Model calculations suggest that the number of patients with cirrhosis, advanced fibrosis, or hepatocellular carcinoma (HCC) could double to triple in the next 10-15 years. Not least because of this, the German Society for Gastroenterology, Digestive and Metabolic Diseases (DGVS) updated the S2k guideline on non-alcoholic fatty liver disease last year.
Patients with non-alcoholic fatty liver disease (NAFLD) typically have a number of comorbidities and risk factors associated with progression. The more NAFLD progresses, the more often they also suffer from concomitant diseases such as type 2 diabetes, heart disease (about 65% of those with fatty liver also have hypertension), or elevated cholesterol, explained Prof. Dr. Wolf Peter Hofmann, gastroenterologist and hepatologist from Berlin (D) [1]. In addition, there are factors that tend to favor faster progression and a higher complication rate (cirrhosis, HCC, decompensation): Obesity, genetic predisposition (e.g. PNPLA3, TM6SF2), age, alcohol use and lifestyle (sedentary activities, fast food, etc.) fall among them. However, there are also factors that improve the prognosis: These include coffee consumption, exercise, Mediterranean diet, vegetables and abstaining from alcohol. Most importantly, weight loss has a beneficial effect on the liver: if it is possible to lose 10% of body weight, even fibrosis may regress.
Hype about the “weight loss injection
Not least because celebrities like Elon Musk use them and also talk about them, a real hype has arisen around so-called “weight loss injections”, which in some cases is already causing availability bottlenecks. A study with the GLP1 analogue semaglutide, which was not about fatty liver but about losing weight, showed a 15-16% reduction in body weight achieved with the help of the injections. Under a combination of GLP1 and GIP analogs, even 20% seems possible, the expert explained. “In studies, we are almost as far along with this in terms of medication as we are with bariatric surgery.” Ultimately, the only question is whether this is sustainable in the long term and how it will be financed – semaglutide is reimbursable for the treatment of diabetes, but as a weight-loss drug the costs currently have to be borne by the patient.
| Therapy for NAFLD – Aim for weight loss of 5-10 kgKG, effect on fibrosis. – Mediterranean diet, fructose-reduced, physical activity – Bariatric surgery with beneficial effect on NASH. – GLP1 analogs (and soon dual GLP1/GIP?) as so-called lifestyle medication. – Comedication “tailor-made”! – FDA/EMA approval of obeticholic acid and resmetirome likely by 2024 |
In the updated guideline, drug treatment recommendations for patients with NAFLD were divided into those without cirrhosis and those with. GLP1 agonists and SGLT2 inhibitors should be used here primarily in combination with metformin in patients with comorbid type 2 diabetes, whereas statins are the agents of choice in patients with hyperlipoproteinemia (Fig. 1) [2]. Metformin, according to Prof. Hofmann, is possibly only partially effective with regard to fatty liver, but has been shown to help reduce the incidence of hepatocellular carcinoma. Moreover, especially if fibrosis is already manifest, inclusion in a clinical trial can never hurt.
New therapeutic approaches
Currently, a large number of Phase 3 trials are underway to investigate new therapeutic approaches in steatohepatitis and fibrosis. As of spring 2023, two positive phase 3 studies were available with positive endpoints in the interim analysis: the farnesoid X receptor agonist obeticholic acid is already known from the treatment of primary biliary cholangitis (PBC). The REGENERATE study evaluated the compound in NASH patients over a 72-week period. This improved fibrosis by at least 1 stage, with no worsening of NASH. Side effects reported included pruritus (especially in the first 3 months), but there were no cardiovascular or liver-associated complications. Obeticholic acid always brings an LDL increase, which has already been observed in PBC, hence the relatively high number of statin prescriptions.
Resmetirone is a thyroid hormone receptor-β agonist. NASH resolution was demonstrated in 966 patients over 52 weeks versus placebo, as well as fibrosis improvement by at least 1 stage (Resmetiron 100 mg 26% vs. placebo 14%). Both obeticholic acid and resmetirone are expected to be approved in the course of the year, Prof. Hofmann concluded.
Sources:
- Hofmann WP: Vortrag «Therapeutika bei nicht-alkoholischer Fettleber», StreamedUp! GastroLive «Die Leber im Fokus», 28.02.2023.
- Aktualisierte S2k-Leitlinie nicht-alkoholische Fettlebererkrankung, April 2022, AWMF-Registernummer: 021–025.
GASTROENTEROLOGIE PRAXIS 2023; 1(1): 25–26
