New Treatment for NASH; Human Milk for Preterm Infants

Derick Alison
Derick Alison
17 Min Read

TTHealthWatch is a weekly podcast from Texas Tech. In it, Elizabeth Tracey, director of electronic media for Johns Hopkins Medicine in Baltimore, and Rick Lange, MD, president of the Texas Tech University Health Sciences Center in El Paso, look at the top medical stories of the week.

This week’s topics include a new treatment for nonalcoholic steatohepatitis (NASH), human milk for preterm infants, psoriasis therapy, and managing gout with uric acid levels.

Program notes:

0:34 NASH treatment

1:34 Two dosages and placebo

2:32 Similar incidence of adverse events

3:32 Minor effects on heart or bone?

4:15 Psoriasis treatment

5:15 Decreased plaques by 75%

6:05 Human milk, preterm infants, neurodevelopment

7:05 Black infants 52%

8:07 Decreased necrotizing enterocolitis

9:14 Uric acid levels and gout flares

10:15 3,600 patients with gout

11:15 Keep levels at 5 mg/dL or below

12:15 End

Transcript:

Elizabeth: Does human milk help preterm infants?

Rick: Uric acid and its association with gout flares.

Elizabeth: A new medicine for treating nonalcoholic steatohepatitis with fibrosis.

Rick: And an oral agent to treat plaque psoriasis.

Elizabeth: That’s what we’re talking about this week on TTHealthWatch, your weekly look at the medical headlines from Texas Tech University Health Sciences Center in El Paso. I’m Elizabeth Tracey, a Baltimore-based medical journalist.

Rick: I’m Rick Lange, president of Texas Tech University Health Sciences Center in El Paso, where I’m also dean of the Paul L. Foster School of Medicine.

Elizabeth: Rick, I’d like to turn first to the New England Journal of Medicine (NEJM) and talk about this issue of nonalcoholic steatohepatitis. This is something that I have actually seen quite a number of times on the MICU [medical intensive care unit] at Johns Hopkins, because folks come there when they are in acute liver failure frequently. They are candidates for transplant and they get evaluated for that and hopefully receive a liver. Of course, this NASH has been increasing quite a lot in incidence. It’s a very concerning situation.

This agent is called resmetirom. It’s an oral, liver-directed, thyroid hormone receptor β-selective agonist. It’s being developed for treating NASH with liver fibrosis. This is part of an ongoing phase III trial involving adults with biopsy-confirmed NASH and a fibrosis stage that is in the early stages.

They had three groups here: one group had once-daily this oral agent, resmetirom, at a dose of 80 mg or a dose of 100 mg or the placebo. They had two primary endpoints at week 52. These were NASH resolution, including a reduction in the nonalcoholic fatty liver disease (NAFLD) activity score by greater than or equal to two points and no worsening of fibrosis. They had almost 1,000 folks in this study.

They were able to show that in the group that had 80 mg of resmetirom, there was no worsening of their NAFLD activity score in 24%-plus of those folks, almost 26% in the 100 mg group, and compared with 14.2% of those in the placebo group. They also showed that there was a change in LDL [low-density lipoprotein] cholesterol levels. This agent was also successful in reducing them quite a bit in both dosages.

They did show that diarrhea and nausea were more frequent with the drug than they were with the placebo. They had a similar incidence of adverse events across all their trial groups. They basically say this stuff is superior to placebo with respect to NASH resolution and improvement in liver fibrosis by at least one stage.

Rick: Elizabeth, this is preliminary results, but it’s good news. The estimated global prevalence of NASH is about 4% to 6% and it’s particularly prevalent in people that have obesity and type 2 diabetes. Currently, there is no approved pharmacologic treatment for NASH and the recommendations are to lower your weight and control your diabetes.

This one is of particular importance because it would be the first if it’s approved. It’s effective in about a fourth of the individuals in either decreasing the hepatitis or decreasing the fibrosis, because it is a thyroid agonist. It has other effects, particularly on the hormonal system, and may have minor effects on the heart or bone, although this is supposed to be more specific with the liver.

We need longer studies, we need larger populations. But for proof of concept, this is good news.

Elizabeth: It is good news, I agree. I would say that the editorialist notes that, of course, obesity and type 2 diabetes are conditions that ought to be addressed. We’d sure like to see them addressed before anybody starts to develop NASH, although I would also note that I have seen patients of normal weight who have also developed this condition.

Rick: NASH is clearly increasing. Part of that is obesity, part of that’s diabetes, but then for some other reasons that we really don’t understand. It’s estimated that there are about 4 to 5 million potential candidates for treatment just in the United States.

Elizabeth: Would you like to stay in NEJM and go to yours?

Rick: Yeah. Let’s do that and let’s talk specifically about psoriasis and a potential oral treatment for it. We think about psoriasis primarily being a skin condition. It’s an immune-mediated, inflammatory disease. It also affects joints, a risk factor for atherosclerotic cardiovascular diseases. The most effective treatments we have are immunotherapy, usually monoclonal antibodies. The downside of those is they have to be given either by a subcutaneous injection or given intravenously, so it would be nice to have an oral therapy.

They took 255 patients with psoriasis and they randomized them to placebo or to an oral agent that blocks interleukin-23 and some of the pathways below it. They used doses from as little as 25 mg once a day to as much as 100 mg twice a day, and then looked at the plaques. The goal was to reduce those by 75%.

What they discovered is that for the individuals that received the highest dose of the oral medication, it decreased the plaques 75% in about 80% of the individuals. In about 40% of the individuals, it decreased the plaques by about 90%. This is really good news. Whether it will help reduce arthritis or atherosclerotic disease, we really don’t know, but at least it reduces the skin manifestations.

Elizabeth: People find those extremely troublesome because, of course, they are often in highly visible locations. I think also this notion that it’s a systemic condition, what about the obesity, diabetes, cardiovascular events? Then the editorialist notes the 5 years’ loss of life for folks who have this condition. I’m wondering about this agent in those places.

Rick: The presumption is if it decreases the immune manifestations on the skin that it will do so systemically as well, but that needs to be proven. This is going to require larger and longer-term studies.

Elizabeth: Let’s turn to JAMA. This is a study looking at human milk for extremely preterm infants in the NICU [neonatal intensive care unit]. There is no question that observational studies have shown in the past that human milk, and specifically maternal milk for babies who are born preterm and who are in the NICU, is better for them.

This study is taking a look at neurodevelopmental outcomes when donor maternal milk is given to extremely preterm infants during their birth hospitalization. They enrolled infants younger than 29 weeks 0 days’ gestation and a birth weight of less than 1,000 g [about 2.2 lbs] and actually looked at this for 7 years.

Their primary outcome measure was the Bayley Scales of Infant and Toddler Development. These were measured at 22 to 26 months corrected age. They had 483 infants who were randomized — half of whom got the donor milk and the other half got preterm formula. Importantly, black infants comprised 52% of these infants.

They assessed, as I said, using this measure at 22 to 26 months corrected age and their cognitive score. Basically, what they found was that there was really no difference between those kids who were fed the donor milk versus those who had the preterm formula. They did show, however — and this, I think, is a really important outcome — that this common side effect of necrotizing enterocolitis among preterm infants was much lower in the group who were fed the donor milk versus those who were fed the preterm formula.

Rick: For those listeners that may not be familiar with this condition called necrotizing enterocolitis, it’s a disease of the intestinal tract. Tissue that lines it becomes inflamed and dies. It actually sloughs off, and it can be a fatal event. As you noted, it’s clear that maternal milk is associated with a decreased risk of necrotizing enterocolitis and also sepsis for mothers that can’t or don’t want to provide maternal milk. The question is if we give pasteurized donor human milk, is that better than formula? Because if it does decrease the risk of necrotizing enterocolitis, it would still be preferred over formula.

Elizabeth: Also, they note that the children who got the donor milk gained weight more slowly than the group who ended up with the preterm formula. When they looked at other outcomes like death, they didn’t really show that there was anything that was noteworthy with regard to differences.

Rick: The reason for that isn’t clear, but as you mentioned there weren’t really any significant side effects from the slower growth associated with donor human milk.

Elizabeth: The editorialist also notes that this donor milk or the energy surrounding that is increasing so that it’s hoped that more preterm infants will be able to have this if the mom is unable to provide it.

Rick: Yeah. In fact, when they started this study about 10 years ago, about 25% of the centers used donor milk. But by the time that study had concluded 10 years later, about 75% were using donor milk.

Elizabeth: This is a good-news study then. It tees up then with yours too.

Rick: I teed this up as the relationship between uric acid levels and the association with the gout flares. When I trained, we just assumed that the level of uric acid predicted gout. Now, what is gout? That’s when the uric acid crystallizes inside the joints and it’s associated with really severe pain, but there are also systemic consequences like cardiovascular morbidity and mortality, chronic kidney disease, and metabolic syndrome.

Again, when I trained, when people had elevated serum uric acid levels and had had gout, we gave them agents to lower it. The thought being is that there was a relationship between serum uric acid and it’s associated with gout flares. But that’s really come into question lately, and the clinical guidelines are kind of at odds with what the arthritis communities are recommending — both the U.S. and Britain.

Is there an association with serum uric acid levels and gout, and hospitalization for gout? Or is there not? The U.K. Biobank has about half a million people in it. From that database, they were able to identify over 3,600 patients that had gout and they followed them for the course of about 8 years; 30% ended up with a gout flare. Then they looked at their serum uric acid levels to decide whether there was any relationship.

They found out that in fact there was. It’s recommended in Britain that you keep the level below 5 [mg/dL] and the U.S. level is below 6. About 98% of the flares and 100% of the associated hospitalizations occurred in people that had levels over 5, levels over 6, and, again, it was about 95% of the cases of gout flares. In fact, if you started at a level of 6, every time it went up by 1 or more — i.e. from 6 to 7 or 7 to 8 — it increases the risk of a gout flare by 60% and the risk of hospitalization by about 85% to 90%.

In individuals that have a history of gout, their baseline serum uric acid levels do predict the risk of subsequent gout flares and hospitalizations for recurrent gout.

Elizabeth: Well, that’s a good piece of information to have. Now, let’s talk about how onerous is it to keep those levels at 5 or below.

Rick: We have medications that are fairly effective, and we can identify people that we know that are at high risk of having a gout flare: if you’re a male, if you have a higher BMI [body mass index], greater alcohol consumption, smoking, and greater red meat intake. But we have, again, very effective medications in addition to the lifestyle changes. What this tells me is that we need to reduce those to levels of less than 5 or 6 if we want to prevent gout.

Elizabeth: Sounds to me like 5 might be the right target.

Rick: Less than 5 I think would be great. That’s what the Brits recommend. In the United States, it’s less than 6. But I think, again, the lower you can get it, the less likely you are to have the uric acid crystallized in the joints and cause gout flares.

Elizabeth: Okay. Another good news study. We like those things. On that note then, that’s a look at this week’s medical headlines from Texas Tech. I’m Elizabeth Tracey.

Rick: I’m Rick Lange. Y’all listen up and make healthy choices.

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