Pharmacological Management of Nonalcoholic Fatty Liver Disease Diana Barb, Paola Portillo-Sanchez, Kenneth Cusi PII: DOI: Reference:
S0026-0495(16)30008-7 doi: 10.1016/j.metabol.2016.04.004 YMETA 53407
To appear in:
Metabolism
Received date: Revised date: Accepted date:
30 March 2016 16 April 2016 18 April 2016
Please cite this article as: Barb Diana, Portillo-Sanchez Paola, Cusi Kenneth, Pharmacological Management of Nonalcoholic Fatty Liver Disease, Metabolism (2016), doi: 10.1016/j.metabol.2016.04.004
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.
ACCEPTED MANUSCRIPT Pharmacological Management of Nonalcoholic Fatty Liver Disease
T
Diana Barb1,2, Paola Portillo-Sanchez1,2 and Kenneth Cusi1,2
1
RI P
Division of Endocrinology, Diabetes and Metabolism, Department of Medicine,
University of Florida College of Medicine, Gainesville, FL and 2Division of
SC
Endocrinology, Diabetes, and Metabolism at Malcom Randall Veterans Affairs Medical
NU
Center, Gainesville, Florida
MA
Correspondence to:
Kenneth Cusi, M.D., F.A.C.P., F.A.C.E
ED
Professor of Medicine, Chief, Division of Endocrinology, Diabetes and Metabolism,
Phone: 352-273-8662
PT
Department of Medicine, University of Florida College of Medicine, Gainesville, FL
AC
CE
Email:
[email protected]
Address: 1600 SW Archer Road, room H-2. Gainesville, Florida 32610 Keywords: obesity, Nonalcoholic fatty liver disease (NAFLD), nonalcoholic steatohepatitis (NASH), metformin, thiazolinediones, PPARγ, pioglitazone, dipeptidyl peptidase 4 (DPP-4) inhibitors, glucagon-like peptide-1 receptor agonists (GLP-1RA), liraglutide, sodium-glucose co-transporter 2 (SGLT2) inhibitors. Figures: 1 Tables: 2 Word count: 5,188 References: 152
1
ACCEPTED MANUSCRIPT Abbreviations: BCAAs (branched-chain amino acids), ARB (angiotensin II receptor antagonists), NAFLD (non-alcoholic fatty liver disease), NASH (non-alcoholic
T
steatohepatitis), GLP-1 (glucagon like peptide 1), GLP-1RA, GLP-1 receptor agonist,
RI P
T2DM (type 2 diabetes mellitus), PPARγ (peroxisome proliferator activated receptor γ), VLDL (very low-density lipoprotein), 1H-MRS: Proton magnetic resonance spectroscopy;
SC
RCT: Randomized controlled trials; PUFAs: Polyunsaturated fatty acids; PPAR:
NU
Peroxisome proliferator-activated receptor; NAS: NAFLD activity score; CVD: Cardiovascular disease; TZDs: Thiazolinediones; DPP-4: Dipeptidyl peptidase-4; ALT:
AC
CE
PT
ED
transforming growth factor beta1.
MA
Alanine aminotransferase; SGLT2: Sodium-glucose co-transporter 2, TGF1:
2
ACCEPTED MANUSCRIPT Abstract Nonalcoholic fatty liver disease (NAFLD) affects one-third of the population and two-
T
thirds of patients with obesity or T2DM. Its more aggressive form is known as
RI P
nonalcoholic steatohepatitis (NASH) and is characterized by hepatocyte necrosis, inflammation and often fibrosis. The presence of fibrosis indicates a more aggressive
SC
course and may lead to cirrhosis. Premature mortality in NASH is related to both hepatic
NU
(cirrhosis and hepatocellular carcinoma) and extra-hepatic complications, largely cardiovascular disease (CVD). Many therapeutic agents have been tested, but still none
MA
approved specifically for NASH. Treatment of NAFLD includes aggressive management of diabetes and cardiovascular risk factors, although the role of controlling
ED
hyperglycemia per se in patients with T2DM and NASH remains unknown. Agents
PT
tested with some success in non-diabetic patients with NASH include pioglitazone, liraglutide, vitamin E and to a lesser degree, pentoxiphylline. In patients with T2DM and
CE
NASH only pioglitazone has shown to significantly improve liver histology, with only a
AC
handful of patients with diabetes having been studied with other modalities. This review focuses on available agents for NASH to assist clinicians in the management of these complex patients. Many novel compounds are being studied and will likely make combination therapy for NASH a reality in the future.
3
ACCEPTED MANUSCRIPT Outline 1. Introduction (Prevalence, significance, disease spectrum, lifestyle
T
intervention).
RI P
2. Pharmacotherapy 2.1. Antioxidants and supplements
SC
2.1.1.Vitamin E
NU
2.1.2. Selenium 2.1.3. Betaine
MA
2.1.4. Branched chain amino acids
2.2.1. Metformin
ED
2.2. Anti-hyperglycemic agents
PT
2.2.2. Incretin-based therapies 2.2.3. SGLT2 inhibitors
CE
2.2.4. Thiazolidinediones
AC
2.3. Lipid lowering agents 2.3.1.Omega 3 / fishoil 2.3.2. Cholesterol lowering drugs (Statins, Ezetimibe) 2.3.3. PPAR agonists including fibrates and dual PPAR agonists 2.4. Phosphodiesterase (PDE) inhibitors 2.4.1.Pentoxiphylline 2.4.2. PDE4 inhibitor ASP9831 2.5. Bile acid/Farnesoid Receptor pathway drugs 2.5.1. Ursodeoxycholic acid (UDCA)
4
ACCEPTED MANUSCRIPT 2.5.2. Obeticholic acid (OCA) 2.6. Weight loss medications
3. Clinical practice: guidelines and reality 4. Future directions, questions unanswered
AC
CE
PT
ED
MA
NU
SC
5. Conclusion
RI P
T
2.7. Angiotensin II receptor antagonist (ARB)
5
ACCEPTED MANUSCRIPT 1. Introduction With obesity reaching epidemic proportions in the 21st century, nonalcoholic fatty liver
T
disease (NAFLD) is on the rise. Its more severe form associated with hepatocyte
RI P
necrosis, lobular inflammation and often with fibrosis (nonalcoholic steatohepatitis or NASH) is now the second cause of liver transplantation in the US (1-4). Nonalcoholic
SC
fatty liver disease is a liver condition characterized by insulin resistance, hepatic
NU
steatosis and often prediabetes or diabetes (5-8). The actual prevalence of NAFLD is probably underestimated, given the lack of a highly reliable non-invasive diagnostic
MA
blood test or imaging technique. By magnetic resonance imaging and spectroscopy (1HMRS) the prevalence of NAFLD in the general population is 34%, being much higher in
ED
obese patients (9). Even in the presence of normal liver aminotransferases, having
PT
T2DM further increases the risk of steatohepatitis in obese patients but reliable estimates of the true prevalence are unavailable. In a relatively small study in 103
CE
patients with T2DM and normal plasma aminotransferases, the prevalence of NAFLD
AC
was 50%, with more than half of those undergoing a liver biopsy having NASH (10). Of note, among the histologic features of NASH, fibrosis is the more strongly correlated with end-stage liver disease and mortality (11, 12). The rate of progression of fibrosis is widely variable and dependent on clinical and histological factors, such as age, diabetes, obesity, hypertension, and the severity of steatohepatitis (13-15). A liver biopsy remains as the gold-standard for diagnosing the disease, staging the severity of fibrosis and overall prognosis, and for assessing treatment response. However, novel imaging approaches like magnetic resonance elastography (either based on ultrasound or magnetic resonance techniques) may be of assistance in differentiating advanced
6
ACCEPTED MANUSCRIPT fibrosis from early disease. For instance, in a large population-based study in 3,041 middle-aged subjects from Rotterdam, Koehler et al. (16) found by using a combined
T
screening approach of liver ultrasound and transient elastography, that an alarming
RI P
17.2% of patients with T2DM had significant liver fibrosis. This is an important study as increased morbidity and mortality in NASH from cirrhosis, HCC and CVD are closely
NU
SC
linked to the severity of liver fibrosis.
Lifestyle modification remains the cornerstone of prevention and treatment of NASH.
MA
Histological improvement in NASH is proportional to the amount of weight loss. Whereas ~5% total body weight loss may improve metabolic abnormalities, a ≥7-10%
ED
decrease in weight is needed to significantly impact steatohepatitis. Less than 5%
PT
weight reduction leads to only minimal changes in liver fat content (17), while a 7–10% decrease in body weight has been associated with a meaningful (40-80%) reduction in
CE
liver fat and in hepatocyte necrosis and inflammation (17-23), as reviewed elsewhere
AC
(24, 25). Weight loss agents appear to offer no liver-specific benefit (22) but may assist with weight loss and cause a secondary improvement in plasma aminotransferases (26, 27). Bariatric surgery improves metabolic and histologic abnormalities in patients with NASH in proportion to the magnitude of weight loss (28), and can lead to resolution of histologic abnormalities in 70-90% of patients (29). Hepatic fibrosis is reversed in 3050% (28-30) but paradoxical increases were reported in some earlier studies (31, 32). There is a need for well-controlled prospective studies to assess the long-term impact of bariatric surgery on liver fibrosis.
7
ACCEPTED MANUSCRIPT 2. Pharmacotherapy As overall weight loss is difficult to achieve and maintain for most patients,
T
pharmacological therapy is often needed. Treatment of NAFLD includes aggressive
RI P
cardiovascular risk factor management (i.e. obesity, dyslipidemia, HTN and diabetes) and specific therapies versus NASH. At present there are no FDA-approved agents
SC
with an indication for the treatment of NASH. Table 1 summarizes approaches under
MA
NU
evaluation in patients with NASH.
2.1. Antioxidants and supplements
ED
These medications are believed to reduce hepatocyte oxidative stress in patients with
PT
active steatohepatitis, although their true mechanism of action is uncertain. With the exception of vitamin E, there are not good large randomized controlled trials (RCTs) in
AC
CE
humans for many of these compounds.
2.1.1. Vitamin E
Vitamin E is an antioxidant believed to act on a variety of targets (3), including transforming growth factor beta 1 (TGF1), peroxisome proliferator-activated receptors (PPARs), and several apoptosis-regulating genes (33). Two RCTs have reported on liver histological outcomes in adults ((34) and in children (35). In adults with biopsy-proven NASH, vitamin E at a dose of 800 IU/day for 96 weeks led to significant benefit in the primary histological endpoint of improvement in ≥2 grades in the NAFLD activity score (NAS), including hepatocellular ballooning, with no worsening of fibrosis (p=0.001) (34). However, resolution of NASH did not reach statistical significance, an endpoint only 8
ACCEPTED MANUSCRIPT reached in the same study by pioglitazone (47%, p= 0.001 vs. placebo). Vitamin E also did not significantly improve histology in a pediatric population with NASH, although
T
hepatocellular ballooning did improve (35). Vitamin E, at the dose used in these trials
RI P
(800 IU per day), appeared to be safe in patients with NASH without T2DM. However, its long-term safety and efficacy has not been fully established in NASH and it has not been
SC
tested in patients with T2DM. It has also not been studied in patients with advanced liver
NU
disease or cirrhosis. The major safety concerns of long-term vitamin E administration include increased risk for the development of hemorrhagic stroke and of prostate cancer
MA
(36, 37).
ED
2.1.2. Selenium
PT
Plasma oxidative stress markers are higher in patients with NASH and correlate inversely with dietary intake of antioxidants like vitamin E, vitamin C and selenium (38). It
CE
has also been observed that hair selenium levels are lower in patients with NASH versus
AC
simple steatosis (39). In cell culture model of human hepatoblastoma (C3A) cells, selenium treatment at a dose that optimized the expression of thioredoxin reductase and glutathione peroxidase, was able to attenuate oleate induced procollagen-1 and interleukin-8 production by C3A hepatocytes in response to TGF1 (40). In mice, a diet with selenium-enriched probiotics was protective against high fat diet induced lipid metabolism and improved liver histology (41). Whether this is relevant to humans remains to be determined as there are no RCT in patients with NASH
2.1.3. Betaine
9
ACCEPTED MANUSCRIPT Betaine, a byproduct of sugar beet processing, is also considered to be an antioxidant, and has been widely used for NAFLD/NASH mainly in the form of supplements. It is
T
thought to reduce S-adenosylhomocysteine, preventing the build-up of homocysteine.
RI P
Although betaine has been proven effective in treating hepatic steatosis in several animal models (42, 43), betaine monotherapy did not show beneficial efficacy against
SC
NAFLD/NASH in a RCT in humans (44). The guidelines (33, 45, 46), do not recommend
NU
betaine as a specific treatment for patients with NASH.
MA
2.1.4 Branched-chain amino acids (BCAAs)
Three essential branched-chain amino acids (BCAAs) - L-leucine, L-isoleucine and L-
ED
valine - are found in various supplements and believed to be important in the regulation
PT
of glucose and lipid metabolism. BCAAs are essential to mediate efficient channeling of carbon substrates for oxidation through mitochondrial TCA cycle. Plasma BCAAs are
CE
elevated in the setting of insulin resistance and T2DM (47) and decrease with weight
AC
loss induced by bariatric surgery (48). Recent work suggests an important cross-talk between BCAAs and hepatic mitochondria in the regulation of fatty acid oxidation and lipid metabolism that is compromised in the setting of NAFLD/NASH (49). Studies in mice suggest that administration of BCAA-rich supplements may halt the progression of NASH by reducing oxidative stress, primarily via the downregulation of the ER stress pathway (50). Similarly, a high-protein diet compared to a high fat diet decreases steatosis, which correlated inversely with the hepatic content of BCAA-derived branchedchain fatty acids (BCFAs), suggesting that perhaps a valine-derived BCFAs could be the antisteatotic mediator of high protein diets (51).
10
ACCEPTED MANUSCRIPT
2.2. Anti-hyperglycemic agents
T
2.2.1. Metformin
RI P
Metformin is an insulin-sensitizer used as first-line therapy for the management of T2DM (52). Early uncontrolled studies of metformin in patients with NAFLD suggested
SC
histological benefit, although related more to concomitant weight loss than to the drug
NU
itself (53, 54). These findings were confirmed in more recent studies and summarized in several meta-analyses (55, 56). Taken together, metformin is not effective for the
MA
treatment of NASH but first-line therapy for the management of hyperglycemia in T2DM.
PT
ED
2.2.2. Incretin-based therapies
2.2.2.1. Glucagon-like peptide-1 (GLP-1) receptor agonists
CE
GLP-1 receptor agonists (GLP-1RA) have become an attractive therapeutic option in
AC
patients with NASH and obesity and/or T2DM, given their potential to induce weight loss and lower plasma glucose levels. They are not rapidly inactivated by circulating dipeptidyl peptidase (DPP)-4 allowing to enhance insulin secretion, lower postprandial glucagon levels and induce weight loss via central nervous system effects (57). There is controversy regarding their binding to hepatic GLP-1 receptors. Several studies have suggested a direct effect through GLP-1 signaling to enhance hepatic insulin sensitivity, as well as for decreasing hepatocyte triglyceride accumulation (58-61) and liver fibrosis (62).
11
ACCEPTED MANUSCRIPT Several clinical trials suggest a potential benefit of GLP-1RA in patients with diabetes. In a meta-analysis of 6 RCT LEAD (Liraglutide Efficacy and Action in Diabetes) trials, a
T
significant decrease in plasma aminotransferase and hepatic steatosis (assessed by CT
RI P
scan) was observed at the higher dose of liraglutide (1.8 mg), an effect closely related to the magnitude of weight loss (63). In contrast, Cuthberson et al. (64) reported a
SC
significant 42% reduction in liver triglyceride content in 25 patients with T2DM treated
NU
either with exenatide or liraglutide for 6 months, that correlated with an improvement in glycemic control but not with weight loss. Other small uncontrolled studies have
MA
reported variable benefit with GLP-1RA (65-67), although reduction in hepatic steatosis
ED
has not been observed in all studies (68).
PT
In the best study to date, significantly histological benefit was observed in 52 biopsyproven NASH patients treated with liraglutide 1.8 mg per day for 48 weeks. Resolution
CE
of NASH occurred in 39% of patients with liraglutide compared to 9% on placebo and
AC
less patients on liraglutide experienced worsening of fibrosis (69). Treatment led to a significant reduction of body weight and improved glycemic control in those with T2DM (about one-third). A modest improvement in insulin sensitivity was observed after 12 weeks of liraglutide treatment in a subgroup that underwent more careful metabolic studies (70).
2.2.2. Dipeptidyl peptidase-4 (DPP-4) inhibitors This class of agents exert glucose-lowering effects primarily by blocking the enzyme (DPP-4) that degrades glucagon-like peptide-1 (GLP-1) (71). However, their potential in
12
ACCEPTED MANUSCRIPT NAFLD/NASH has not been extensively tested, although positive effects have been reported in mice models of diabetes (72). In small clinical trials, reduction of plasma ALT
T
levels has been reported by some (67, 73), but not all (74), studies with sitagliptin.
RI P
Treatment with vildagliptin for 6 months may also lead to a modest decrease in plasma aminotransferase concentration and of hepatic steatosis (from 7.3% to 5.3% measured
SC
by 1H-MRS; normal being ≤5.5%) (75), as expected from the close correlation between
NU
plasma ALT levels and liver triglyceride content (76). The decrease in liver triglycerides correlated with the lower fasting plasma glucose but not with the modest weight loss
ED
treatment in patients with NASH.
MA
observed. There have been no studies examining liver histology following DPP-4
PT
2.2.3. Sodium-glucose co-transporter 2 (SGLT2) inhibitors These agents inhibit the reabsorption of glucose in the proximal tubular system with a
CE
marked reduction of plasma glucose levels. Their use is associated with a modest
AC
reduction of total body weight, likely from caloric loss related to glycosuria (77). A recent clinical trial reported a reduction in cardiovascular mortality (78), which may be of interest given the increased cardiovascular risk of patients with NAFLD . Interest has arisen, at least in part, from animal studies observing an effect on steatohepatitis (79, 80). Treatment with canagliflozin (81) or dapagliflozin (82) decreases plasma aminotransferases, although there are no studies assessing their effect on liver histology.
13
ACCEPTED MANUSCRIPT 2.2.4. Thiazolidinediones Thiazolinediones (TZDs) modulate the transcription factor PPAR-γ to have profound
T
effects on insulin action, glucose metabolism, inflammation and adipocyte biology (83,
RI P
84). Many of these effects are related to the high abundance of PPAR-γ receptors in adipose tissue. However, they are also present in other tissues involved in glucose and
SC
lipid metabolism, such as the liver. Treatment with piogitazone in NASH is often
NU
associated with an increase in plasma adiponectin and improved insulin sensitivity in adipose tissue, liver and skeletal muscle (85). Thiazolidinediones prevent the
MA
progression to T2DM in patients with prediabetes (86), an effect that may be linked to
ED
their ability to reduce hepatic steatosis.
PT
Early studies with TZDs were small, uncontrolled and reported mixed clinical results (55). In the first RCT with a TZD, Belfort et al (87) reported significant improvement in hepatic
CE
steatosis and necroinflammation after 6 months of pioglitazone treatment of 55 patients
AC
with biopsy-proven NASH patients with prediabetes or T2DM (see Figure 1). The NAFLD activity score (NAS) improved in 73% of patients with pioglitazone versus 24% on placebo with a trend for less fibrosis. This study established that NASH could be reversed within a relatively short period of time, but the effect on fibrosis was inconclusive. In patients with NASH but without diabetes, positive but less striking results were also reported, although a lower dose of pioglitazone was used in these studies (34, 88). Unexpectedly, rosiglitazone reduced steatosis but did not improve hepatocyte necrosis or lobular inflammation (89).
14
ACCEPTED MANUSCRIPT Recently, a long-term study in 101 patients with prediabetes or T2DM and NASH has confirmed the safety and efficacy of pioglitazone in this setting (90). The TZD improved
T
insulin sensitivity in adipose tissue, liver and muscle as well as histology on sequential
RI P
liver biopsies at 18 and 36 months (Dr. Cusi’s unpublished data in press). Of note, the mean fibrosis scores improved when compared to placebo, suggesting an effect on
SC
fibrogenesis and potential to modify the natural history of the disease (91). The safety
NU
isseus related to TZDs have been reviewed elsewhere (84), but treatment over 3 years was overall safe, with a weight gain of ~3 kilograms and no patient having to discontinue
MA
treatment. Improved adipose tissue insulin sensitivity from PPAR agonists promotes triglyceride synthesis and expansion of body fat. Occasionally weight gain is from fluid
ED
retention. Thiazolidinediones decrease cardiovascular mortality (92) and stroke (93).
PT
Rarely congestive heart failure (CHF) may develop when treatment is initated in a patient with unknown diastolic disfunction or history of CHF. Bone loss may occurr in women
CE
and should be monitored (94, 95). A recent long-term prospective study failed to confirm
AC
an association between pioglitazone and bladder cancer (96) while a number of studies have reported its use associated with a decrease in a broad spectrum of cancers (97, 98).
2.3. Lipid lowering agents 2.3.1. Omega-3 polyunsaturated fatty acids (PUFAs) There has been a long held belief that PUFAs could reduce hepatic steatosis and downregulate pro-inflammatory pathways in NAFLD/NASH as they activate peroxisome proliferator-activated receptor (PPAR) α receptors and upregulate several genes
15
ACCEPTED MANUSCRIPT involved in fatty acid oxidation. This view was supported by small, uncontrolled studies that reported a reduction in plasma aminotransferases and liver steatosis. However,
T
recent RCTs have been overall negative (99-102) and there appears to be no major role
RI P
for PUFAs for the treatment of NASH.
SC
2.3.2. Cholesterol-lowering drugs: statins, ezetimibe and colesevelam
NU
Most studies with agents that modify cholesterol metabolism, such as statins (HMGCoA reductase inhibitors) or ezetemibe (an inhibitor of intestinal cholesterol absorption),
MA
have been of poor quality and not conducted specifically in patients with biopsy-proven NASH (24, 103, 104). Although several small, short-term, uncontrolled trials have
ED
reported a lowering of plasma aminotransferases or a reduction in steatosis on imaging,
PT
most did not report on liver histology. The only controlled study with a statin reporting liver histology as the primary endpoint was negative (105). There is consensus that
CE
statins do not improve histology in NASH but can be safely prescribed to ameliorate
AC
their increased cardiovascular risk (45, 46). In small open label studies ezetimibe has also been reported to decrease plasma ALT (106) and steatosis (107) as well as modestly improve the NAS score, but not fibrosis (108). The 2015 Japanese guidelines for treatment of NASH (33) do recommend ezetimibe as a potential treatment for hypercholesterolemia in NAFLD (level C), although overall it is unlikely to have a major impact on liver histology in NASH. Finally, neither niacin (109) or colesevelam (110) improve hepatic steatosis in NAFLD.
2.3.3. Peroxisome proliferator-activated receptor alpha (PPAR) agonists: fibrates
16
ACCEPTED MANUSCRIPT In mice models of NASH, PPAR activation exerts anti-inflammatory effects and may counteract different stages of NAFLD (111). PPAR activation, reduces plasma
T
triglycerides and increases plasma HDL-C by many mechanisms that include increased
RI P
hepatic beta-oxidation, induction of lipoprotein lipase, modulation of hepatic lipogenic
SC
pathways, and stimulation of synthesis of HDL-C major apolipoproteins, apoliproteins AI and -AII. However, despite their many effects on lipid metabolism, they do not
NU
improve insulin sensitivity in adipose tissue, liver or skeletal muscle (112).
MA
The hallmark of NAFLD/NASH-associated dyslipidemia is high plasma triglyceride with low-HDL-C concentration and an increase in apolipoprotein B and LDL-C particles.
ED
Recently, it has become evident that lipid profiles, as usually measured in the clinic,
PT
may overlook defects in lipoprotein metabolism in patients with NAFLD, who typically have significantly a higher plasma apolipoprotein B to apolipoprotein A1 ratio and
CE
smaller LDL particle size, independent of the presence of obesity or the severity of
AC
steatohepatitis (113). Activation of liver PPAR-dependent pathways by fenofibrate reduces cardiovascular events when added to statins in patients with T2DM who have plasma triglycerides >200 mg/dL and a low HDL-C (114). Several studies that tested fenofibrate in patients with NAFLD alone or with statins and have been overall negative in terms of their ability to improve hepatic insulin sensitivity (109, 112), lower plasma aminotransferases, decrease hepatic triglyceride concentration assessed by 1H-MRS or improve histology in NASH (109, 115). Compared to animal studies where PPAR activation ameliorates steatohepatitis, and even liver fibrosis (111), the lack of efficacy of fibrates in humans as compared to animal studies could be a result of the weaker
17
ACCEPTED MANUSCRIPT potency of PPAR agonists available for clinical use, but more likely that in rodents PPAR pathways play a much larger metabolic role. A novel and more selective
T
PPARα agonist (K-877) that appears to have greater triglyceride-lowering activity than
RI P
fenofibrate is now in phase 2 clinical trials (116). In 423 patients with
SC
hypertriglyceridemia, it significantly reduced liver enzymes when added to a statin (117),
2.3.4. Dual PPAR-agonists (α/γ and α/δ)
NU
a promising finding that deserves further exploration as a treatment for NAFLD/NASH.
MA
Several dual PPAR-α/γ agonists (muraglitazar, tesaglitazar, ragaglitazar) have been tested in clinical trials for the treatment of T2DM, but none of their development made it
ED
beyond phase 3 due to increased risk of cardiovascular events, weight gain and/or
PT
edema (116). Perhaps aleglitazar was the most promising (118), but its landmark phase 3 clinical trial was halted prematurely due to lack of efficacy in reducing cardiovascular
CE
events compared to placebo and increased rates of gastrointestinal hemorrhages (2.4%
AC
versus 1.7% on placebo, p=0.03) and renal dysfunction (7.4% versus 2.7% on placebo, P
