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  The Liver Meeting
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November 13 - 16 - 2021
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HTD1801 Lowers Liver Fat Content With Presumed NASH and Diabetes
  AASLD, The Liver Meeting, November 12-15, 2021
Mark Mascolini
HTD1801-which may improve nonalcoholic steatohepatitis (NASH) by several mechanisms-significantly lowered liver fat content in an 18-week placebo-controlled trial [1,2]. Falling liver fat content correlated with weight loss, improved glycemic control, and lower alanine aminotransferase (ALT) [1], findings that could help researchers optimize HTD1801 for treating NASH and metabolic comorbidities like diabetes.
Berberine ursodeoxycholate (HTD1801) may improve NASH by taming insulin resistance, regulating lipoprotein metabolism, and activating AMP kinase (which prompts glucose and fatty acid uptake and oxidation when cellular energy is low). A recently published phase 2 trial comparing two doses of HTD1801 with placebo in a double-blind design found that this novel agent lowered liver fat content, improved glycemic control, and was associated with weight loss, reduced liver-associated enzymes, and lower lipids [2].
The phase 2 trial recruited participants from specialized US liver centers from December 2018 to September 2019 (NCT03656744). Participants had type 2 diabetes (on stable therapy for at least 90 days) and presumed NASH, defined by magnetic resonance imaging-derived proton density fat fraction (MRI-PDFF) of 10% or more [2]. Additional inclusion criteria meant to improve the likelihood of selecting participants with NASH were corrected T1 [3] more than 830 ms on MRI and aspartate aminotransferase (AST) at or above 20 U/L. Participants had to be overweight or obese, with a body mass index of 25 kg/m2 or more.
The trial randomized 100 participants to 500 or 1000 mg of HTD1801 twice daily or to placebo. The primary endpoint was MRI-PDFF-determined change in liver fat content from baseline to week 18. The 500- and 1000-mg HTD1801 groups and the placebo group were similar in average age (58, 53, 58), proportions of women (79%, 71%, 67%), proportions of whites (89%, 91%, 94%), body mass index (36.7, 36.3, 35.0 kg/m2), and liver fat content (18.4%, 19.4%, 20.2%).
At 18 weeks absolute liver fat content fell 1.9% with placebo, 2.9% with 500 mg of HTD1801 twice daily (not significant vs placebo), and 4.8% with 1000 mg HTD1801 twice daily (P < 0.05 vs placebo). Respective declines in relative liver fat content were 8.3%, 15.1%, and 24.1% (P < 0.05 vs placebo).
At the 18-week point weight fell at average 3.5% with 1000 mg of HTD1801 versus 1.0% with placebo; the blood sugar marker HbA1c fell 7.4% with 1000 mg of HTD1801 while rising 1.5% with placebo; alanine aminotransferase (ALT) dropped 21% with 1000 mg of HTD1801 and 5% with placebo; gamma-glutamyl transferase (GGT) fell 29% with 1000 mg of HTD1801 while rising 5% with placebo; low-density lipoprotein (LDL) cholesterol dropped 13% with 1000 mg of HTD1801 while rising a fraction with placebo; and triglycerides fell 11% with 1000 mg of HTD1801 while climbing 10% with placebo.
Univariate analysis of individual factors associated with change in liver fat content determined that weight loss, drop in HbA1c, ALT decline, and GGT decrease were significantly associated. In a multivariate model incorporating these four variables, GGT did not retain a significant association with change in liver fat content, so the final model considered the other three predictors-lower weight (slope 0.317, P = 0.0111), declining HbA1c (slope 1.461, P = 0.0049), and falling ALT (slope 0.055, P = 0.0081). But together these three variables explained only 33% of the change in liver fat content.
In an analysis that held HbA1c and ALT constant, a 3.15-kg drop in weight resulted in an absolute 1% decline in liver fat content. An HbA1c drop of 0.68% or an ALT fall of 18.2 U/L also resulted in an absolute 1% decline in liver fat content.
The researchers concluded that HTD1801-induced drops in liver fat content in people with presumed NASH are closely associated with weight loss, improved glycemic control (declining HbA1c), and reduced liver injury (declining ALT). Each of these three changes, they proposed, "represents a benefit to patients with NASH and metabolic comorbidities." But further, longer-term research is needed to fine-tune HTD1801 for treating NASH and related metabolic complications.
1. Harrison SA, Gunn N, Neff G, Kohil A, Hirman J, DiBisceglie AM. Reduction in liver fat content with HTD1801 (berberine ursodeoxycholate) is closely associated with improved glycemic control, weight loss, and reduced ALT. AASLD, The Liver Meeting, November 12-15, 2021. Abstract 140.
2. Harrison SA, Gunn N, Neff GW, et al. A phase 2, proof of concept, randomised controlled trial of berberine ursodeoxycholate in patients with presumed non-alcoholic steatohepatitis and type 2 diabetes. Nature Communications. 2021;12;article number 5503. https://doi.org/10.1038/s41467-021-25701-5
3. "Corrected T1 (cT1) value is a novel MRI-based quantitative metric for assessing a composite of liver inflammation and fibrosis. It has been shown to distinguish between non-alcoholic fatty liver disease (NAFL) and non-alcoholic steatohepatitis." Mojtahed A, Kelly CJ, Herlihy AH, et al. Reference range of liver corrected T1 values in a population at low risk for fatty liver disease-a UK Biobank sub-study, with an appendix of interesting cases. Abdom Radiol (NY). 2019;44:72-84. doi: 10.1007/s00261-018-1701-2.