years of age, who had abdominal obesity (waist-to-hip ratio was >0.9 for men and >0.85 for women) and hypertriglyceridaemia (fasting TG of >1.7 mmol/L). The combination of hypertriglyceridaemia and abdominal obesity indicates a high likelihood of insulin resistance [18,19]. The study included a 6-week, single-blind run-in period during which subjects took one placebo tablet each morning. At the end of this period, subjects were randomized to one of five daily treatments: placebo, or 0.1, 0.25, 0.5, or 1 mg of tesaglitazar, taken as a single tablet once each morning for 12 weeks. Subjects continued to take the treatment for up to 86 days and then entered a 14-day follow-up period during which they took neither placebo nor tesaglitazar. 2.1. Lipid, lipoprotein, and apolipoprotein analysis All blood samples were sent to the central laboratory (Quest Diagnostics, Heston, UK) for baseline analysis of serum HDL-C and serum TG, or for distribution (of frozen samples) to other laboratories for measurement of LDL particle and apolipoprotein concentrations. LDL particle concentration (nanomoles of lipoprotein particles per litre) was determined at baseline and after 12 weeks of tesaglitazar treatment using nuclear magnetic resonance spectroscopy (LipoScience Incorporated, Raleigh, USA). Venous blood samples for analysis of serum apoA-I, apoB, and apoCIII were drawn three times during the study: at the start of the run-in period (42 days before randomization), at baseline (day 0), and at the end of the 12-week randomized treatment period (day 84). Apolipoproteins were measured using immunoturbidimetric assay (Pacific Biometrics, California, USA). Results from the apoB and apoA-I measurements were used to calculate the apoB/apoA-I ratio. 2.2. Statistical analysis Data were analyzed on the basis of the intent-to-treat (ITT) principle, with the last observation carried forward. The ITT population comprised all subjects who took at least one dose of drug during the double-blind phase and for whom some efficacy data were obtained both at baseline and after randomization. Efficacy variables were log-transformed before statistical testing; end-of-treatment values are therefore geometric means. Changes in apolipoprotein concentrations from baseline were calculated for each group (placebo; 0.1, 0.25, 0.5, or
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1 mg of tesaglitazar) and analyzed in a linear model, using a fixed-effect analysis of covariance, with treatment and country as factors and baseline value as covariate. Confidence intervals (CI) were two-sided. Any trend to a dose–response relationship for changes in apolipoproteins was examined using the Jonckheere–Terpstra test; the null hypothesis of equal underlying distribution was tested versus the twosided alternative hypothesis of a trend at the 5% significance level (that changes in serum apolipoproteins were related to increasing doses of tesaglitazar). Mean changes were also calculated for subsets of subjects within each treatment group. Subjects were divided into subgroups according to sex and to the following baseline variables: <65 years of age or ≥65 years of age; body mass index (BMI) <30 kg/m2 or ≥30 kg/m2 ; baseline TG <2.3 mmol/L or ≥2.3 mmol/L (less than or at least 200 mg/dL); and baseline HDL-C <1.03 mmol/L or ≥1.03 mmol/L (less than or at least 40 mg/dL). The results for the subgroup analyses were analyzed separately and no formal comparison was made between subgroups. Throughout the study, confidence intervals and p-values were corrected using Dunnett’s method for multiple comparisons. Significance was assumed at p < 0.05.
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trend, p < 0.009). A statistically significant placebo-corrected increase from baseline in apoA-I (4%) was apparent only at the highest dose (1 mg) of tesaglitazar (Table 2). 3.2. ApoB concentrations A statistically significant trend towards decreasing apoB concentrations with increasing tesaglitazar dose was observed (p < 0.0001). Placebo-corrected reductions from baseline in serum apoB concentrations with tesaglitazar were only statistically significant at the 1-mg dose of tesaglitazar (12% placebo-corrected reduction from baseline; p < 0.0001) (Table 2). 3.3. ApoB/apoA-I ratio Changes in apoA-I and apoB resulted in significant reductions in the apoB/apoA-I ratio. There was a significant dose-dependent decrease in the apoB/apoA-I ratio with increasing tesaglitazar dose (p < 0.0001). Significant placebo-corrected reductions from baseline in the apoB/apoA-I ratio were observed at the two highest doses (0.5 and 1 mg) of tesaglitazar used (Table 2). 3.4. ApoCIII
3. Results A total of 397 individuals were randomized into the study: 137 to the placebo group, 62 to the tesaglitazar 0.1-mg group, 70 to the 0.25-mg group, 61 to the 0.5-mg group, and 67 to the 1-mg group. Seven of these 397 randomized subjects were excluded from the ITT population because they did not receive a drug treatment or had no efficacy data. There were more men than women in the study, but no important differences in baseline variables between any of the treatment groups were seen (Table 1). At baseline, subjects had a mean BMI of 31 kg/m2 (range 21–41 kg/m2 ) and mean serum TG levels of 3.0 ± 0.9 mmol/L. 3.1. ApoA-I concentrations There was a dose-dependent increase in apoA-I concentration with tesaglitazar (Jonckheere–Terpstra test for
There was a dose-dependent reduction in apoCIII following treatment with tesaglitazar (p < 0.0001 for trend). Placebo-corrected reductions in apoCIII from baseline were statistically significant (p < 0.0001) for tesaglitazar 0.25, 0.5, and 1 mg (Table 2). A maximal 25% placebo-corrected reduction from baseline was observed at the 1-mg dose of tesaglitazar (p < 0.0001). 3.5. LDL particle concentration The LDL particle concentration, measured by nuclear magnetic resonance, was dose-dependently reduced after 12 weeks of treatment with tesaglitazar 0.25–1 mg (Jonckheere–Terpstra test for trends, p < 0.0001). Placebocorrected reductions of 2% (p > 0.2), 9% (p = 0.007), 8% (p = 0.03), and 15% (p < 0.0001) were seen for the 0.1-, 0.25-, 0.5-, and 1-mg doses, respectively (Table 2).
Table 1 Baseline patient characteristics in the ITT population Placebo (n = 137)
Age (years) Men/women (n) BMI (kg/m2 ) Serum TG (mmol/L) Serum HDL-C (mmol/L)
50 (31–74) 107/30 31 (22–40) 3.0 (1.0) 1.12 (0.3)
Tesaglitazar 0.1 mg (n = 60)
0.25 mg (n = 70)
0.5 mg (n = 58)
1 mg (n = 65)
52 (34–72) 43/17 31 (21–41) 3.2 (1.1) 1.18 (0.3)
49 (31–74) 60/10 30 (24–40) 2.9 (1.0) 1.15 (0.3)
51 (31–76) 43/15 31 (24–40) 2.8 (0.7) 1.09 (0.2)
51 (29–77) 49/16 31 (23–39) 2.9 (0.9) 1.07 (0.2)
Values are means (range) for age and BMI, and means (S.D.) for TG and HDL-C. BMI: body mass index; HDL-C: high-density lipoprotein cholesterol; ITT: intent to treat; S.D.: standard deviation; TG: triglycerides.
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Table 2 Effect of tesaglitazar on concentrations of apolipoprotein and LDL particles in subjects with insulin resistance: mean values (S.D.) at baseline and 12 weeks Placebo (n = 135)
ApoA-I Baseline (g/L) 12 weeks (g/L) P-CC (%) 95% CI (%); p-value ApoB Baseline (g/L) 12 weeks (g/L) P-CC (%) 95% CI (%); p-value ApoB/apoA-I Baseline 12 weeks P-CC (%) 95% CI (%); p-value ApoCIII Baseline (g/L) 12 weeks (g/L) P-CC (%) 95% CI (%); p-value
0.1 mg (n = 58)
0.25 mg (n = 68)
0.5 mg (n = 56)
1 mg (n = 62)
1.31 (0.23) 1.36 (0.23)
1.39 (0.27) 1.42 (0.24) 0 −4, 4; >0.20
1.35 (0.25) 1.38 (0.22) 0 −4, 3; >0.20
1.30 (0.23) 1.39 (0.23) 3 −1, 7; >0.20
1.28 (0.17) 1.39 (0.19) 4 0, 8; 0.03
1.31 (0.22) 1.37 (0.26)
1.31 (0.22) 1.35 (0.23) −1 −6, 5; >0.20
1.33 (0.22) 1.33 (0.23) −4 −9, 1; 0.18
1.31 (0.21) 1.30 (0.24) −5 −10, 1; 0.12
1.27 (0.22) 1.18 (0.25) −12 −17, −7; <0.0001
1.02 (0.23) 1.03 (0.24)
0.96 (0.20) 0.97 (0.20) 0 −6, 6; >0.20
1.01 (0.22) 0.98 (0.22) −3 −9, 2; >0.20
1.03 (0.21) 0.97 (0.24) −7 −13, −2; 0.004
1.01 (0.23) 0.87 (0.23) −16 −20, −11; <0.0001
0.17 (0.05) 0.17 (0.05)
0.19 (0.06) 0.17 (0.06) −5 −12, 4; >0.20
0.17 (0.04) 0.15 (0.03) −13 −20, −6; <0.0001
0.16 (0.04) 0.13 (0.03) −18 −25, −11; <0.0001
0.17 (0.04) 0.13 (0.03) −25 −31, −19; <0.0001
Placebo (n = 134)
LDL particles Baseline (nmol/L) 12 weeks (nmol/L) P-CC (%) 95% CI (%); p-value
Tesaglitazar
1633 (384) 1707 (457)
Tesaglitazar 0.1 mg (n = 59)
0.25 mg (n = 68)
0.5 mg (n = 56)
1 mg (n = 61)
1588 (392) 1634 (368) −2 −9, 7; >0.20
1713 (402) 1578 (348) −9 −16, −2; 0.007
1633 (344) 1552 (343) −8 −16, −1; 0.03
1596 (356) 1429 (341) −15 −22, −8; <0.0001
Apo: apolipoprotein; CI: confidence intervals; LDL: low-density lipoprotein; P-CC: placebo-corrected change from baseline to 12 weeks; S.D.: standard deviation.
3.6. Apolipoprotein changes in subgroups
4. Discussion
ApoA-I, apoB, apoCIII, and the apoB/apoA-I ratio were dose-dependently improved with tesaglitazar treatment in all subgroups analyzed (data not shown). ApoA-I concentrations increased in all subgroups at the highest dose of tesaglitazar used, and there were no apparent differences between subgroups (Fig. 1A). ApoB concentrations and the apoB/apoA-I ratio were both consistently reduced from baseline in all subgroups at the 1-mg dose of tesaglitazar with the exception of gender (Figs. 1B and 2). A greater reduction in apoB concentrations (and consequently in the apoB/apoA-I ratio) occurred in women than in men at the highest dose (1 mg) of tesaglitazar used. ApoCIII was reduced in all subgroups analyzed at the highest dose of tesaglitazar (Fig. 1C). The only difference in a subgroup analysis of apoCIII concentrations was observed when comparing individuals with different baseline serum TG levels (<2.3 mmol/L versus ≥2.3 mmol/L). A tendency towards a greater reduction in placebo-corrected apoCIII concentrations from baseline was seen in individuals with high serum TG concentration at baseline.
Tesaglitazar, in previously published results from SIR, significantly improved the lipid profile of insulin-resistant subjects [16]. The current investigation extends these findings to include dose-dependent reductions in plasma levels of apoB and apoCIII, increased levels of apoA-I, and reductions in LDL particle concentration with 12 weeks of tesaglitazar treatment in these subjects. The study participants had both hypertriglyceridaemia and abdominal obesity, a combination of factors that indicates a high likelihood of insulin resistance [18,19]. Triglyceriderich lipoproteins are hydrolyzed to produce high levels of plasma free fatty acids (FFA), leading to insulin resistance and excessive deposition of visceral fat [20,21]. Insulin resistance at the level of adipose and hepatic tissue in turn contributes to an increased flux of FFA to the liver and the overproduction of TG-rich lipoproteins. TG concentrations are decreased by PPAR␣ agonism. Activation of PPAR␣ increases FFA catabolism, increases the expression of lipoprotein lipase and decreases apoCIII concentration, thereby lowering TG levels [22]. PPAR␣ agonists may also
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Fig. 1. (A–C) Placebo-corrected changes from baseline (95% confidence intervals) in serum concentrations of apolipoprotein (apo) A-I (A), apoB (B) and apoCIII (C) after 12 weeks of tesaglitazar 1 mg in different subgroups of individuals defined according to baseline characteristics of gender, age, body mass index (BMI), triglyceride (TG) and high-density lipoprotein (HDL).
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Fig. 2. Placebo-corrected changes from baseline (95% confidence intervals) in the apolipoprotein (apo) B/apoA-I ratio after 12 weeks of tesaglitazar 1 mg in different subgroups of individuals defined according to the baseline characteristics of gender, age, body mass index (BMI), triglyceride (TG) and high-density lipoprotein (HDL).
influence the assembly of VLDL particles and decrease the biosynthesis of TG in hepatocytes [23]. In addition, some studies suggest that fibrates lower insulin resistance [24,25], possibly through their modest FFA-lowering effects. This reduction in insulin resistance may contribute to the lowering of triglycerides, as may the improvement in insulin sensitivity that accompanies PPAR␥ treatment [22,23,26]. Tesaglitazar (0.25–1 mg) significantly reduced levels of apoCIII in the present investigation. Previously published results from both the SIR and Glucose and Lipid Assessment in Diabetes (GLAD) trials with tesaglitazar indicated a significant reduction in plasma VLDL concentrations [16,17]. ApoCIII inhibits the catabolism of triglyceride-rich lipoproteins and the corresponding delay in the clearance of VLDL from plasma contributes to its atherogenicity by promoting its uptake by cells involved in atherosclerosis [27,28]. Data from the Cholesterol And Recurrent Events (CARE) trial and information from other studies indicate that a high plasma concentration of apoCIII is a strong, significant predictor of coronary events in subjects with normal levels of LDL cholesterol [3,4,29]. Improvements in VLDL clearance may contribute to decreased atherogenicity and cardiovascular risk. Activation of PPAR␣ or of PPAR␥ has antiatherogenic properties at the level of reverse cholesterol transport [22,30,31]. In the current study, the significant increase in apoA-I levels with tesaglitazar at the highest dose is likely to have resulted from PPAR␣ modulation because the transcription of apoA-I and apoA-II is upregulated by activated PPAR␣ [22]. This increase in apoA-I and apoA-II forms the molecular basis for increased HDL with fibrate treatment. Studies performed in human macrophages in vitro showed that PPAR␣ activation also reduced intracellular cholesterol esterification, resulting in increased availability of free cholesterol for efflux [31]. In addition, both PPAR␣ and PPAR␥ activation has been shown to stimulate ATP bind-
ing cassette transporter A1-mediated cholesterol efflux in human macrophages [30]. These data indicate key potential roles for PPAR␣/␥ agonism in promoting reverse cholesterol transport. The current results showing tesaglitazar-mediated reductions in apoB concentration and the apoB/apoA-I ratio support and strengthen previous observations of reductions in non-HDL-C, VLDL-C, and the LDL-C/HDL-C ratio in the individuals examined here [16]. There is increasing support in the literature for the measurement of apolipoproteins (particularly apoB, apoA-I, and the apoB/apoA-I ratio) as markers of CVD risk and as measures of the efficacy of lipidlowering therapies [2,5–7,32]. The AMORIS study set out to compare concentrations of LDL-C and apoB as predictors of fatal acute myocardial infarction in 175,553 adults, followed up for 5.5 years [6]. It showed that both apoB and apoA-I were highly significant predictors across the population and that the apoB/apoA-I ratio not only had superior predictive power compared with LDL-C but that it was the strongest predictor of risk of fatal myocardial infarction [6]. The apoB/apoA-I ratio reflects the balance between atherogenic apoB-containing lipoprotein particles (LDL, VLDL, lipoprotein [a], and IDL) and the antiatherogenic HDL. It may therefore be a more comprehensive measure of lipoprotein profile than measurement of a single lipoprotein species. Additionally, the use of apolipoprotein concentrations to define coronary risk acknowledges the known association of particle number with increased atherogenic potential [9–11]. Thus, the ability of tesaglitazar to significantly reduce the apoB/apoA-I ratio in insulin-resistant subjects in the current study highlights the antiatherogenic potential of this dual PPAR␣/␥ agonist. The subgroup analyses performed here showed that in this patient population, whose selection was based on abdominal obesity and high TG (and thus with high likelihood of insulin resistance), the changes in apolipoproteins observed with the
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highest dose of tesaglitazar were independent of age, sex, BMI, or lipid levels at baseline. The dose-dependent reduction in LDL particle concentration with tesaglitazar treatment, reported here in insulin-resistant individuals, supports previous observations of a tesaglitazar-mediated increase in LDL particle size without a concomitant increase in LDL-C [16]. The presence of both small LDL and an increased LDL particle number are positively associated with an increased risk for CVD [1,9–11]. The placebo-controlled GLAD study also showed that tesaglitazar dose-dependently improved apoB and apoCIII levels and the apoB/apoA-I ratio and, at the 1-mg dose, dose-dependently improved TG, HDL-C, and LDL-C in patients with type 2 diabetes [17]. In conclusion, the current findings show that tesaglitazar dose-dependently reduced serum concentrations of apoB and apoCIII, increased serum concentrations of apoA-I, reduced the apoB/apoA-I ratio, and decreased LDL particle concentrations in insulin-resistant individuals. The development of tesaglitazar was discontinued because of reversible elevations in serum creatinine concentration with associated decreases in glomerular filtration rate that were observed in Phase III studies. Safety concerns have also led to the discontinuation of the clinical programmes of other dual PPAR␣/␥ agonists (e.g. muraglitazar, ragaglitazar, MK-0767, naveglitazar, and imiglitazar), but other PPAR modulators (e.g. metaglidasen, GSK-677954) are in development. The data presented here provide further evidence that dual PPAR␣/␥ agonism improves the atherogenic dyslipidaemic profile associated with insulin resistance and should help guide future research with PPAR agonists.
Acknowledgements We wish to thank Anna Palmer of PAREXEL MMS for providing medical writing support on behalf of AstraZeneca. This study was funded by AstraZeneca.
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