Nonalcoholic steatohepatitis (NASH) is a progressive liver disease with no approved treatment. Resmetirom is an oral, liver-directed, thyroid hormone receptor beta–selective agonist in development for the treatment of NASH with liver fibrosis.
Methods
We are conducting an ongoing phase 3 trial involving adults with biopsy-confirmed NASH and a fibrosis stage of F1B, F2, or F3 (stages range from F0 [no fibrosis] to F4 [cirrhosis]). Patients were randomly assigned in a 1:1:1 ratio to receive once-daily resmetirom at a dose of 80 mg or 100 mg or placebo. The two primary end points at week 52 were NASH resolution (including a reduction in the nonalcoholic fatty liver disease [NAFLD] activity score by ≥2 points; scores range from 0 to 8, with higher scores indicating more severe disease) with no worsening of fibrosis, and an improvement (reduction) in fibrosis by at least one stage with no worsening of the NAFLD activity score.
Results
Overall, 966 patients formed the primary analysis population (322 in the 80-mg resmetirom group, 323 in the 100-mg resmetirom group, and 321 in the placebo group). NASH resolution with no worsening of fibrosis was achieved in 25.9% of the patients in the 80-mg resmetirom group and 29.9% of those in the 100-mg resmetirom group, as compared with 9.7% of those in the placebo group (P<0.001 for both comparisons with placebo). Fibrosis improvement by at least one stage with no worsening of the NAFLD activity score was achieved in 24.2% of the patients in the 80-mg resmetirom group and 25.9% of those in the 100-mg resmetirom group, as compared with 14.2% of those in the placebo group (P<0.001 for both comparisons with placebo). The change in low-density lipoprotein cholesterol levels from baseline to week 24 was −13.6% in the 80-mg resmetirom group and −16.3% in the 100-mg resmetirom group, as compared with 0.1% in the placebo group (P<0.001 for both comparisons with placebo). Diarrhea and nausea were more frequent with resmetirom than with placebo. The incidence of serious adverse events was similar across trial groups: 10.9% in the 80-mg resmetirom group, 12.7% in the 100-mg resmetirom group, and 11.5% in the placebo group.
Conclusions
Both the 80-mg dose and the 100-mg dose of resmetirom were superior to placebo with respect to NASH resolution and improvement in liver fibrosis by at least one stage.
Vitamin B12 and folic acid were found to significantly impact nonalcoholic steatohepatitis (NASH), for which there is no pharmaceutical treatment option
NASH is the second stage of nonalcoholic fatty liver disease (NAFLD); a few potential causes of which include consuming high fructose corn syrup, low-level exposure to glyphosate or choline deficiency
Although NAFLD may have no symptoms it can progress to NASH, fibrosis and finally cirrhosis, with a higher risk of liver cancer. Supplementation with B12 and folic acid appeared to slow the progression of NASH and reverse fibrotic tissue changes in the liver
Iron overload is also associated with liver damage and high iron levels are found in individuals with alcoholic liver disease and NAFLD
Consider protecting your liver by eliminating high-fructose corn syrup from your diet, don’t use Roundup, and make sure to purchase organic, non-GMO produce. Also, take care to get enough B vitamins and choline from your food.
According to the American Liver Foundation,1 approximately 100 million people in the U.S. have nonalcoholic fatty liver disease (NAFLD). Research2 published by Duke-NUS Medical School3 revealed that two B vitamins may have a significant effect on an advanced form of the disease, for which there is no pharmaceutical treatment.4
Your liver weighs just over 3 pounds and is located on the right side of your abdomen, protected by your rib cage.5 It’s the largest solid organ in your body and one of the largest glands, carrying out over 500 essential tasks to maintain optimal health.6
The liver has two main lobes and each of those has eight segments. Every segment is made up of approximately 1,000 lobules that are connected to small ducts. The liver filters your blood, regulates many chemical levels and excretes bile into your intestines to help break down fat. The liver also produces cholesterol, stores and releases glucose and regulates blood clotting.7 Each of these vital functions is impacted by the four stages of NAFLD.
NAFLD is a serious liver condition caused by excess fat in the liver, and not from being exposed to alcohol. The medical term is hepatic steatosis, and it is the most common chronic liver disease in developed countries.8 In one population-based study,9 18.9% of the participants had confirmed NAFLD, which was more prevalent in men than women.
Risk factors in this study were being over age 40, male, and being diagnosed with central obesity and elevated fasting blood sugar, aspartate transaminase (AST) and alanine transaminase (ALT). Dietary fructose is a significant link in the development of NAFLD,10,11,12 chronic hepatic inflammation and an increased risk of developing the next stage of liver disease, nonalcoholic steatohepatitis (NASH).
The results of one study13 presented at the 2022 Endocrine Society annual meeting found a significant link between those whose diet contained the most fructose and the development of NAFLD. In a press release, one researcher on the study, Dr. Theodore Friedman from Charles R. Drew University, said:14
“We found that when adjusting for the demographics and behavioral factors (smoking, modest alcohol consumption, diet quality and physical activity), high fructose consumption was associated with a higher chance of NAFLD among the total population and Mexican Americans.”
Vitamin B12 and Folic Acid May Reverse NASH
The researchers in the featured study15 were studying the effect that vitamins B12 and B9 might have on NASH. After years of inflammation from NAFLD and fatty deposits on the liver, it is possible to develop NASH.16
Dr. Madhulika Tripathi, a senior research fellow with the Laboratory of Hormonal Regulation at Duke-NUS’ Cardiovascular & Metabolic Program, said in a press release,17 “While fat deposition in the liver is reversible in its early stages, its progression to NASH causes liver dysfunction, cirrhosis and increases the risk for liver cancer.”
The researchers were seeking to understand the relationship between hyperhomocysteinemia and NASH.18 Using an animal model, they administered vitamin B12 and folic acid, attempting to reverse the cellular features of NASH. While evaluating preclinical models,19 they discovered that homocysteine attaches to a protein called syntaxin 17 and blocks the protein. This in turn appears to induce the development and progression of NASH.
However, when mice were supplemented with vitamin B12 and folic acid, the levels of syntaxin 17 rose, which slowed the progression of NASH and reversed fibrosis. One of the scientists in the study, Dr. Brijesh Singh, said:20
“Our findings are both exciting and important because they suggest that a relatively inexpensive therapy, vitamin B12 and folic acid, could be used to prevent and/or delay the progression of NASH. Additionally, serum and hepatic homocysteine levels could serve as a biomarker for NASH severity.”
The researchers were excited by the possibilities since the early stages of NAFLD often have no symptoms and don’t usually cause any harm.21 Yet, without identification, the condition can progress to NASH or fibrosis. This can lead to extreme tiredness, unexplained weight loss and weakness.
There are four stages of NAFLD which begin with simple fatty liver steatosis.22 This can progress to NASH, then fibrosis and finally cirrhosis. In the latter stages, patients are also at higher risk for liver cancer.23 During all stages of NAFLD, a person has a higher risk of developing cardiovascular diseases.
Vitamin B12 and Choline Deficiencies?
One reason there is such a high prevalence of individuals with NAFLD and NASH may be a deficiency or insufficiency in Vitamin B12, folic acid and/or choline. According to the National Institute of Diabetes and Digestive and Kidney Diseases,24 NAFLD is more common in individuals who are obese or have obesity-related conditions, such as Type 2 diabetes.
The National Institutes of Health25 reports that the rate of vitamin B12 deficiency is close to 20% in those who are older than 60. This data is from the National Health and Nutrition Examination Survey (NHANES) from 2015 to 2016. Data from another large, nationally representative sample26 demonstrated that serum levels of B12 are inversely associated with obesity.
In other words, people who are obese have a higher risk of NAFLD. A vitamin B12 deficiency may allow NASH to progress and the rate of vitamin B12 deficiency is close to 20% in those older than 60 and higher in those who are obese.
Vitamin B12 is also called cobalamin.27 It’s found in animal food and is a key component in the function and development of the central nervous system. A second essential nutrient for human health that is also associated with central nervous system health and the risk of NAFLD is choline. Choline was identified in 186228 and officially recognized as an essential nutrient by the Institute of Medicine in 1998.29
Choline plays a significant role in human health, from neurotransmitter synthesis to cell structures and has a large impact on the development of NAFLD, atherosclerosis30 and neurological disorders.31 The body can produce some choline endogenously in the liver but not enough to meet human needs. There is an interrelationship between folic acid and choline deficiencies as both are methyl donors.32
When the diet is deficient in folic acid, choline becomes the primary methyl donor, creating greater insufficiency or deficiency of the nutrient. Nearly 12 years ago,33 Chris Masterjohn, who has a Ph.D. in nutritional science, wrote that choline insufficiency or deficiency may play a more significant role in the development of fatty liver disease than fructose.
According to Masterjohn,34 your body uses choline to rid itself of excess fat. Without enough choline, it can trigger fatty liver. Yet, the most significant culprit remains excessive fructose, as it must be metabolized by the liver and is primarily converted into body fat as opposed to being used for energy like glucose. Without enough choline, the fat is deposited in the liver.
The Importance of Iron Levels for Liver Health
Another factor that is associated with liver damage is iron overload. Iron may be one of the most common nutritional supplements that can be found as a single supplement or added to multivitamins and processed foods. However, damage from too much iron may be greater than that from iron deficiency anemia.35
Although it is necessary for biological functions, too much can do tremendous damage. Nearly all adult men and postmenopausal women are at risk for iron overload since there are no efficient means for the body to excrete excess iron. In other words, these populations do not lose blood on a regular basis.
Blood loss is a primary way to lower excess amounts of iron which, if left untreated, can contribute to neurodegenerative diseases, diabetes, heart disease and cancer. Additionally, high iron levels are found in individuals with alcoholic liver disease and NAFLD.36
Low-Levels of Roundup Exposure Damage the Liver
Glyphosate, which is the active ingredient in the herbicide Roundup, is also linked to NAFLD and NASH. Researchers37 from the University of California San Diego School of Medicine38 found patients with NASH had higher residues of glyphosate in their urine, an association that held true regardless of other factors in liver health, such as body mass index, diabetes, age or race.
Exposure to glyphosate may lead to more severe forms of liver disease, and subsequently an increased risk of liver cirrhosis, liver cancer and higher mortality rates than the general population from liver-related and non-liver-related causes.39
In a UC San Diego news release, study researcher Paul J. Mills, Ph.D., explained, “There have been a handful of studies, all of which we cited in our paper, where animals either were or weren’t fed Roundup or glyphosate directly, and they all point to the same thing: the development of liver pathology. So, I naturally thought: ‘Well, could it be exposure to this same herbicide that is driving liver disease in the U.S.?’”40
Glyphosate is also known to trigger the production of reactive oxygen species, leading to oxidative stress. As noted in Scientific Reports, “Elevation in oxidative stress markers is detected in rat liver and kidney after subchronic exposure to GBH [glyphosate-based herbicides] at the United States’ permitted glyphosate concentration of 700 μg/L in drinking water.”41
Researchers from King’s College London also showed an “ultra-low dose” of glyphosate-based herbicides was damaging.42 The study involved glyphosate exposures of 4 nanograms per kilogram of body weight per day, which is 75,000 and 437,500 times below EU and U.S. permitted levels, respectively.43
After a two-year period, female rats showed signs of liver damage, specifically NAFLD and progression to NASH. The researchers noted44 that glyphosate may bring about toxic effects via different mechanisms, depending on the level of exposure, including possibly mimicking estrogen and interfering with mitochondrial function.
Consider These Tips for Liver Support
There are several steps you can take to protect your liver. Among those are eliminating high-fructose corn syrup from your diet, not using Roundup or other glyphosate-based herbicides in your garden, purchasing organic, non-GMO produce and foods, lowering your risk of iron overload and taking care to ensure you get enough B vitamins and choline.
However, we would need to live in a perfect world to ensure our liver is not inundated with a ubiquitous chemical assault commonly found in our industrialized world. As the featured research pointed out, even those with NASH, an advanced form of NAFLD, can benefit from supplementing with vitamins B12 and folic acid.
While the focus of the featured study was NAFLD, overconsumption of alcohol also drives liver damage, cirrhosis and death. Data45 gathered between 1999 and 2016 revealed a 65% increase in annual deaths from cirrhosis, with 25- to 34-year-olds experiencing the greatest relative increase in mortality driven entirely by alcohol-related disease.
Milk thistle is an herb that has been used for thousands of years to support liver, kidney and gallbladder health. In modern times, silymarin, the active ingredient in milk thistle, has been used to treat alcoholic liver disease and hepatitis.46 Silymarin may help suppress cellular inflammation47 and inhibit the mammalian target of rapamycin (mTOR), a pathway that, when overactivated, increases your risk of cancer.48
Coenzyme Q10 (CoQ10) is the third-most consumed supplement,49 yet many people don’t realize how clinically effective it is, including the role it plays to protect your liver. In one study,50 44 patients were divided into two groups. One group was given 100 mg of CoQ10 each day, while the other was given a placebo.
After four weeks, the group taking CoQ10 dropped weight and had lower levels of serum AST, a blood marker that indicates liver disease and/or damage. The reduced version of CoQ10 is ubiquinol. As you age, the body’s ability to absorb and utilize CoQ10 drops, but it can still use ubiquinol.51 Ubiquinol is absorbed three to four times better than CoQ10.52
N-acetylcysteine (NAC) is a precursor needed to produce glutathione, also called the “master antioxidant.”53 NAC helps support liver health in those with hepatitis C and other chronic liver diseases.54
An animal study showed NAC could effectively minimize damage associated with alcohol consumption55 and is used as an antidote for acetaminophen toxicity, which causes liver damage by depleting glutathione.56,57 Research published in Hepatitis Monthly58 has also shown NAC supplementation helps improve liver function in patients with NASH.
The incidence of nonalcoholic fatty liver disease and nonalcoholic steatohepatitis continues to rise with obesity and type 2 diabetes, and all clinicians must screen patients at high cardiometabolic risk, according to a speaker.
Approximately 30% to 37% of U.S. adults have nonalcoholic fatty liver disease, known as NAFLD, and about 8-12% have nonalcoholic steatohepatitis (NASH), which leads to fibrosis and liver failure and a leading indication for liver transplant, Christos S. Mantzoros, MD, DSc, PhD, professor of medicine at Harvard Medical School and chief of endocrinology at VA Boston Healthcare System, said during a presentation at the Heart in Diabetes CME Conference. Often such patients are not diagnosed until serious liver or cardiometabolic complications develop, Mantzoros said.
Mantzoros is a professor of medicine at Harvard Medical School and chief of endocrinology at VA Boston Healthcare System.
“In our society, as the prevalence of obesity goes up, the prevalence of type 2 diabetes goes up, and the prevalence of NAFLD and steatosis goes up,” Mantzoros said. “The NASH epidemic is part of a cardiometabolic disease group. All of us need to be vigilant to make the diagnosis and to prevent and treat it. All of us need to apply all of the tools we have when we make the diagnosis.”
In the U.S., about 7 in 10 people with diabetes will have NAFLD, Mantzoros said, whereas up to 80% of people with NASH will have metabolic syndrome, leading to type 2 diabetes over time. Additionally, these risk factors lead to cardiovascular morbidity and mortality, he said.
“NAFLD and NASH are common, especially among people with obesity, diabetes and metabolic syndrome, and unfortunately most of the time it remains undiagnosed,” Mantzoros told Healio. “We need to think about it, screen and treat it.”
Strategies to treat NAFLD, prevent NASH
There are currently no FDA-approved therapies specifically for NASH; however, Mantzoros highlighted several strategies that can reduce fat in the liver and inflammation:
Weight loss is associated with mild to moderate improvement in NASH, though maintaining weight loss is very challenging, Mantzoros said. The Mediterranean diet is inversely associated with liver steatosis and decreases 10-year CV risk in NAFLD, according to evidence from the ATTICA prospective cohort study recently published in Clinical Nutrition. “In a meta-analysis we put together, we do know that if we follow a Mediterranean diet or Dietary Approaches to Stop Hypertension (DASH) diet, lowering total fat or saturated fat — even if high in monounsaturated fat — we decreased risk for NAFLD and CVD,” Mantzoros said. Similar outcomes are expected in response to the DASH diet.
Bariatric surgery and endoscopic devices have demonstrated improvement in NASH and metabolic syndrome, but evidence for fibrosis improvement is limited, Mantzoros said. “We know from several studies that if we decrease weight by 10% for 1 year, there is NASH resolution in more than 90% of the cases, fibrosis regression in 80% and steatosis improvement in 100% of cases,” Mantzoros said. “Today, we can do this only with bariatric surgery. In the future, we hope we will be able to do this with new anti-obesity drugs.”
Irrespective of the statin used, data show improvements with statin therapy in lipid levels and inflammation, as well as an improvement in NAFLD and NASH. “In an editorial we recently published in Metabolism, we recommend that patients continue statin therapies, unless one has late stage of the disease,” Mantzoros said. “Statins should not be discontinued.”
Some diabetes therapies show promise. Pioglitazone improves liver histology in patients with and without type 2 diabetes with biopsy-proven NASH, and may be used to treat those patients, Mantzoros said. Currently, it is premature to consider GLP-1 receptor agonists or SGLT2 inhibitors to specifically treat liver disease in people with NAFLD or NASH, though data shows the agents can lead to weight loss and decrease steatosis. “They do not improve fibrosis to the degree that we want,” Mantzoros said. “We need larger, longer studies with stronger GLP-1 analogues or combination therapies.”
“When adipose tissue storage is exceeded, triglycerides will be stored in muscle and the liver and this leads to insulin resistance, metabolic syndrome, and not only CVD, chronic kidney disease or diabetes, but also NAFLD,” Mantzoros said. “In addition to lifestyle intervention, many of the same medications [used in diabetes] are expected to be used to treat NAFLD.”
A call to action
As Healio previously reported, eight professional societies issued a joint report on the dangers associated with NAFLD and NASH in July, calling on clinicians to work together across specialties and align treatment strategies.
“We need to realize that this is not a disease only for hepatologists,” Mantzoros said. “Cardiometabolic experts, endocrinologists and primary care physicians need to focus on this epidemic along with nutritionists and exercise physiologists. So many patients who come to our offices go unrecognized.”
Mantzoros said patients must be screened for NAFLD and NASH at the primary care level and diagnosed early to avoid serious complications. Similarly, the joint report also notes that most patients with NAFLD — and many with NASH — have a low risk for clinically significant fibrosis and should be managed by primary care providers.
“We must optimize management with the tools that we have at our disposal today,” Mantzoros said. “Industry and academia need to work together on improving new treatments for this metabolic disorder. There is more coming soon from our working group in terms of recommendations, algorithms, and pathways to follow.”
A study of more than 1,300 women demonstrated that HIV is an independent risk factor for nonalcoholic steatohepatitis with significant nonalcoholic fatty liver disease activity and fibrosis, researchers reported.
“Nonalcoholic fatty liver disease (NAFLD) is common among people with and without HIV and is a leading cause of liver-related morbidity and mortality,” Jennifer C. Price, MD, PhD, associate professor of medicine at the University of California, San Francisco, told Healio. “However, most patients with NAFLD do not go on to develop cirrhosis.”
Women living with HIV faced a higher risk for nonalcoholic steatohepatitis with significant nonalcoholic fatty liver disease activity and fibrosis.
According to Price, the FibroScan-AST (FAST) score can identify patients at risk for developing cirrhosis, or those with nonalcoholic steatohepatitis with an elevated NAFLD activity score and significant liver fibrosis.
“The advantage of the FAST score is that it does not require liver biopsy,” Price said. “We conducted this study to see if HIV was independently associated with higher risk of an elevated FAST score in a cohort of women with and without HIV.”
Jennifer C. Price
Price and colleagues assessed 1,309 women without history of chronic viral hepatitis at 10 U.S. sites 928 with HIV and 381 who were HIV negative — and evaluated associations between HIV, demographic, lifestyle and metabolic factors with a FAST score higher than 0.35, which is considered elevated.
Women with HIV were more likely to have an elevated FAST score compared with those without HIV (6.3% vs 1.8%; P = .001). The researchers calculated that HIV infection was associated with 3.7-fold higher odds of elevated FAST score (P = .002), whereas a greater waist circumference was associated with 1.7-fold higher odds per each 10 cm (P <.001).
The study also showed that undetectable HIV RNA and current protease inhibitor use were independently associated with lower odds of elevated FAST score.
“HIV may increase the risk of more advanced NAFLD histology and liver disease progression,” Price said. “Unsuppressed HIV viral load and increased waist circumference are risk factors for elevated FAST in women, underscoring the importance of ART adherence and weight management in clinical practice.”
Although numerous drugs for nonalcoholic steatohepatitis (NASH) have shown positive results in phase 2 clinical trials, the cure might lie in combinations of drugs with different mechanisms, experts say.
In fact, curing NASH might turn out to be as challenging as curing type 2 diabetes, said Sidney Barritt IV, MD, from the University of North Carolina at Chapel Hill.
Unlike hepatitis C, which can be treated with the blockbuster antiviral drugs that have recently proven so effective, NASH is more complicated because there are no effective drugs to treat it.
With the obesity epidemic, NASH is increasingly common, and results from phase 2 trials attracted throngs of conference-goers with questions here at The Liver Meeting 2018.
Some of the results look encouraging, Barritt told Medscape Medical News. “I think they’re clinically significant.”
Phase 2 results have been positive for MGL-3196 (Madrigal Pharmaceuticals), GS-9674 (Gilead Sciences), NGM282 (NGM Bio), arachidyl amido cholanoic acid (Aramchol, Galmed Pharmaceuticals), tropifexor (Novartis), and VK2809 (Viking Therapeutics).
All the drugs reduced liver fat measured with MRI-derived proton density fat fraction (PDFF). The drugs also improved various other measures of the disease, such as NASH Activity Score, fibrosis, and alanine aminotransferase.
These NASH agents add to the four already in phase 3 trials: obeticholic acid (Ocaliva, Intercept Pharmaceuticals), elafibranor (Genfit), selonsertib (Gilead), and cenicriviroc (Tobira Therapeutics).
But no clear winner has emerged from these studies. It’s hard to know how well the biomarkers measured in trials will protect patients from sickness and death, Barritt explained. NASH destroys the liver gradually; most of its victims die from the heart disease or cancer that results from this damage, which takes decades.
The real test is going to be real-world efficacy. Are the drugs going to have the impact that we expect them to have based on the clinical trial data?
“The real test is going to be real-world efficacy,” he said. “Are the drugs going to have the impact that we expect them to have based on the clinical trial data?”
The development of NASH is mostly related to lifestyle factors, such as overeating and lack of exercise, so there is no obvious target for a drug as there is with a virus. As a result, drug makers have focused on various aspects of inflammation, fat accumulation, and scar formation.
Like obeticholic acid, GS-9674 and tropifexor are farnesoid X receptor (FXR) agonists, which help regulate bile acids, carbohydrate and lipid metabolism, and insulin sensitivity. They also play a role in growth and regeneration after liver injury.
MGL-3196 and VK2809 are thyroid hormone-receptor beta agonists designed to mediate the effects of the thyroid hormone on the liver, on low-density-lipoprotein cholesterol, on triglycerides, on fatty liver, and on insulin sensitivity.
Arachidyl amido cholanoic acid inhibits stearoyl CoA desaturase. It has a “dual mode of action on liver fibrosis, downregulation of steatosis, and a direct effect on hepatic stellate cells, the human collagen-producing cells,” according to Galmed Pharmaceuticals.
The potential for all these approaches was evident in the phase 2 results presented. But the most effective treatments might be a combination of drugs that act on different pathways, said Keyur Patel, BM, from Duke University in Durham, North Carolina, who is a GS-9674 investigator.
In a separate phase 2 trial now underway, Gilead is testing the combination of GS-9674 plus selonsertib, a small-molecule inhibitor of apoptosis signal-regulating kinase 1 (ASK1), plus GS-9676, an acetyl-CoA carboxylase inhibitor, Patel told Medscape Medical News.
A Strong Placebo Effect
Combining the drugs makes sense because the drugs now in phase 3 trials have not shown the potential to cure NASH on their own, according to Jerry Colca, PhD, chief scientific officer of Cirius Therapeutics in Kalamazoo, Michigan. “They have shown minimal effects in phase 2b,” he said.
One of the challenges that researchers have is the strong placebo effect, Colca told Medscape Medical News. Patients in placebo groups typically diet and exercise, which addresses the underlying cause of NASH, and drugs don’t always show much improvement over that.
Cirius is currently conducting a phase 2b study of MSDC-0602K, an insulin sensitizer “designed to selectively modulate the mitochondrial pyruvate carrier (MPC), which at the cellular level mediates the effects of overnutrition,” the company reports.
The effect of MSDC-0602K on NASH might be broader than that of competing drugs because it acts further upstream, Colca noted.
In the phase 2 studies presented, the drugs appear to be well tolerated, although some adverse events, such as pruritus and diarrhea, were reported.
Many of the questions about these drugs might not be addressed until they are already on the market.
“What we don’t know from these trials is what the expected duration of therapy will be,” Barritt said. “Are they drugs for 1 to 3 years to reset the clock while the patient addresses diet and exercise? Or are they going to be lifetime medications?”
Adults with type 2 diabetes randomly assigned Actos therapy were more likely to experience a reduction in nonalcoholic steatohepatitis activity vs. those assigned a placebo, according to study findings published in Annals of Internal Medicine.
In a single-center, parallel-group study, Kenneth Cusi, MD, FACP, FACE,chief of the division of endocrinology, diabetes and metabolism at the University of Florida in Gainesville and Endocrine Today Editorial Board member, and colleagues analyzed data from 101 patients with prediabetes or type 2 diabetes (confirmed via oral glucose tolerance test) and histologically confirmed nonalcoholic steatohepatitis activity (NASH). After baseline measurements (OGTT, euglycemic insulin clamp, DXA scan and liver biopsy), researchers assigned patients to a 500-kcal deficit diet and then randomly assigned them to 30 mg daily Actos (pioglitazone, Takeda Pharmaceuticals), titrated at 2 months to 45 mg daily (n = 50; mean age, 52 years; 72% men; 28% white; 48% with type 2 diabetes), or placebo (n = 51; mean age, 49 years; 69% men; 22% white; 55% with type 2 diabetes) for 18 months. At 18 months, patients again underwent metabolic measurements and a liver biopsy; those on pioglitazone were asked to continue therapy for another 18 months while participants in the placebo group whose NASH resolved were asked to discontinue use; those with persistent disease were invited to initiate pioglitazone therapy for 18 months.
Kenneth Cusi
The primary outcome was a reduction of at least two points in the nonalcoholic fatty liver disease activity score (NAS) without a worsening of fibrosis at 18 months.
Within the cohort, 18 patients (nine in each group) withdrew from the study before 18 months after being informed in 2011 about a potential risk for bladder cancer with pioglitazone. An additional four patients in each group withdrew during the open-label phase (months 18 to 36) for similar reasons.
Researchers found that more patients assigned to pioglitazone achieved the primary outcome vs. those assigned placebo (58% vs. 17%; P < .001); more patients in the pioglitazone group also had resolution of NASH vs. placebo (51% vs. 19%; P < .001). Pioglitazone therapy also was associated with improvement in individual histologic scores, including fibrosis score, with progression of any fibrosis during 18 months occurring in 12% of pioglitazone patients vs. 28% of placebo patients (P = .039).
Pioglitazone also reduced hepatic triglyceride content from 19% to 7% vs. 15% to 11% in the placebo group, and improved adipose tissue, hepatic and muscle insulin sensitivity (P < .001 for all). All 18-month metabolic and histologic improvements persisted during 36 months of therapy.
There were no between-group differences for adverse events; weight gain was greater with pioglitazone (2.5 kg).
“This histologic benefit, combined with improvement in the mean fibrosis score, suggests that pioglitazone may alter the natural history of the disease,” the researchers wrote. “Evidence of this was the reduction in fibrosis progression over 18 months in patients treated with pioglitazone compared with those receiving placebo.”
The study results are likely to change management of patients with type 2 diabetes and fatty liver, Cusi told Endocrine Today. Pioglitazone, he said, could potentially become for NASH what metformin is to the treatment of type 2 diabetes.
“Until this study, we lacked definitive long-term treatment evidence of safety and benefit for such patients,” Cusi said in an interview. “This study shows now that if you have type 2 diabetes, or even prediabetes, and you take pioglitazone, more than half [of patients] have resolution of NASH. What this means is that endocrinologists will have to think about whether the patient has a fatty liver or not as they consider their second-line therapy after metformin.
“This really is a big game changer,” Cusi said. “NASH may lead to end-stage liver disease, and is currently the second cause of liver transplantation in the United States. We have a drug that may change the natural history of liver disease, prevent the onset of type 2 diabetes as shown in ACT NOW, and ameliorate the risk for coronary artery disease or that of stroke, as recently shown by Kernan et al this year in the New England Journal of Medicine. The cost of pioglitazone will decrease over time, as it currently has a generic formulation, and its safety profile has been tested for over 15 years with issues such as bladder cancer having been cleared from the study published by Lewis et al in JAMA last year. Now endocrinologists will think about and diagnose NASH more often in daily practice, having a safe and effective treatment option at hand.– by Regina Schaffer
The same was true for nonalcoholic steatohepatitis.
Nonalcoholic fatty liver disease (NAFLD) is associated with cirrhosis, liver cancer, and several cardiovascular (CV) risk factors such as diabetes and obesity. Prior studies, however, have not established a clear association between NAFLD and early mortality, and most of these studies were based on highly selected patient populations (e.g., those with biopsy-proven NAFLD). To assess this association, researchers conducted a prospective cohort study based on data from the Third National Health and Nutrition Examination Survey (1988–1994), which involved more than 11,000 adults (age range, 20–74) who underwent baseline hepatic ultrasonography.
NAFLD was defined as “the presence of moderate to severe hepatic steatosis with normal liver enzyme levels.” Nonalcoholic steatohepatitis (NASH) was defined as “the presence of moderate to severe hepatic steatosis with increased levels of liver enzymes,” without evidence of hepatitis B or C infection or iron overload. The prevalence of NAFLD was 16%, the prevalence of NASH was 3%, and median follow-up was 14.5 years. Neither NAFLD nor NASH was associated with elevated all-cause mortality or death from CV disease, cancer, or liver disease. These outcomes were noted both in analyses that were adjusted for CV risk factors and in those that were not.
Comment: In this large prospective study, NAFLD and NASH were not associated with elevated risk for all-cause mortality or death from CV disease, cancer, or liver disease. However, these results should be interpreted with some caution, in part because the authors had to create their own ultrasound- and laboratory-based definitions. Although ultrasonography accurately detects hepatic steatosis, ultrasound-detected hepatic steatosis combined with elevated liver enzymes has limited sensitivity and specificity for NASH. The authors call for further studies with large samples and more-refined diagnostic methods to determine the effects of NASH on mortality.
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