A phase 2, proof of concept, randomised controlled trial of berberine ursodeoxycholate in patients with presumed non-alcoholic steatohepatitis and type 2 diabetes

Abstract

Non-alcoholic steatohepatitis is frequently associated with diabetes and may cause progressive liver disease. Current treatment options are limited. Here we report on a prospective, randomised, double-blind, placebo-controlled trial of two doses of HTD1801 (berberine ursodeoxycholate, an ionic salt of berberine and ursodeoxycholic acid), versus placebo that was conducted in 100 subjects with fatty liver disease and diabetes (NCT03656744). Treatment was for 18 weeks with a primary endpoint of reduction in liver fat content measured by magnetic resonance imaging proton density fat fraction. Key secondary endpoints included improvement in glycemic control, liver-associated enzymes and safety. The pre-specified primary endpoint was met. Thus, subjects receiving 1000 mg twice a day of berberine ursodeoxycholate had significantly greater reduction in liver fat content than in placebo recipients (mean absolute decrease −4.8% vs. −2.0% (p = 0.011). Compared to placebo, subjects receiving this dose also experienced significant improvement in glycemic control as well as reductions in liver-associated enzymes and significant weight loss. Diarrhea and abdominal discomfort were the most frequently reported adverse events. We conclude that berberine ursodeoxycholate has a broad spectrum of metabolic activity in patients with presumed NASH and diabetes. It is relatively well tolerated and merits further development as a treatment for NASH with diabetes.

Dietary Supplements and Natural Products: An Update on Their Clinical Effectiveness and Molecular Mechanisms of Action During Accelerated Biological Aging

“…It is an isoquinoline quaternary alkaloid distributed in the roots, rhizomes, stems, and bark of several botanicals or herbs like Coptis chinensis (Chinese goldthread), Coptis rhizome , Berberis vulgaris , Argemone mexicana , etc., In aging research, berberine has been shown to extend the lives of several laboratory-adapted species. Regarding aging-related diseases, berberine is known to exert numerous beneficial outcomes in individuals with diabetes type II because of its profound effects on alleviating endothelial dysfunction and lipid metabolic imbalance and improving glycemic control, insulin sensitivity, and insulin secretion via targeting KCNH6 potassium channels ( Zhang et al, 2008 ; Harrison et al, 2021 ; Zhao et al, 2021 ). Aside from diabetes type II, berberine has been demonstrated to have neuroprotective effects on aging-cognitive disorders and is also considered a potent chemosensitizer and chemoprotector for numerous cancers ( Shang et al, 2020 ; Devarajan et al, 2021 ).…”

Pharmacotherapy for Non-Alcoholic Fatty Liver Disease: Emerging Targets and Drug Candidates

“…UDCA, in turn, is a bile acid long used for the treatment of NASH and chronic cholestatic diseases, whose hepatoprotective effects are confirmed by several systematic reviews and meta-analyses [ 200 , 201 ]. In a phase 2 proof-of-concept RCT in T2DM patients with presumed NASH, BUDCA reduced liver enzyme levels and liver steatosis by MRI-PDFF [ 202 ].…”

Apoptosis Induction, a Sharp Edge of Berberine to Exert Anti-Cancer Effects, Focus on Breast, Lung, and Liver Cancer

“…Sixthly, recently, clinical research on BBR has increased, primarily focusing on metabolic diseases, such as nonalcoholic liver disease, diabetes, and hyperlipidemia ( Li et al, 2019a ; Zhang et al, 2020c ; Di Bisceglie et al, 2020 ; Zhao et al, 2021b ; Harrison et al, 2021 ), and digestive system diseases, such as ulcerative colitis ( Xu et al, 2020 ) and colorectal adenoma ( Chen et al, 2020 ). BBR ursodeoxycholate and BBR chloride are involved in this process.…”