medwireNews: Treatment with berberine ursodeoxycholate (HTD1801), a first-in-class gut–liver anti-inflammatory metabolic modulator, significantly reduces glycated hemoglobin (HbA1c) and improves hepatic and cardiometabolic parameters versus placebo in people with type 2 diabetes, research shows.
The phase 2 study findings “suggest that the multifaceted effects demonstrated by HTD1801 support this new molecular entity as a unique oral treatment option for [type 2 diabetes] and its comorbidities,” write Liping Liu (Shenzhen HighTide Biopharmaceutical Ltd, China) and co-authors in JAMA Network Open.
The investigators examined the effects of HTD1801, which is designed to activate adenosine monophosphate kinase and inhibit the NLRP3 inflammasome, leading to insulin receptor stimulation and induction of the low-density lipoprotein receptor.
The treatment “may result in improved insulin sensitivity” and “help regulate an obesity-induced inflammatory state, therefore improving glucose homeostasis and insulin resistance,” they explain.
The study included 113 Chinese people (mean age 54 years, 64% men) with type 2 diabetes that was inadequately controlled by diet and exercise. At baseline, participants had a mean HbA1c level of 8.2% (66.0 mmol/mol), a mean fasting plasma glucose (FPG) level of 160.7 mg/dL (8.9 mmol/L), and a mean BMI of 25.5 kg/m2.
The researchers report that, after 12 weeks of treatment, individuals given HTD1801 1000 mg twice daily (n=38) or HTD1801 500 mg twice daily (n=37) had significantly greater improvements in HbA1c than those given placebo (n=38), with least squares mean reductions of 1.0%, 0.7%, and 0.3%, respectively.
Liu et al note that the improvements in HbA1c were evident by week 8 and continued a downward trajectory without plateau to week 12.
By week 12, 55.9% of patients given HTD1801 1000 mg had achieved an HbA1c target of less than 7.0% (53 mmol/mol) and 29.4% a target level below 6.5% (48 mmol/mol), compared with just 15.2% and 6.1% of controls, respectively.
In line with the reduction in HbA1c was a dose-dependent improvement in FPG, which fell by a mean of 18.4 mg/dL (1.0 mmol/L) between baseline and week 12 in participants given HTD1801 1000 mg, and by 13.0 mg/dL (0.7 mmol/L) in those given the 500 mg dose. In the placebo group, mean FPG increased by 0.3 mg/dL (0.01 mmol/L) during the study and the difference relative to both HTD1801 doses was statistically significant.
The team also observed significant improvements with HTD1801 1000 mg versus placebo in 0.5-hour postprandial plasma glucose, homeostatic model assessment for insulin resistance, fasting C-peptide, total cholesterol, low-density lipoprotein cholesterol, and reductions in levels of the liver enzymes alanine aminotransferase, aspartate aminotransferase, and γ-glutamyltransferase.
Together the data “suggest an overall improvement in the metabolic profile and a potential reduction in cardiovascular risk,” Liu et al remark.
Body weight and high-density lipoprotein cholesterol were stable across treatment groups throughout the study, and there were also no differences observed between HTD1801 and placebo in fasting insulin, or the change in 0.5-hour postprandial insulin and 0.5-hour postprandial C-peptide levels.
Finally, the researchers report that “HTD1801 was safe and well tolerated.” No patients discontinued treatment due to adverse events (AEs) and 97.3% completed the study overall. Treatment-emergent AEs were “generally mild in severity” and occurred in 71.1% of patients in the HTD1801 1000-mg group, 46.0% of those in the 500-mg group, and 39.5% of those in the placebo group.
Liu et al conclude that “HTD1801 treatment provides a spectrum of therapeutic effects that appear to address comorbid conditions that exacerbate disease and worsen prognosis of patients with [type 2 diabetes].”
They are now confirming their findings in phase 3 studies among people with type 2 diabetes and in those with metabolic dysfunction–associated steatohepatitis.
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