Semaglutide improves fatty liver disease and inflammation in people with HIV

Semaglutide, best known as a weight-loss medication, reduced liver fat build-up and appears to lower inflammation in people with HIV and metabolic dysfunction-associated steatotic liver disease (MASLD), according to study results presented last week at the Conference on Retroviruses and Opportunistic Infections (CROI 2024).

Findings from the SLIM LIVER study showed that semaglutide taken for six months reduced liver fat by 31%. “What we saw were really great, clinically significant reductions in liver fat even over that short period of time,” Dr Jordan Lake of the University of Texas in Houston said at a media briefing.

Fatty liver disease and HIV

Metabolic dysfunction-associated steatotic liver disease (MASLD), formerly known as non-alcoholic fatty liver disease (NAFLD), is responsible for a growing share of advanced liver disease worldwide. As the new name suggests, it is associated with obesity, type 2 diabetes and other metabolic abnormalities. Over time, the build-up of fat in the liver can lead to inflammation, liver fibrosis, cirrhosis and liver cancer.

MASLD is common among people living with HIV. Earlier in the epidemic, severe hepatomegaly with steatosis (enlarged fatty liver) was a side effect of first-generation nucleoside/nucleotide reverse transcriptase inhibitors, and drugs in that class still carry a warning. Today, other risk factors are more relevant, but HIV likely plays a role in accelerating liver injury, Lake said.

At CROI, Dr Jennifer Price of the University of California San Francisco reported that among 654 people with well-controlled HIV, a high CD4 count and no other known causes of chronic liver disease, 53% showed evidence of MASLD according to transient elastography imaging, and about 20% had moderate to advanced liver fibrosis.

Risk factors for MASLD included older age, male sex, a high body mass index (BMI) or large waist circumference and high triglycerides, while Black people were at lower risk. Liver biopsies showed that, compared with HIV-negative people, those with HIV were less likely to have liver steatosis, portal inflammation or ‘ballooning’ of liver cells, but more likely to have fibrosis. “These findings may suggest that HIV-specific factors beyond necroinflammation contribute to hepatic fibrosis” in HIV-positive people with MASLD, the researchers concluded.

Semaglutide and MASLD

There are currently no approved medical therapies for fatty liver disease, and management has relied on lifestyle changes such as weight loss and exercise. Researchers have studied a wide variety of potential therapies, but many medications that looked promising in early studies have not succeeded in larger trials.

One possible treatment approach is glucagon-like peptide-1 (GLP-1) agonists, which mimic a natural hormone that suppresses appetite, regulates insulin and blood sugar and slows emptying of the stomach. One of these, semaglutide, is approved for the treatment of type 2 diabetes under the brand name Ozempic, and a higher dose is authorised for the treatment of obesity under the brand name Wegovy. Recent studies have shown than semaglutide reduces the risk of cardiovascular events and kidney disease progression in people without HIV.

Semaglutide and other weight-loss medications look promising for people with HIV, although data are limited. Professor Heidi Crane of the University of Washington in Seattle presented further evidence at CROI, showing that semaglutide led to significant weight loss among people with HIV (an average of 6.5kg, or about 6% of body weight) over one year. Those who started with the highest BMI lost the most weight (almost 9kg), and people without diabetes lost even more weight than those with the condition.

At the same session, Lake presented results from SLIM LIVER (ACTG A5361; NCT04216589), a phase IIb trial to evaluate the effects of semaglutide on liver fat content in people with HIV.

Studies of semaglutide for more advanced metabolic dysfunction-associated steatohepatitis (MASH) have yielded mixed results. SLIM LIVER evaluated the drug for earlier-stage disease, aiming to improve cardiometabolic health by reducing weight and liver fat. “It’s more of a way to either treat or prevent early disease, not a way to reverse existing liver disease,” Lake said.

The pilot study enrolled 51 adults on suppressive antiretroviral therapy (mostly using integrase inhibitors) in the United States and Brazil. Eligible participants had a large waist circumference, insulin resistance or pre-diabetes, and MASLD (defined as at least 5% liver fat content by MRI imaging). The median age was 52 years. More than half were men, 18 were cisgender women, six were transgender women and they were ethnically diverse (39% Latino, 33% Black, 27% White and 2% Native American). The median BMI was within the range  for obesity.

Participants self-administered subcutaneous injections of semaglutide once weekly for 24 weeks, ramping up the dose to 1.0 mg. They used the lower dose approved for diabetes because the higher weight-loss dose was not yet available, Lake noted. At six months, the mean absolute decline in liver fat was 4.2% while the mean relative decline was 31.3%. More than a quarter (29%) experienced complete MASLD resolution (liver fat below 5%) and 58% had at least a 30% relative decline in liver fat (the amount associated with histological improvements on a biopsy).

“It’s more of a way to either treat or prevent early disease, not a way to reverse existing liver disease.”

The reduction in liver fat was accompanied by significant improvements in weight (a median 7.8kg loss), waist circumference and fasting glucose and triglyceride levels. Women, people over age 60, and Latino and White participants experienced greater liver fat reduction. Around 20% of participants did not respond to semaglutide, similar to the proportion in the general population.

Semaglutide was generally well tolerated, with just two severe adverse events possibly related to treatment. Side effects were similar to those seen in the general population (mainly gastrointestinal) and there were no additional safety signals specific to people with HIV.

Semaglutide is a safe and effective pharmacologic therapy for MASLD in people with HIV, the researchers concluded. Weight loss and liver fat reduction were “very tightly correlated,” Lake reported. “If you responded and lost weight, then your liver fat got better, and if you did not respond and you did not lose weight, then you also did not have improvements in your liver fat.”

Another analysis from SLIM LIVER, presented by University of Colorado PhD student Grace Ditzenberger, looked at the effects of semaglutide on muscle structure and function. One concern with GLP-1 agonists is that they can lead to a loss of lean body mass along with fat.

The researchers evaluated changes in muscle quality, quantity and function, focusing on the psoas, a pair of large core muscles that run from the lower back, through the pelvis, to the thigh bone. Psoas volume and fat content were assessed from liver MRIs and physical function was measured by chair-rise and gait speed tests at baseline and six months.

Overall psoas muscle volume decreased but muscle fat content did not change significantly over the 24 weeks on semaglutide. The volume decrease was greatest among people over age 60, but no sex differences were observed. Participants saw a small improvement in the time it took to do chair rises and how fast they could walk, but these did not reach statistical significance, Ditzenberger  reported.

Speaking from the audience, Professor Frank Palella, director of the Potocsnak HIV and Aging Center at Northwestern University, suggested that given the benefits of substantial weight loss, some muscle loss might not matter if function is maintained.

Semaglutide and inflammation

MASLD and other metabolic problems in people living with HIV are still not fully understood.

“While in most people with HIV, traditional risk factors are driving their fatty liver disease, we do think there is a component of liver disease that is HIV-specific, so some of the secondary effects of semaglutide may have unique benefits in people with HIV,” Lake said.

Find out more: Fatty liver disease and HIV

One of those benefits may be reduced inflammation and immune activation. Dr Allison Ross Eckard of the Medical University of South Carolina and colleagues looked at the effect of semaglutide on inflammation and immune biomarkers in people with HIV-associated lipohypertrophy, or abnormal fat accumulation around the abdomen.

This analysis included 108 non-diabetic adults on stable antiretroviral therapy with viral suppression. They had a BMI of 25 or higher (indicating being overweight or obesity), a large waist circumference or waist-to-hip ratio and reported that they developed increased abdominal girth after starting antiretrovirals. They were randomly assigned to receive semaglutide or a placebo once weekly for 32 weeks.

At IDWeek 2023, senior investigator Professor Grace McComsey of Case Western Reserve University in Ohio reported that semaglutide significantly decreased central fat in people with lipohypertrophy, primarily driven by a reduction in visceral adipose tissue. McComsey noted that it’s not just weight that matters, but also where fat is located. Visceral fat within the abdomen is more strongly associated with cardiovascular disease and other health problems.

The new analysis assessed immune activation biomarkers that are known to be increased in people with HIV and are associated with cardiovascular disease. In the semaglutide group, the researchers saw significant changes between baseline and 32 weeks for high-sensitivity C-reactive protein (a 39.9% decrease), interleukin-6 (a 18.8% decrease) and soluble CD163, a marker of macrophage activation (a 12.3% decrease). The anti-inflammatory effects of semaglutide were not fully explained by decreases in weight, according to Eckard.

While these study results are welcome, long-term HIV advocate Simon Collins of i-Base noted that most trials of semaglutide and other weight-loss medications have excluded people living with HIV. SLIM LIVER was sponsored by the US National Institutes of Health rather than a pharmaceutical company. Lake acknowledged that it is common for HIV-positive people to be excluded from MASLD/MASH trials because HIV is thought to be a secondary cause of steatosis and fibrosis. “It was a really big deal for us to get a trial completely focused on people with HIV,” she said.

Another issue, as weight-loss medications are shown to have benefits beyond diabetes and obesity, is their high cost. Noting that Novo Nordisk, the maker of semaglutide, has a net worth exceeding US$550 billion, Collins said: “We should be working with the Medicines Patent Pool so that people in South Africa and other countries with obesity epidemics also have access to this product.”