HTD1801, an investigational oral combination of berberine and ursodeoxycholate, significantly reduced A1c when added to metformin in patients with type 2 diabetes (T2D) whose glucose levels remained inadequately controlled with metformin alone, according to results from a phase 3 trial.

“For clinicians managing T2D, the key takeaway is that HTD1801 offers a comprehensive approach to patient care,” lead author Linong Ji, MD, of Peking University People’s Hospital, Beijing, China, and senior author Liping Liu, PhD, MBA, of HighTide Therapeutics Inc, told Medscape Medical News in an email on behalf of the study authors.

“By simultaneously improving glycemia, lowering atherogenic lipids (low-density lipoprotein cholesterol [LDL-C] and non-high-density lipoprotein cholesterol [non-HDL-C]), and reducing markers of metabolic stress, HTD1801 addresses the systemic, root-cause disturbances of type 2 diabetes rather than focusing solely on blood glucose,” they said. “It represents a promising, multi-targeted oral option for patients inadequately controlled by metformin alone.”

The findings were published in NEJM Evidence.

Building on Traditional Chinese Medicine

The investigators describe HTD1801 as an anti-inflammatory metabolic modulator under investigation for metabolic diseases. It combines berberine, a plant-derived compound, with ursodeoxycholate, a bile acid currently approved in the US for selected cholestatic liver diseases.

In an accompanying editorial, Binh Ngo, MD, of the Keck School of Medicine of the University of Southern California, Los Angeles, and Marc Rendell, MD, of the Association of Diabetes Investigators, noted that berberine has been used in traditional Chinese medicine for more than 1000 years to treat diabetes, although it has not been approved as a therapeutic agent use in Western medicine. Ursodeoxycholic acid was originally derived from bear bile and used traditionally to treat liver conditions. A synthetically produced version is currently approved by the FDA to treat hepatic biliary disease.

T2D is characterized not only by hyperglycemia but also by insulin resistance, dyslipidemia, and chronic inflammation, which together accelerate cardiovascular disease, the investigators noted. Although metformin remains first-line therapy worldwide, approximately one third of patients do not achieve adequate glycemic control with metformin alone, and the drug does not directly address these broader cardiometabolic comorbidities.

An earlier phase 2 trial of HTD1801 showed a 0.7% reduction in A1c after 12 weeks, along with improvements in cardiometabolic and inflammatory markers. This prompted evaluation of the drug in the phase 3 SYMPHONY-1 trial, which found that 24 weeks of HTD1801 monotherapy significantly reduced A1c.

SYMPHONY-2: Glycemic Benefits and Beyond

For the phase 3 SYMPHONY-2 trial, investigators randomly assigned patients with T2D and A1c levels of 7.0%-10.5% despite stable metformin therapy to receive additional oral HTD1801 1000 mg twice daily (n = 365) or placebo (n = 184) for 24 weeks. The primary endpoint was change in A1c from baseline.

After 24 weeks, HTD1801 reduced A1c significantly more than placebo (adjusted least-squares mean difference, -0.5%; P < .0001). Additionally, 33% of patients receiving HTD1801 achieved the clinical target of A1c below 7.0% compared with 11% of those receiving placebo (P < .0001).

HTD1801 also significantly reduced LDL-C by 13.8 mg/dL and non-HDL-C by 18.6 mg/dL compared with placebo (both P < .0001). Gamma-glutamyl transferase, a marker of oxidative stress and liver health, also declined significantly (P < .01).

Benefits were sustained through the 52-week open-label extension period. Patients treated with HTD1801 throughout the study experienced a mean A1c reduction of 1.1% from baseline. Among patients initially assigned to placebo, switching to HTD1801 produced a 1.2% reduction in A1c, along with improvements in fasting plasma glucose, LDL-C, gamma-glutamyl transferase, and high-sensitivity C-reactive protein. After switching, 41% achieved an A1c target level below 7%.

The most common adverse event was mild-to-moderate diarrhea, reported in 23.8% of HTD1801-treated patients vs 1.1% of placebo-treated patients. Most cases occurred early in treatment initiation and declined over time. There were no cases of severe hypoglycemia reported in either group.

Although the trial enrolled only Chinese patients, the investigators noted that participants’ demographic and cardiometabolic characteristics were similar to those of patients with T2D receiving metformin in many other populations.

Expert Perspective

Commenting for Medscape Medical News, Dace Trence, MD, professor emeritus of medicine in the Division of Metabolism, Endocrinology, and Nutrition at the University of Washington, Seattle, noted that berberine has been used for thousands of years to treat diabetes, primarily in China, and has also been associated with improvements in blood pressure, liver enzymes, and body weight.

“On the web, it’s sometimes called ‘Nature’s Ozempic,’” Trence said. Although she noted that many of its mechanisms have been described, it remains incompletely understood.

Trence, president of the American Association of Clinical Endocrinology, also emphasized several limitations of the trial.

“The company producing the product not only funded but participated in the collection, management, analysis of data, and preparation of the manuscript,” she said. While HTD180 appears promising and may offer a relatively inexpensive option, she added that additional studies in more diverse populations and independent of the sponsor are needed.

In their editorial, Ngo and Rendell wrote that agents derived from traditional Chinese medicine “have the potential to markedly reduce treatment costs, compared with newly developed expensive Western agents.”

They added that evidence supporting HTD1801 should encourage similarly rigorous investigation of other longstanding therapies in traditional Chinese practice.

The study was sponsored by Shenzhen HighTide Biopharmaceutical. Ji reported consulting or other relationships with Abbott Pharmaceuticals, AstraZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, Fosun Pharma, Gan & Lee Pharmaceuticals, Innovent Biologics, Merck, Merck Sharp & Dohme, Novo Nordisk, Sanofi, Shanghai Benemae Pharmaceuticals, Sibionics, and Sinocare. Liu is employed by HighTide Therapeutics, Inc. The remaining authors’ disclosures are listed in a supplement to the paper. Ngo, Rendell, and Trence reported having no relevant financial relationships.

Batya Swift Yasgur, MA, LSW, is a freelance writer with a counseling practice in Teaneck, New Jersey. She is a regular contributor to numerous medical publications, including Medscape and WebMD, and is the author of several consumer-oriented health books as well as Behind the Burqa: Our Lives in Afghanistan and How We Escaped to Freedom (the memoir of two brave Afghan sisters who told her their story).