New Peroxisome Proliferator Activated Receptor Agonists - Potential Treatments for Atherogenic...

1. Introduction

2. PPAR family

3. ABT-335

4. K-877

5. Dual PPAR-a/g agonists

6. GW501516

7. MBX-8025

8. GFT-505

9. INT131

10. Conclusion

11. Expert opinion

Review

New peroxisome proliferator-activated receptor agonists:potential treatments foratherogenic dyslipidemia andnon-alcoholic fatty liver diseaseAmirhossein Sahebkar, Gerard T Chew & Gerald F Watts

Lipid Disorders Clinic, Cardiovascular Medicine, Royal Perth Hospital and Metabolic Research

Centre, School of Medicine and Pharmacology, University of Western Australia Perth, Australia

Introduction: Novel peroxisome proliferator-activated receptor (PPAR) modu-

lators (selective PPAR modulators [SPPARMs]) and dual PPAR agonists may

have an important role in the treatment of cardiometabolic disorders owing

to lipid-modifying, insulin-sensitizing and anti-inflammatory effects.

Areas covered: This review summarizes the efficacy of new PPAR agonists and

SPPARMs that are under development for the treatment of atherogenic

dyslipidemia and non-alcoholic fatty liver disease (NAFLD).

Expert opinion: ABT-335 is a new formulation of fenofibrate that has been

approved for concomitant use with statins. K-877, a SPPARM-a with encour-aging preliminary results in modulating atherogenic dyslipidemia, and

INT131, a SPPARM-g with predominantly insulin-sensitizing actions, may alsohave favorable lipid-modifying effects. Although the development of dual

PPAR-a/g agonists (glitazars) and the SPPARM-d GW501516 has been aban-doned because of safety issues, another SPPARM-d (MBX-8025) and a dualPPAR-a/d agonist (GFT-505) have shown promising efficacy in decreasingplasma triglyceride and increasing high-density lipoprotein cholesterol con-

centrations, as well as improving insulin sensitivity and liver function. The

beneficial effects of GFT-505 are complemented by preclinical findings that

indicate reduction of hepatic fat accumulation, inflammation and fibrosis,

making it a promising candidate for the treatment of NAFLD/nonalcoholic

steatohepatitis (NASH). Long-term trials are required to test the efficacy and

safety of these new PPAR agonists in reducing cardiovascular outcomes and

treating NAFLD/NASH.

Keywords: dyslipidemia, fatty liver, high-density lipoprotein,

peroxisome proliferator-activated receptor, triglyceride

Expert Opin. Pharmacother. [Early Online]

1. Introduction

Atherogenic dyslipidemia is characterized by a triad of hypertriglyceridemia, lowhigh-density lipoprotein cholesterol (HDL-C) and increased small dense low-density lipoprotein (LDL) particles [1]. It is the most common form of dyslipidemiain subjects with type 2 diabetes, metabolic syndrome and obesity, and is associatedwith an increased risk of atherosclerotic cardiovascular (CV) disease and coronaryevents beyond the effect of each individual component [2,3]. Atherogenic dyslipide-mia is also a constant feature of nonalcoholic fatty liver disease (NAFLD), beingcausally related to the formation of triglyceride (TG)-laden hepatocytes, known ashepatic steatosis [4].

10.1517/14656566.2014.876992 2014 Informa UK, Ltd. ISSN 1465-6566, e-ISSN 1744-7666 1All rights reserved: reproduction in whole or in part not permitted

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Pharmacotherapy for atherogenic dyslipidemia ischallenging, since its individual components, such as elevatedTG and low HDL-C, are not readily correctable by statins.However, agonists of peroxisome proliferator-activated recep-tors (PPARs) have shown promise in the management ofatherogenic dyslipidemia and its associated comorbidities, inparticular NAFLD -- a common condition for which there isno approved specific drug treatment [5,6]. Therapies forNAFLD should ideally not only reverse the accumulation ofTG in hepatocytes but should also effectively suppress hepaticinflammation, thereby preventing progression of simple steato-sis to nonalcoholic steatohepatitis (NASH), fibrosis andcirrhosis. Current treatment modalities, such as statins, fenofi-brate and ezetimibe, can target the risk factors of NASH, suchas dyslipidemia, insulin resistance, oxidative stress and inflam-mation [7,8]. The adverse effects of NAFLD are not confined tothe hepatic tissue, since this condition is also strongly associ-ated with increased CV risk. Whereas the underlying mecha-nism for this association is not fully understood, it appearsthat the chronic inflammation which accompanies NAFLDcan further contribute to atherogenesis [9]. There is also evi-dence from a post-hoc analysis of the Greek Atorvastatin andCoronary Heart Disease Evaluation Study (GREACE), indi-cating a greater reduction of CV event rate by statin therapyin patients with abnormal liver enzymes due to NAFLD com-pared with patients with normal liver enzymes. These closeassociations between NAFLD and CV risk, along with the pre-dominance of CV disease as the most important cause of mor-tality among NAFLD patients, further highlight the necessityfor proper management of NAFLD [10].With respect to vascular risk, findings from large-scale Feno-

fibrate Intervention and Event Lowering in Diabetes (FIELD)and Action to Control Cardiovascular Risk in Diabetes(ACCORD) trials have shown that treatment with PPAR-a

agonists (fibrates) reduces the risk of CV events in subgroupsof diabetic subjects with atherogenic dyslipidemia, as bothmonotherapy and combination therapy with statins [11,12].Regarding CV effects of PPAR-g agonists, thiazolidinediones(TZDs), the major concern has been an increased risk ofcongestive heart failure [13], although this is not associatedwith an increased mortality [14,15]. Findings of the large-scaleProspective Pioglitazone Clinical Trial In MacrovascularEvents (PROactive) trial in diabetic patients with a history ofCV disease indicated that pioglitazone significantly reducesthe risk of major adverse CV events, as well as the risk of secondmyocardial infarction and stroke in respective subgroups ofpatients [16-18].

The purpose of this review is to provide a summary ofclinical findings on the efficacy of new PPAR agonists andselective PPAR modulators (SPPARMs) that are under devel-opment for the treatment of atherogenic dyslipidemia andNAFLD (Table 1).

2. PPAR family

PPARs are a superfamily of ligand-activated nuclear receptorsthat regulate energy balance by influencing the metabolism oflipids and glucose. Three PPAR isotypes have been identified,including PPAR-a (NR1C1), PPAR-g (NR1C3) andPPAR-b/d (NR1C2). PPARs are transcription factors thatpromote their biological effects by altering the gene expres-sion. The activated PPAR binds to the retinoid X receptorto form a heterodimeric complex that then binds to conservedsequences of DNA, known as PPAR response elements,located in the promoter regions. This interaction results inthe upregulation or downregulation of a cascade of down-stream genes (Figure 1) [19-21].

PPAR-a is most frequently expressed in metabolicallyactive tissues such as liver, kidney, muscle, myocardium andbrown fat. Synthetic ligands of PPAR-a, such as fibrates, arewell-established lipid-modifying agents that act throughenhancing TG-rich lipoprotein (TRL) lipolysis, hepatic fattyacid uptake and subsequent b-oxidation, reducing TRLbiosynthesis and increasing HDL production and reverse cho-lesterol transport [22,23]. Moreover, PPAR-a agonists downre-gulate the NF-kB pathway and reduce hepatic inflammation,and also upregulate the expression of both adiponectin andadiponectin receptors [24,25], which might be especially impor-tant for preventing progression of simple steatosis to NASHthrough enhancement of insulin sensitivity and reduction ofhepatic fat [26].

PPAR-g is the most abundant PPAR subtype in whiteadipose tissue, and its main function is the regulation of fattyacid uptake, insulin sensitivity and glucose homeostasis.TZDs, also referred to as glitazones, are agents that activatePPAR-g and promote their effects through improving periph-eral tissue insulin sensitivity and reducing fatty acid flux to theliver. Further, PPAR-g activation enhances adiponectinexpression, which further improves insulin sensitivity and

Article highlights.

. Atherogenic dyslipidemia is characterized byhypertriglyceridemia, low high-density lipoproteincholesterol (HDL-C), and increased small denselow-density lipoprotein particles.

. The efficacy of statins in correcting hypertriglyceridemiaand low HDL-C is limited, thereby rendering manytreated patients at a high residual cardiovascular risk.

. Selective peroxisome proliferator-activated receptormodulators, K-877 (a), MBX-8025 (d), INT131 (g), andthe peroxisome proliferator-activated receptor-a/dagonist GFT-505 have demonstrated efficacy inimproving several components of atherogenicdyslipidemia.

. MBX-8025 and GFT-505 have also been shown toimprove liver function and glucose homeostasis, andGFT-505 has been reported to reduce hepatic fataccumulation in rodent models.

This box summarizes key points contained in the article.

A. Sahebkar et al.

2 Expert Opin. Pharmacother. (2014) 15 (4)

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hepatic fatty acid b-oxidation and also attenuates hepaticinflammation, stellate cell proliferation and adipogenesis[27-29]. Although the PPAR-g agonists pioglitazone and rosigli-tazone have been shown to exert beneficial effects on bothmetabolic (improvement in insulin sensitivity and glucose tol-erance) and histological parameters (reduction of hepatic fatand inflammation) in patients with biopsy-provenNASH [30-36], clinical use of these agents has been limitedby off-target adverse effects, such as fluid retention and weightgain, worsening cardiac failure and an increased risk of boneloss and fractures [37-39]. Although the use of rosiglitazone ishighly restricted in Europe and United States, current Guide-line of the American Association for the Study of Liver Dis-eases still recommends the use of pioglitazone in patientswith biopsy-proven NASH [40]. These treatments have mixedbeneficial as well as less favorable effects on fasting and post-prandial lipid concentrations and subfractions, with alsoagent-specific differences in lipid effects between pioglitazoneand rosiglitazone [41].

PPAR-b/d (or PPAR-d) is ubiquitously distributed in dif-ferent tissues, and its physiological and pharmacologicalactions are less clear. Although there are no synthetic ligandsof PPAR-d currently in clinical use, preliminary data fromanimal and clinical studies indicate that PPAR-d activationhas several favorable metabolic effects, including enhance-ment of fatty acid b-oxidation and lipid catabolism anddecrease in hepatic insulin resistance and inflammation [42].

The development of SPPARMs is a useful strategy fordecoupling the beneficial metabolic effects of PPAR agonistsfrom their unwanted adverse effects. PPARs undergo differentstructural conformations on interaction with different ligands,and each ligand-receptor conformation has a specific bindingaffinity for coactivators, corepressors and transcription factors,leading to different patterns of gene expression modulation(Figure 2) [43,44]. Therefore, several SPPARMs a and d, anddual SPPARMs a/d and a/g have been developed with theaim of potentiating the metabolic effects associated with therespective PPAR subtypes, while minimizing their off-targetadverse effects. However, preliminary studies of these newagents have shown variable clinical effects as detailed in thefollowing sections.

3. ABT-335

ABT-335, the first fibrate approved by the FDA for combineduse with statins, was developed as a delayed-release formula-tion with minimal pharmacokinetic interaction with statins.ABT-335 is the choline salt of fenofibric acid and does notrequire hepatic first-pass metabolism for activation, therebyreducing its potential for interaction with the hepatic glucur-onidation enzymes involved in statin metabolism [45].

The efficacy and safety of ABT-335 has been confirmed inthree Phase III studies in subjects with mixed dyslipidemia(TG 1.69 mmol/l, HDL-C < 1.03 mmol/l and LDL-C 3.36 mmol/l), where ABT-335 was given as monotherapyTa

ble

1.Asummary

ofnew

PPARagonists

andSPPARMsin

development.

Drugclass

Target

PPAR

subtype

%changein

lipids

%change

inHOMA-IR

Reductionof

hepaticinjury

biomarkers

Severe

adverseevents

Testedin

Phase

IIItrials

ab/d

gTG

HDL-C

LDL-C

TC

Non-HDL-C

ABT-335

32

--33%#

15

--20%"

4--6%

#12

--13%#

15

--18%#

NR

--

Yes

K-877

4

--14%

#NR

NR

NR

NR

NR

--

No

Aleglitazar

29

--54%#

20

--56%"

16

--47%

#NR

NR

64

--96%

-Bonefractures,

gastrointestinalbleeding

andheartfailure

Yes

MBX-8025

28%#

9--12%

"18

--22%

#14

--16%#

18

--22%#

1.4

--21%

GGT/ALP

-No

GW501516

9

--31%

#7

--17%

"23%

#--4%

"20%#-

-5%

"NR

22%

-Increasedrisk

ofcancer

No

GFT-505

17

--25%#

8--9%

"0

--13%#

0--9%

#1

--13%#

4--31%

AST/ALT/GGT/ALP

-No

INT131

NR

NR

NR

NR

NR

NR

--

No

ALP:Alkalinephosphatase;ALT:Alanineaminotransferase;AST:Aspartate

aminotransferase;GGT:g-glutamyltransferase;HDL-C:High-density

lipoprotein

cholesterol;HOMA-IR:Homeostaticmodelassessment-insulin

resistance;LD

L-C:Low-density

lipoprotein

cholesterol;NR:Notreportedin

percentageofchange;PPAR:Peroxisomeproliferator-activatedreceptor;SPPARM:Selectiveperoxisomeproliferator-activatedreceptor

modulator;TC:Totalcholesterol;TG:Triglyceride.

New PPAR agonists: potential treatments for atherogenic dyslipidemia and NAFLD

Expert Opin. Pharmacother. (2014) 15(4) 3

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or in combination with statin [46-48]. The combination ofABT-335 with statin was associated with a greater decreasein TG and increase in HDL-C compared with statin mono-therapy (Figures 3 and 4) and greater LDL-C reduction com-pared with ABT-335 monotherapy. In addition, subjectsreceiving combination therapy had significantly greater reduc-tions in non-HDL-C and very low-density lipoprotein choles-terol (VLDL-C). A 2-year extension study in subjects whocompleted either of the abovementioned trials showed thatthe lipid-modifying effects of the ABT-335/statin combina-tion were sustained (46% decrease in TG, 17% increase inHDL-C, 40% decrease in LDL-C). Moreover, long-termmonitoring did not indicate that ABT-335 treatment wasassociated with any increase in mortality or drug-related seri-ous adverse events, including rhabdomyolysis, and drug dis-continuation was low (2.9%). A post-hoc pooled analysis ofpatients with mixed dyslipidemia and type 2 diabetes in theabovementioned trials also confirmed the efficacy and safetyof the ABT-335/statin combination in this group. Interest-ingly, the percentage of subjects achieving optimal levels ofTG, HDL-C, LDL-C, non-HDL-C and apolipoprotein B(apoB) simultaneously was fivefold higher with combinationtherapy than with statin monotherapy [46-48].

4. K-877

K-877 is a SPPARM-a that can activate PPAR-a with muchgreater potency than fenofibrate (EC50 = 1 vs 14,000 --22,400 nM for fenofibrate) [49]. In a Phase II study in subjects

with atherogenic dyslipidemia, K-877 improved both fasting(decrease in TG; increase in HDL-C) and post-prandial(decrease in TG, remnant lipoprotein cholesterol andapoB-48) lipid concentrations in a dose-dependent manner,with greater lipid changes than those achieved with fenofibrate.K-877 also improved the quality of lipoprotein subfractions bydecreasing the proportion of large VLDL and small LDLparticles and by increasing small HDL particles [50]. Thesefindings confirm the preclinical findings of K-877slipid-lowering and anti-atherosclerotic effects in LDL-receptorknockout mice [49]. Both animal and clinical studies have alsoshown that K-877 increases fibroblast growth factor-21 -- aregulator of glucose and lipid metabolism [49].

5. Dual PPAR-a/g agonists

Dual PPAR-a/g agonists, also referred to as glitazars, weredeveloped with the anticipation of simultaneously achieving,with a single drug, the TG-lowering and HDL-raising effectsof fibrates, as well as the insulin-sensitizing and anti-hyperglycemic effects of TZDs. Such a combination of effectswould be ideal for the treatment of type 2 diabetes, metabolicsyndrome and NAFLD, which share atherogenic dyslipidemiaand insulin resistance as common features. Increased lipidcatabolism due to PPAR-a activation was also expected tooffset the weight gain associated with TZD use.

Muraglitazar and tesaglitazar were the first dual PPAR-a/gagonists tested in clinical trials. Although early trial findingswere promising and indicated improvements in both lipidprofile and insulin sensitivity [51,52], safety evaluations inPhase III trials revealed an increased risk of heart failurewith muraglitazar [53], and elevation of serum creatininewith tesaglitazar [54]. This led to withdrawal of these drugsfrom ongoing studies and discontinuation of their furtherresearch and development.

Further attempts focused on developing a dual PPAR-a/gagonist with balanced affinity for both receptors, and aleglita-zar emerged as a balanced PPAR-a/g agonist with promisingeffects in preclinical and Phase I/II studies [55,56]. However, arecent Phase III trial (AleCardio; NCT01042769) investigat-ing its safety and efficacy in patients with type 2 diabetes andacute coronary syndrome was halted due to an increase inbone fractures, heart failure and gastrointestinal bleeding inthose receiving aleglitazar. This led to other simultaneousPhase III aleglitazar trials, including the large-scale AlePreventstudy, also being stopped.

6. GW501516

GW501516 is a potent SPPARM-d (EC50 = 1 nM). Two earlyPhase I trials in healthy subjects demonstrated its efficacy inreducing TG, LDL-C, apoB and insulin levels and improvingHDL-C and insulin sensitivity [57,58], with one of the trials alsofinding that GW501516 significantly reduced hepatic fatcontent by 20% [58]. A later study confirmed GW501516s

RA

Protein

mRNA

Transcription

DNA

PPAR/RXRheterodimer

Effects on lipidmetabolism and

glycaemic control

PPAR activator

Figure 1. PPAR activation and its regulatory effect on gene

transcription, protein synthesis and cellular function are

shown.Reproduced with permission from [8] (Rightslink license code:

3246371243629).

PPAR: Peroxisome proliferator-activated receptor; RA: Retinoic acid;

RXR: Retinoid X receptor.

A. Sahebkar et al.


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lipid-modifying effects in dyslipidemic subjects with abdominalobesity and also provided evidence of its effects in modulatinglipoprotein kinetics (increase in catabolism of VLDL and pro-duction of apoA-I and apoA-II; decrease in production ofapoC-III and LDL-apoB). GW501516 was also associatedwith a decrease in cholesteryl ester transfer protein activity buthad no effect on insulin resistance [59]. Finally, Olson et al.reported that GW501516 treatment was associated with signif-icant improvements in multiple lipid profile components (TG,LDL-C,HDL-C, free fatty acids and apoB, apoA-I and apoA-II)and a shift in LDL particle size from small dense to larger, lessdense particles [60]. Despite these promising early results, the fur-ther investigation and development of GW501516 was discon-tinued after observations in animal studies of its associationwith the rapid induction of cancers in several organs (liver,stomach, tongue, skin, bladder, ovaries, womb and testes).

7. MBX-8025

The efficacy of MBX-8025, a potent SPPARM-d(EC50 = 2 nM), was demonstrated in a proof-of-conceptstudy in overweight subjects with mixed dyslipidemia, whereMBX-8025, given asmonotherapy or in combination with ator-vastatin, resulted in significant reductions in plasma LDL-C(18 -- 43%), apoB-100 (20 -- 38%), non-HDL-C (18 -- 41%),TG (26 -- 30%) and free fatty acids (16 -- 28%). MBX-8025seffects in lowering LDL-C and apoB-100 were enhanced whencombined with atorvastatin but did not exceed that of ator-vastatin monotherapy. However, the MBX-8025/atorvastatin

combination was more efficacious in lowering TG and raisingHDL-C than atorvastatin alone, but not MBX-8025 alone [61].Further, LDL particle size distribution analysis revealed thatMBX-8025 treatment results in a reduction in small and verysmall LDL particles and an increase in large LDL particles. Itseffect on HDL elevation was also confined to the small HDLparticles. These changes were accompanied by a concomitantreduction in large VLDL particles and increase in LDL peakdiameter, and reversal of LDL pattern B (characterized by a pre-ponderance of small LDL particles) in > 90% of subjects. Theseimprovements in the lipoprotein subfractions were greaterthan those seen with atorvastatin treatment [62]. Finally,MBX-8025 also showed beneficial effects in improving insulinresistance and plasma markers of liver function [61].

8. GFT-505

GFT-505 is a dual PPAR-a/d agonist, with preferential a(EC50 = 6 nM) and complementary d (EC50 = 47 nM) recep-tor agonistic activity. It is a compound targeted at the liver,where it is converted to its main active metabolite,GFT-1007, in a dose-dependent manner. GFT-505 is themost widely studied SPPARM, and it is the agent with themost promising results in clinical trials to support its furtherdevelopment [63-65].

The lipid-modifying efficacy of GFT-505 has beenconfirmed in healthy subjects [63], as well as in patients withtype 2 diabetes (NCT01261494), combined abdominalobesity and mixed dyslipidemia [64], combined abdominalobesity and pre-diabetes [64], atherogenic dyslipidemia(NCT01271751) and insulin resistance [65]. The lipid effectsof GFT-505 include decreases in TG (34% in patients withtype 2 diabetes) (NCT01261494), non-HDL-C and total cho-lesterol (9% in patients with insulin resistance, and patientswith abdominal obesity and pre-diabetes), LDL-C (13% inpatients with insulin resistance) [65], apoB (14% in patientswith insulin resistance) [65] and apoC-III (20% in patientswith abdominal obesity and pre-diabetes) [64], as well asincreases in HDL-C (15% in patients with type 2 diabetes)(NCT01261494), apoA-I (6% in patients with abdominalobesity and mixed dyslipidemia and in patients with athero-genic dyslipidemia) ([64], NCT01271751) and apoA-II (18%in patients with abdominal obesity and pre-diabetes) [64].A Phase I study in healthy subjects also showed thatGFT-505 decreases post-prandial free fatty acid levels [63].

GFT-505 has also been reported to have favorable effects onglucose homeostasis. In patients with abdominal obesity andpre-diabetes, GFT-505 increased insulin sensitivity anddecreased fasting plasma glucose, C-peptide, insulin andfructosamine levels, but this was not seen in patients withabdominal obesity and mixed dyslipidemia [64]. The insulin-sensitizing effects of GFT-505 were demonstrated in two latertrials in treatment-nave subjects with newly diagnosedtype 2 diabetes (decrease in fasting glucose and HbA1c levels;decrease in 2-h post-challenge glucose level and glycemic area

SPPARMs

PPAR

Ligandreceptordistinct and specificconformations

Selective cofactorrecruitment

Common and selective biological responses

Figure 2. Selective modulation of peroxisome proliferator-

activated receptor activity is shown.PPAR: Peroxisome proliferator-activated receptor; SPPARMs: Selective PPAR

modulators.



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under the curve following oral glucose tolerance test)(NCT01261494) and in insulin-resistant subjects (decrease inhepatic glucose production; improvements in both hepaticand peripheral insulin sensitivity, measured by hyperinsulinemic-euglycemic clamp) [65].In addition, GFT-505 may have potential to prevent the

development and progression of NAFLD/NASH by reducinghepatic fat content [66] and by decreasing biomarkers ofhepatic inflammation and injury ([64,65], NCT01271751,NCT01261494). Preclinical studies in rodent models ofNAFLD/NASH (Western diet-fed human apo-E2 transgenicmice; methionine- and choline-deficient diet-fed db/db miceand CCl4-induced fibrotic rats) consistently demonstratedthat GFT-505 treatment decreases hepatic steatosis, inflam-mation and fibrosis, decreases liver dysfunction biomarkersand suppresses proinflammatory and profibrotic gene expres-sion, being effective in both the prevention and treatment ofhepatic fibrosis [66]. Interestingly, these same effects werereplicated in apo-E2-KI/PPAR-a-KO mice, suggesting aPPAR-a-independent hepatoprotective mechanism [66].In clinical studies, GFT-505 treatment has been reported

to decrease a range of biomarkers of hepatic dysfunction,including alanine aminotransferase (20% in insulin-resistantsubjects) [65], alkaline phosphatase (24% in patients withabdominal obesity and pre-diabetes) [64] and g-glutamyl

transferase (30% in insulin-resistant subjects) [65], withsimilar findings seen in dyslipidemic (NCT01271751),pre-diabetic [64], insulin-resistant [65] and diabetic patients(NCT01261494). Together with its unique pharmacokineticprofile (hepatic accumulation and extensive enterohepaticrecycling), these beneficial effects of GFT-505 support itspotential as a hepatoprotective agent. These promising find-ings, along with positive data from other SPPARM-d studies,have prompted a Phase IIb trial (NCT01694849) ofGFT-505 in patients with biopsy-proven NASH, the resultsof which are awaited with interest.

9. INT131

In trying to decouple the beneficial from the adverse effects offull PPAR-g agonists, there has been interest in developingSPPARMs that target alternate regions of the PPAR-g receptor,resulting in limited recruitment of coregulators and restrictedbut more favorable metabolic effects [67]. Of the SPPARMs-gstudied, only INIT131 is currently under clinical developmentfor the treatment of insulin resistance. Preclinical and earlyPhase II clinical studies showed that INIT131 improves insulinsensitivity and glycemia without some of the side effects of gli-tazones, such as fluid retention, but it did increase body weightwhen given in higher, more efficacious dose [68]. Importantly,

Statin alone

TG re

duct

ion

(%)

50

45

40

35

3025

05

10

15

20

Simvastatin (20 mg) ABT-335 (135 mg)Atorvastatin (20 mg) ABT-335 (135 mg)

Atorvastatin (40 mg) ABT-335 (135 mg)

Rosuvastatin (10 mg) ABT-335 (135 mg)


Simvastatin (40 mg) ABT-335 (135 mg)

Statin + ABT-335

Figure 3. Incremental reductions in triglycerides (TGs) following addition of ABT-335 (135 mg) to different doses of statins

are shown. Red bars represent percentage reduction in TGs or percentage elevation in high-density lipoprotein cholesterol

incremental to the changes achieved by statin monotherapy. All differences between statin monotherapy and

statin + ABT-335 were statistically significant [32-34].

A. Sahebkar et al.


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potentially beneficial dose-dependent lipid effects (decrease infree fatty acids, increase in HDL-C, trend to decrease in TG)were reported [69].

10. Conclusion

Atherogenic dyslipidemia contributes significantly to theresidual CV risk in statin-treated patients, even those at opti-mal LDL-C levels, and it is causally related to NAFLD. Theefficacy of fibrates in decreasing TG and raising HDL-C levelsis established, but progress continues to be made in the devel-opment of PPAR agonists with greater receptor specificity,higher efficacy, and improved safety, particularly when usedin combination with statins.

ABT-335 is an improved formulation of fenofibrate that hasbeen approved for combination therapy with statins.K-877 and MBX-8025 are SPPARMs (a and d, respectively)with enhanced lipid-modifying effects. INT131 (SPPARM-g)improves insulin sensitivity and glycemia but might also havefavorable lipid effects relevant to the treatment of atherogenicdyslipidemia. Despite considerable lipid-modifying efficacy,the development of dual PPAR-a/g agonists (muraglitazar,tesaglitazar and aleglitazar) and the SPPARM-d GW501516has been discontinued due to the emergence of associatedsignificant adverse events. Finally, animal and clinical studies

of the dual PPAR-a/d agonist GFT-505 show great promiseof its efficacy in correcting dyslipidemia, enhancing insulinsensitivity and reducing hepatic fat accumulation andinflammation.

11. Expert opinion

Atherogenic dyslipidemia is the predominant lipid disorder inpatients with metabolic syndrome and type 2 diabetes, whoare at high risk of CV disease. It is characterized by increasedplasma levels of TG and TRL remnants, predominance ofsmall dense LDL and decreased levels of HDL-C [1]. Statinsare the mainstay of pharmacotherapy for dyslipidemia, andtheir efficacy in reducing CV outcomes has been establishedin both primary and secondary prevention trials [70]. How-ever, a significant proportion of statin-treated subjects, eventhose at target LDL-C levels on high-dose therapy, have ahigh residual risk of CV disease [71]. Further reductions inLDL-C may be achieved by adding ezetimibe to statin, butclinical trial evidence for the specific CV benefits of this com-bination is scarce. The Study of Heart and Renal Protectionshowed a reduction in the incidence of major atheroscleroticevents following combination therapy with simvastatin andezetimibe (vs placebo) in patients with advanced chronic kid-ney disease [72]; however, further evidence from outcome trials

Statin aloneStatin + ABT-335

HD

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20

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Simvastatin (20 mg) ABT-335 (135 mg)Atorvastatin (20 mg) ABT-335 (135 mg)

Atorvastatin (40 mg) ABT-335 (135 mg)



Simvastatin (40 mg) ABT-335 (135 mg)

Figure 4. Incremental elevations in high-density lipoprotein cholesterol (HDL-C) following addition of ABT-335 (135 mg) to

different doses of statins are shown. Red bars represent percentage reduction in triglycerides or percentage elevation in

HDL-C incremental to the changes achieved by statin monotherapy. All differences between statin monotherapy and

statin + ABT-335 were statistically significant [32-34].



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are required to assess the impact of such a combination versusstatin monotherapy and also in other patient populations.Although according to the recent ACC/AHA guidelines thereis still inadequate clinical trial outcome evidence to supportthe use of non-statin drugs in the prevention of atheroscleroticCV disease [73], there are many agents currently in variousstages of development for the treatment of dyslipidemia asoutlined above. These non-statin agents may be particularlyuseful for patients intolerant or refractory to statins and canbe used as an add-on to statins to enhance TG reductionand HDL-C elevation. Since residual CV risk in statin-treatedsubjects may be related to coexistent atherogenic dyslipide-mia, adjunctive use of lipid-modifying agents with specificeffects on TG and HDL-C may also be indicated. Fibrateshave been shown to be especially efficacious in reducing CVoutcomes in patients with atherogenic dyslipidemia. Hence,newer potent PPAR agonists and SPPARMs are expected tohave comparable promising effects in reducing CV risk. How-ever, this needs to be demonstrated in clinical outcome trials.The value of adding niacin to statins in patients with

optimal LDL-C lowering but high residual CV risk is notsupported by recent clinical trials (AIM-HIGH andHPS2-THRIVE) [74,75], and the use of high dose n-3 polyun-saturated fatty acids (given as pure eicosapentanoic acid) iscurrently being investigated in the REDUCE-IT trial(NCT01492361). Clinical outcome studies have shown thatfenofibrate, an agonist of PPAR-a, can significantly reduceCV events in patients with atherogenic dyslipidemia [11,12,76].However, to improve the beneficial lipid-modifying effects ofPPAR activation, while minimizing off-target adverse effects,newer agents are being developed that have less potential foradverse pharmacokinetic interactions with statins (e.g.,ABT-335), greater specificity for PPAR subtypes (SPPARMs)and balanced activation of different PPAR subtypes (dualagonists).

Early studies of the SPPARMs K-877 (a) [36],MBX-8025 (d) [47], INT131 (g) [54,55] and the PPAR-a/d ago-nist GFT-505 ([49-51], NCT01271751) have demonstratedefficacy in improving several components of atherogenicdyslipidemia. In addition, MBX-8025 and GFT-505 havealso been shown to improve liver function ([47,50,51],NCT01271751), with the latter demonstrating beneficialeffects in reducing hepatic steatosis, inflammation and fibrosisin animal studies [52]. These findings suggest a possible role forthese agents in the treatment of NAFLD/NASH -- a conditioncausally related to atherogenic dyslipidemia, for which there isno specific pharmacotherapy at present. The results of anongoing Phase IIb trial of long-term GFT-505 treatment inpatients with NASH (NCT01694849) are keenly awaited.

However, despite the aforementioned promising data andresults, the development of other similar agents with poten-tially beneficial lipid-modifying and metabolic effects, suchas GW501516 (SPPARM-d) and the dual PPAR-a/g agonists(glitazars), has been abandoned because of associated seriousoff-target adverse effects. This emphasizes the importance oflonger-term studies to evaluate drug safety and also therequirement for randomized controlled clinical trial data todemonstrate not only the efficacy of these new agents inimproving lipid and metabolic end points but also in improv-ing meaningful clinical outcomes.

Declaration of interest

GF Watts has received honoraria for lectures and commentar-ies from Genfit, Pfizer, AstraZeneca, Merck Sharp & Dohme,Novartis, Amgen, Abbott and Sanofi-Aventis. With respect tothe content of the article, GT Chew has previously receivedresearch grant funding from Pfizer and GlaxoSmithKlineand has participated in research sponsored by LaboratoiresFournier. A Sahebkar has no conflict of interest.

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AffiliationAmirhossein Sahebkar1,2, Gerard T Chew3 &

Gerald F Watts4

Author for correspondence1Biotechnology Research Center,

Mashhad University of Medical Sciences,

Mashhad, Iran2Cardiovascular Research Center,

Department of Medical Biotechnology,

School of Medicine, Mashhad University of

Medical Sciences, Mashhad, Iran3School of Medicine and Pharmacology,

Royal Perth Hospital, University of

Western Australia, Perth, Australia4Lipid Disorders Clinic, Cardiovascular

Medicine, Royal Perth Hospital and Metabolic

Research Centre, School of Medicine and

Pharmacology, University of Western Australia,

GPO Box X2213, Perth, Western Australia 6847,

Australia

Tel: +61 8 92240245;

Fax: +61 8 92240246;

E-mail: [email protected]



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AbstractIntroductionPPAR familyABT-335K-877Dual PPAR-/ agonistsGW501516MBX-8025GFT-505INT131ConclusionExpert opinionDeclaration of interestBibliography

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