Reference: JAMA Netw Open 2025 Mar 3;8(3):e2462185 and JAMA Netw Open 2026 Jan 2;9(1):e2554152
Practice Point: Pharmaceutically enhanced berberine improves HbA1c and other metabolic markers, but this isn’t the berberine you can buy off the shelf.
EBM Pearl: When disparate results are found by two high-quality drug trials, check the formulation. The devil is pretty much always in the details.
If you haven’t heard about the benefits of berberine yet, you probably aren’t following wellness influencers or shopping the entry displays of certain wholesale retailers. If those two things just made you less likely to believe the benefits, good job not buying into the hype—YET. Berberine has been used for more than 2,000 years to treat a host of afflictions from tumors to dysentery, but its modern application for diabetes and metabolic dysfunction comes by way of pharmaceutical enhancement that drastically improves bioavailability. Translation: You can’t buy the good stuff off the shelf (but you also can’t get a prescription yet, either).
The study that launched berberine to the pages of pop culture was published in March 2025 and evaluated the metabolic effects of berberine ursodeoxycholate (HTD1801), a salt that dissociates into its two active moieties in the gut, leading to improved bioavailability of each component compared to the parent molecules. The investigators randomized 113 adults with type 2 diabetes living in China 1:1:1 to receive either placebo or HTD1801 dosed at 500 mg twice daily or 1,000 mg twice daily. Patients in that study had a baseline HbA1c of about 8% and were not on any medications for diabetes. At 12 weeks, there were impressive dose-dependent improvements in glycemic control, lipids, liver enzymes, and inflammatory markers. For those assigned to receive high-dose HTD1801, HbA1c was reduced by 0.7% compared to placebo, and 56% achieved an HbA1c of < 7%, compared to 15% of those in the placebo group. There was no significant hypoglycemia or other adverse events reported. High-dose HTD1801 was also associated with mean baseline reductions in metabolic markers such as LDL (12 mg/dL), triglycerides (27 mg/dL), AST (4 units/L), GGT (9 units/L), and HS-CRP (1.7 mg/L).
Fast forward 1 year later, and results of a new trial failed to find any significant benefits of berberine for many of the same metabolic markers studied in the 2025 trial. There were two key differences between these trials, however, that should bring outcome comparisons to a screeching halt. First, the 2026 trial studied diabetes-free individuals with obesity and metabolic dysfunction-associated steatotic liver disease (MASLD), whereas the 2025 trial studied patients with diabetes. Important? Yes. But it’s not something that would entirely explain disparate results for outcomes that don’t have to do with glycemic control. Second, and something surprisingly not discussed by the 2026 study authors, the newer trial evaluated berberine as a dietary supplement, not the pharmaceutically enhanced salt. Unfortunately, mass media, influencers, and AI have missed this major difference and are calling it all “berberine”, especially when referring to its benefits.
The moral of this story is that the ancient remedy of basic berberine should probably remain in the past when it comes to cardiovascular and metabolic health. However, several pharmaceutically enhanced prescription forms of berberine salts are in development that seem to hold promise for a number of disorders, including diabetes, which may resonate with those looking for a more “natural” remedy. In the meantime, the message that the “proven benefits of berberine” don’t apply to dietary supplements should be shouted rather than whispered to all the consumers out there buying berberine, especially those paying $100 for a 45-day supply of “enhanced” versions sold by wellness companies.
For more information, see the topic Complementary and Alternative Treatments in Adults With Type 2 Diabetes in DynaMed.
DynaMed EBM Focus Editorial Team
This EBM Focus was written by Katharine DeGeorge, MD, MS, Executive Editor at DynaMed and Associate Professor of Family Medicine at the University of Virginia. Edited by Alan Ehrlich, MD, FAAFP, Executive Editor at DynaMed and Associate Professor in Family Medicine at the University of Massachusetts Medical School; McKenzie Ferguson, PharmD, BCPS, Senior Clinical Writer at DynaMed; Rich Lamkin, MPH, MPAS, PA-C, Senior Clinical Writer at DynaMed; Claire Symanski, PhD, Medical Editor and Team Lead for ENT at DynaMed; Michael Butler, PhD, Medical Writer at DynaMed; Matthew Lavoie, BA, Senior Medical Copyeditor at DynaMed; Hannah Ekeh, MA, Senior Associate Editor II at DynaMed; and Jennifer Wallace, BA, Senior Associate Editor at DynaMed.