Safety and metabolic effects of HTD1801 in type 2 diabetes and MASLD: a phase Ib randomized trial

Abstract

Background

HTD1801 is a novel compound composed of equal parts berberine (BBR) and ursodeoxycholic acid (UDCA). It functions as a gut–liver metabolic modulator with a unique mechanism of action that may offer therapeutic benefits for patients with type 2 diabetes mellitus (T2DM) and metabolic dysfunction-associated steatotic liver disease (MASLD).

Methods

A total of 48 patients were enrolled in this study. Thirty-six treatment-naïve patients were randomized to receive HTD1801 at doses of 500 mg, 750 mg, or 1000 mg, or placebo, administered twice daily for 28 days. An additional 12 patients on stable metformin therapy were randomized (3:1) to receive either HTD1801 1000 mg or placebo.

Results

HTD1801 was generally well tolerated, with most adverse events classified as mild to moderate in severity. No serious adverse events were reported. Berberine exhibited saturation kinetics, whereas UDCA demonstrated linear pharmacokinetics. Accumulation was low to moderate (range: 0.9673 to 2.6659). Compared to placebo, HTD1801 improved glucose and lipid metabolism and reduced liver enzyme levels. A dose-dependent effect was observed, with metabolic improvements increasing with higher administered doses. In the metformin group, HTD1801 (1000 mg) resulted in greater reductions in fasting glucose (mean absolute decrease: −1.271 vs. +0.423 mmol/L), 2-h postprandial glucose (-4.167 vs. +0.290 mmol/L), LDL-C (-0.623 vs. +0.290 mmol/L), total cholesterol (-1.090 vs. +0.023 mmol/L), and GGT (-9.28 vs. -4.43).

Conclusion

HTD1801 was safe and demonstrated potential metabolic benefits in patients with T2DM and MASLD. Further investigation is warranted.

Trial registration

Retrospectively registered, ChiCTR2500110932 (date: 22nd Oct. 2025), https://www.chictr.org.cn.

Supplementary Information

The online version contains supplementary material available at 10.1186/s13098-026-02202-3.

Background

The global burden of diabetes continues to rise, and individuals with type 2 diabetes mellitus (T2DM) are at significantly higher risk of cardiovascular mortality and stroke compared to the general population. Among these patients, those with coexisting metabolic dysfunction-associated steatotic liver disease (MASLD) tend to experience more severe hepatic damage [1, 2]. Current treatments for T2DM primarily address insulin resistance and impaired insulin secretion and include agents such as metformin, dipeptidyl peptidase-4 inhibitors, glucagon-like peptide-1 receptor agonists, sodium–glucose cotransporter-2 inhibitors, and insulin analogs [3–6]. However, both diabetes and fatty liver disease are frequently associated with atherosclerotic cardiovascular disease, for which dyslipidemia—particularly elevated low-density lipoprotein cholesterol (LDL-C) and triglycerides—is a major risk factor. Statins are widely prescribed to manage dyslipidemia, though some patients experience intolerance. In such cases, non-statin therapies such as ezetimibe or proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors may be considered [7]. A single agent capable of simultaneously lowering blood glucose, improving lipid profiles, and reducing hepatic fat accumulation and inflammation would represent a significant therapeutic advancement for patients with T2DM and MASLD [8, 9].

Berberine (BBR) lowers serum cholesterol and blood glucose levels and simultaneously benefits glucose–lipid metabolism by modulating an integrated metabolic signaling hub centered on AMPK [10–14]. Ursodeoxycholic acid (UDCA), a naturally occurring bile acid, is used in the treatment of gallstones and chronic cholestatic liver diseases such as primary biliary cholangitis [10, 15–18]. HTD1801 is a novel compound developed by Shenzhen Junshengtai Biotechnology Co., Ltd., composed of equimolar amounts of BBR and UDCA, forming an ionic salt known as berberine ursodeoxycholate (BUDCA). Upon ingestion, BUDCA dissociates in the gastrointestinal tract, allowing BBR and UDCA to be absorbed and metabolized independently. UDCA is further converted into glycoursodeoxycholic acid (GUDCA) and tauroursodeoxycholic acid (TUDCA), which contribute to its total pharmacological activity [18]. The combined actions of BBR and UDCA may include the inhibition of gluconeogenesis, promotion of glycolysis, reduced intestinal carbohydrate absorption, modulation of bile acid metabolism, hepatoprotection, and decreased synthesis of cholesterol and fat [19–25]. However, the effect of potential histologic improvements on metabolic dysfunction-associated steatohepatitis remains to be investigated [26].

In patients with T2DM and fatty liver, the concurrent use of glucose- and lipid-lowering medications can complicate the interpretation of clinical trial outcomes. To address this, a 28-day Phase Ib clinical study was conducted to evaluate the safety, pharmacokinetics (PK), and pharmacodynamics (PD) of HTD1801 in two cohorts: (1) treatment-naïve patients receiving HTD1801 monotherapy and (2) patients on stable metformin therapy receiving either HTD1801 or placebo. The study aimed to assess drug tolerability, PK profiles (by separately measuring plasma concentrations of BBR and UDCA), and effects on serum lipids, glucose metabolism, and liver-associated enzymes.

Methods

Study design

This was a randomized, double-blind, placebo-controlled Phase 1b study (China Clinical Trial Registration Number: ChiCTR2500110932) conducted at Phase I Clinical Research Center of the First Hospital of Jilin University (Jilin, China) between June 8 and September 9, 2022.

A total of 48 patients with T2DM and nonalcoholic fatty liver disease (NAFLD) were enrolled. Of these, 36 treatment-naïve patients were randomized into four groups (n = 9 per group) to receive HTD1801 monotherapy at doses of 500 mg, 750 mg, or 1000 mg, or placebo, in a 1:1:1:1 ratio. The remaining 12 patients, who were on stable metformin therapy, were assigned in a 3:1 ratio to receive either HTD1801 1000 mg (n = 9) or placebo (n = 3). All patients received either the study drug or placebo twice daily (BID) for 28 days.

Dosing was administered on-site on days 1 and 28 following consumption of a standardized meal (85 g flatbread with controlled calories). All other doses were taken at home under the same dietary conditions between clinical visits. Follow-up visits were scheduled on days 8, 15, and 22, or at the time of early termination, whichever came first.

The study protocol was prepared per the principles of the Declaration of Helsinki and approved by the Institutional Review Board of the First Hospital of Jilin University (21Y345-001). All recruited patients provided written informed consent before participating in any study-related procedures.

Participants

The main inclusion criteria included: (1) Male or female participants aged 18 to 75 years, not of childbearing potential; (2) Body mass index (BMI)  ≥  18 kg/m²; (3) Clinically diagnosed with T2DM based on the 1999 WHO criteria; (4) Fasting blood glucose between 7.0 and 13.3 mmol/L and Hemoglobin A1c (HBA1c) between 7.5% and 11.5%; and (5) Diagnosed with fatty liver by ultrasound.

Specific inclusion criteria for the HTD1801 arm (treatment-naïve group): Participants had no prior hypoglycemic treatment or had used such drugs for no more than 2 weeks within the past 3 months.

For the HTD1801 + Metformin arm (metformin group): Participants had been on stable metformin therapy for at least 3 months.

The main exclusion criteria included: (1) Acute diabetic complications (e.g., ketoacidosis, hyperosmolar coma), chronic kidney disease, or diabetic retinopathy; (2) More than two severe hypoglycemic events in the past 3 months. (3) Known glucose-6-phosphate dehydrogenase (G6PD) deficiency; (4) Use of medications that may affect blood glucose levels within 30 days before enrollment, such as systemic corticosteroids (excluding stable hormone replacement therapy for ≥ 3 months), growth hormone, non-selective beta-blockers (e.g., propranolol), thiazide diuretics > 25 mg/day, aspirin > 300 mg/day, and Chinese herbal medicine; (5) Use of weight-loss drugs, supplements, or participation in a weight-loss program or special diet within 30 days; and (6) Abnormal lab results: ALT ≥ 2.5×ULN, ALP > 2×ULN, TBIL > 1.5×ULN, eGFR < 60 mL/min/1.73 m², triglycerides ≥   4.52 mmol/L (400 mg/dL), or LDL-C > 5.69 mmol/L (220 mg/dL).

Randomization and blinding

This study followed a randomized, double-blind, placebo-controlled, parallel-group design. Random numbers were generated by an independent statistician not involved in the study.

Randomization for both the HTD1801 arm and the HTD1801 + Metformin arm was performed using the PLAN procedure in SAS 9.4, based on a block randomization method. Each eligible participant received a random number during the screening process and was assigned to the corresponding treatment based on that number.

To maintain blinding, all participants took four capsules per dose in different groups as follows: (1) 500 mg group: 2 HTD1801 capsules + 2 placebo capsules, (2) 750 mg group: 3 HTD1801 capsules + 1 placebo capsule, (3) 1000 mg group: 4 HTD1801 capsules, and (4) Placebo group: 4 placebo capsules.

Evaluation of tolerability

The tolerability of the investigational drug was evaluated by comparing post-treatment findings with baseline data. All participants underwent routine clinical assessments, including 12-lead electrocardiograms, vital signs monitoring, abdominal ultrasound, and physical examinations.

Treatment-emergent adverse events (TEAEs) were identified and graded according to the National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), version 5.0. All TEAEs were coded using the Medical Dictionary for Regulatory Activities (MedDRA), version 25.1 (McLean, VA, USA).

Pharmacokinetic assessment

Blood samples were collected at predefined time points for analysis of BBR, UDCA, and its metabolic derivatives, glycine ursodeoxycholic acid and tauroursodeoxycholic acid. Samples were collected using K2-EDTA as the anticoagulant and then centrifuged at 1,500 g for 10 min at 4 °C to isolate the plasma.

Assessment of effectiveness

Blood glucose levels were measured on day − 1 (baseline), day 1 (first dose), and day 28 (last dose) at the following time points: -0.5, 0.5, 1, 2, 4, 6, 12, 14, 16, and 24 h after drug administration (administered at 0 h). Insulin and C-peptide levels were measured on days − 1 and 28 at time points of -0.5, 0.5, 1, 2, and 4 h. Liver function and lipid profiles were assessed on days 1, 8, 15, 22, and 28.

Statistical analysis

Pharmacokinetic (PK) parameters were calculated using noncompartmental analysis, including maximum plasma concentration (C_max), time to reach C_max (T_max), area under the concentration–time curve (AUC) from time 0 to the last measurable point (AUC₀_–t), area under the curve extrapolated to infinity (AUC₀_–∞), terminal elimination half-life (t_1/2), clearance (CL), volume of distribution (V), and accumulation ratio (Rac). All PK calculations were performed using the validated Phoenix WinNonLin^® v8.3 software (Certara L.P., Princeton, NJ, USA).

The dose proportionality of HTD1801 was assessed using both the power model and a linear fixed-effect model.

Descriptive statistics were used to summarize tolerability, PK, and pharmacodynamic (PD) data. Categorical variables were reported as counts and percentages, while continuous variables were expressed as means and standard deviations. Statistical analyses were performed using SAS 9.4 (SAS Institute, USA).

Data and resource availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author upon reasonable request.

Results

In the HTD1801 arm, 99 subjects were screened, of whom 62 failed screening. A total of 37 subjects were enrolled; however, one participant withdrew prior to dosing due to personal reasons. Consequently, 36 subjects received the study drug. One subject (S01008, 750 mg group) withdrew during the study, and the remaining 35 completed it.

In the HTD1801 + Metformin arm, 27 subjects were screened, with 15 failing the screening process. Twelve subjects were enrolled, all of whom received the study drug and completed the study (Supplementary Fig. 1).

Demographics and baseline characteristics

Participants across groups were aged between 45.72 and 54.41 years, with BMI values ranging from 25.40 to 27.96 kg/m². The majority were Han Chinese, comprising 77.8% to 100% of each group. Demographic characteristics were generally balanced among the groups, except for the gender distribution. The average duration of T2DM ranged from 3.09 to 3.93 years, and mean HbA1c levels were between 8.64% and 9.32%. Baseline clinical parameters—including liver-associated enzymes, blood glucose, and lipid profiles—were comparable across the different dose groups (Table 1).

Table 1.

Baseline demographics and disease characteristics

Baseline parameter	The HTD1801 arm				The HTD1801 + metformin arm
	500 mg (N = 9)	750 mg (N = 9)	1000 mg (N = 9)	Placebo (N = 9)	HTD1801 1000 mg/metformin (N = 9)	Placebo/metformin (N = 3)
Age, mean(SD), Year	45.72(11.326)	52.10(5.521)	51.98(5.588)	49.03(10.893)	51.76(5.208)	54.41(4.940)
Gender, male, n(%)	1 (11.1)	4 (44.4)	6 (66.7)	6 (66.7)	7 (77.8)	1 (33.3)
BMI, mean (SD), kg/m2	27.96 (2.750)	26.00 (2.260)	26.60 (1.360)	25.41 (2.184)	27.00(3.347)	25.40(2.425)
Fasting blood-glucose (mmol/L)	10.889 (1.9936)	10.879 (1.9471)	9.433 (1.2306)	9.168 (1.5062)	10.202 (1.6908)	9.433 (0.7837)
Fasting insulin (pmol/L)	95.178 (50.8227)	60.039 (24.0629)	89.379 (37.7937)	83.294 (39.6982)	63.462 (24.0566)	40.123 (11.5375)
HbA1c (%)	9.32 (0.847)	9.23 (0.485)	8.64 (0.714)	8.79 (0.909)	8.67 (0.492)	8.67 (0.153)
ALT level (U/L)	15.91 (8.286)	18.71 (5.523)	25.53 (9.889)	29.41 (27.166)	25.09 (9.736)	14.10 (4.504)
AST level (U/L)	14.77 (4.251)	16.62 (3.145)	19.32 (6.342)	31.90 (41.267)	18.67 (4.477)	17.40 (5.336)
γ-GGT (U/L)	22.16 (9.444)	31.38 (9.038)	42.72 (26.301)	68.89 (74.838)	34.97 (15.609)	31.23 (25.179)
Low density lipoprotein cholesterin (mmol/L)	2.911 (0.6681)	3.150 (0.1959)	2.941 (0.4764)	3.058 (0.9790)	3.037 (0.6580)	2.747 (0.5969)
High density lipoprotein cholesterol (mmol/L)	0.886 (0.1243)	0.924 (0.1488)	0.877 (0.1058)	1.051 (0.2590)	0.943 (0.1973)	0.980 (0.3381)
Triglyceride (mmol/L)	3.401 (1.4285)	3.142 (1.0881)	3.357 (1.4005)	3.046 (1.7557)	3.179 (0.9090)	5.677 (4.4218)

Except for gender and ethnicity, variance analysis was used for the remaining baseline variables, and there were no differences among the groups (P > 0.0)

In the HTD1801 arm (based on the safety set), three subjects used concomitant medications during the treatment period. Subject S01012 placebo group received amlodipine besylate and irbesartan for hypertension. Subject S01045 1000 mg group used montmorillonite to manage diarrhea. Subject S01056 also took nifedipine for hypertension.

In the HTD1801 + Metformin arm (based on the safety set), all 12 subjects used metformin during the treatment period. In the 1000 mg HTD1801 group, 2 subjects took 0.5 g/day, 3 took 1 g/day, 1 took 1.5 g/day, and 3 took 1.7 g/day of metformin. All three subjects in the placebo group took metformin 1 g/day. All subjects had started metformin between 2019 and October 2021. In addition, subject S01305 in the 1000 mg group also took amlodipine besylate and irbesartan for hypertension.

Safety and tolerability

In the HTD1801 arm, 19 subjects experienced adverse events (AEs), all of which were classified as TEAEs. The incidence of TEAEs was 44.4% (4/9), 55.6% (5/9) and 44.4% (4/9) in the 500 mg, 750 mg, and 1,000 mg HTD1801 groups and 66.7% (6/9) in the placebo group. Drug-related TEAEs occurred in 44.4% (4/9) of subjects in both the 500 mg and 750 mg groups and 22.2% (2/9) of subjects in the 1000 mg group, which was lower than the placebo group at 55.6% (5/9). No clear dose-dependent trend in drug-related TEAE incidence was observed. One subject (S01008, 750 mg group) withdrew early due to a serious adverse event (multiple trauma), which was clearly unrelated to the study drug.

In the HTD1801 + Metformin arm, TEAEs were reported in 8 subjects—6 in the 1000 mg HTD1801 group and 2 in the placebo group—resulting in incidence rates of 66.7% (6/9) and 66.7% (2/3), respectively. Drug-related TEAEs were observed in 55.6% (5/9) of subjects in the HTD1801 group and 66.7% (2/3) in the placebo group.

In both parts, most drug-related TEAEs were mild to moderate (grade I–II). Only one Grade III event (hypertriglyceridemia) was reported, and it occurred in the placebo group in the HTD1801 + Metformin arm. Common TEAEs included diarrhea, hypertriglyceridemia, elevated alanine aminotransferase (ALT) and aspartate aminotransferase (AST), and detectable urinary protein. No hypoglycemic events were reported. Overall, HTD1801 was well tolerated and safe (Table 2).

Table 2.

Drug-Related TEAEs in patients with T2DM and fatty liver disease

	The HTD1801 arm				The HTD1801 + metformin arm
	500 mg (N = 9)	750 mg (N = 9)	1000 mg (N = 9)	Placebo (N = 9)	HTD1801 1000 mg/metformin (N = 9)	Placebo/metformin (N = 3)
Diarrhea	1(11.1%)	1(11.1%)	1(11.1%)		1(11.1%)
Vomit					1(11.1%)
Hypertriglyceridemia	1(11.1%)		1(11.1%)	1(11.1%)		1(33.3%)
ALT level elevation				3(33.3%)	1(11.1%)
AST level elevation				1(11.1%)	1(11.1%)
Detectable urinary protein		2(22.2%)			1(11.1%)
Neutrophil count decreased				1(11.1%)
Creatine phosphokinase level elevation	1(11.1%)
γ-GGT level elevation				1(11.1%)
Bilirubin level elevation					1(11.1%)
Amylase level elevation		1(11.1%)
Hypokalemia	1(11.1%)
Hypophosphatemia	1(11.1%)
Hyponatremia		1(11.1%)
Hyperuricemia					1(11.1%)
Hypertension						1(33.3%)

PK profiles of BBR and UDCA

Profiles of BBR

The median time to reach peak concentration (T_max) was between 3.00 and 6.00 h. BBR reached a steady state by day 8. There was mild drug accumulation, with a mean accumulation ratio (Rac) ranging from 0.9673 to 2.6659. The average half-life (t_1/2) at steady state ranged from 8.97 to 17.56 h. As the dose increased, both clearance (CL) and volume of distribution (V) also increased (Table 3).

Table 3.

Pharmacokinetic parameters of BBR (mean (%CV))

Group		The HTD1801 arm			The HTD1801 + metformin arm
		500 mg (N = 9)	750 mg (N = 9)	1000 mg (N = 9)	HTD1801 1000 mg/metformin (N = 9)
D1 First dosing	Tmax(h) *	4.00(2.00, 6.01)	4.00(1.00, 6.01)	6.00(1.00, 6.00)	3.00(1.00, 6.00)
	Cmax(ng/mL)	2.7401 (97.55)	3.3216 (70.48)	1.6360 (45.52)	3.8822 (80.66)
	AUC0-12 h (ng×h /mL)	15.7027 (79.41)	16.1847 (61.90)	9.0726(52.40)	20.3959(94.29)
D28	Tmax, ss(h) *	4.00(0.50, 6.01)	4.00(1.00, 6.01)	4.00(2.00, 6.00)	3.00(0.50, 4.00)
	t 1/2,ss(h)	14.22 (33.98)	8.97 (38.62)	17.56(64.92)	15.31(98.15)
	AUCtau, ss(ng×h /mL)	22.6276(47.43)	24.1787 (73.44)	21.0325 (39.12)	23.3897(73.69)
	Cmax, ss(ng /mL)	2.6192(47.17)	2.8480(63.91)	2.4271(44.58)	2.7978 (66.30)
	Cmin, ss(ng /mL)	1.0982(50.89)	1.2529(75.19)	1.1982(51.49)	1.2163(70.95)
	CL/F,ss(L/h)	14328.8754 (72.96)	23796.5550(70.58)	27461.5946(62.51)	31682.4975(64.02)
	Vd/F,ss(L)	1275101.8152(106.48)	24704194.6930 (228.33)	4380278.3235 (158.71)	6971616.9707(232.29)
	Rac_AUC	1.8888 (47.07)	1.5519(30.66)	2.6659 (50.36)	1.4898(93.74)
	Rac_Cmax	1.3529(49.50)	0.9944(36.13)	1.6327(47.23)	0.9673 (84.96)

*: Median (min, max)

BBR plasma exposure did not increase proportionally with higher doses. There was significant individual variation in PK parameters after a single dose (day 1). When 1000 mg HTD1801 was administered together with a stable dose of metformin, the day 1 plasma exposure (C_max and AUC_0–12 h) was higher than when 1000 mg HTD1801 was administered alone. However, by day 28, steady-state exposure (as measured by C_max and AUC) was similar between the two groups.

Baseline corrected UDCA and total UDCA

Changes in mean plasma concentrations of ursodeoxycholic acid (UDCA), baseline-corrected UDCA, and total UDCA were comparable across dose groups (see Table 4 for baseline-corrected values). The median T_mₐₓ ranged from 2.00 to 3.00 h for baseline-corrected UDCA and from 2.00 to 4.00 h for total UDCA. Steady-state levels were achieved by day 8.

Table 4.

Pharmacokinetic parameters of baseline-corrected UDCA (Mean of %CV)

Group		The HTD1801 arm			The HTD1801 + metformin arm
		500 mg (N = 9)	750 mg (N = 9)	1000 mg (N = 9)	HTD1801 1000 mg/metformin (N = 9)
D1 First dosing	Tmax(h) *	2.00(0.50, 3.00)	2.00(1.00, 6.01)	2.00 (0.50, 6.00)	3.00 (1.00,4.00)
	Cmax(ng/mL)	1613.94 (50.57)	3330.90 (51.40)	3378.94 (72.85)	3072.43 (31.05)
	AUC0-12 h (ng×h /mL)	5168.279(21.88)	8558.596 (25.57)	10590.919 (19.32)	9711.557 (21.53)
D28	Tmax, ss(h) *	3.00(0.25, 4.00)	2.50 (1.00, 6.01)	2.00(0.25, 4.00)	3.00(0.50, 6.00)
	t 1/2,ss(h)	6.38 (56.58)	7.88 (64.48)	10.31 (40.27)	10.09 (29.55)
	AUCtau, ss(ng×h /mL)	7183.305 (30.40)	12226.460 (38.29)	16946.229 (22.23)	17471.115 (33.53)
	Cmax, ss(ng /mL)	1854.94(31.10)	3542.75 (51.91)	3863.39 (31.85)	3814.66 (36.44)
	Cmin, ss(ng /mL)	141.95(80.26)	343.07(61.60)	585.17(58.79)	498.77(78.94)
	CL/F,ss(L/h)	40.825 (32.56)	39.808 (55.85)	33.615 (29.64)	33.271 (25.60)
	Vd/F,ss(L)	1264.765 (74.54)	1017.207 (80.77)	1360.099 (123.28)	959.346 (69.68)
	Rac_AUC	1.400 (26.71)	1.451 (41.66)	1.686 (34.77)	1.786 (18.89)
	Rac_Cmax	1.360 (43.51)	1.138 (58.40)	1.496 (47.96)	1.273 (29.21)

*: Median (min, max)

Mild accumulation was observed, with Rac ranging from 1.138 to 1.786 for baseline-corrected UDCA and from 1.5694 to 2.4317 for total UDCA. Mean half-lives (t_1/2) at steady state were between 6.38 and 10.31 h for baseline-corrected UDCA and between 12.31 and 15.61 h for total UDCA, supporting the appropriateness of a twice-daily dosing regimen for HTD1801.

Plasma exposure levels, including C_max and AUC, increased with escalating doses for both baseline-corrected and total UDCA. These exposure levels were comparable between the 1000 mg HTD1801 monotherapy group and the group receiving 1000 mg HTD1801 in combination with metformin. PK values before and after baseline correction were consistent (data not shown), and CL and V were also similar among groups.

UDCA was primarily metabolized to glycine ursodeoxycholate, followed by tauroursodeoxycholate. At steady state, the AUC ratio of glycine conjugate to UDCA was 1.20–1.58, and for taursodeoxycholic acid, it was 0.02–0.03.

Dose-exposure relationships were assessed using a power model. For BBR, the regression coefficients of the power model for C_max and AUC ranged from − 0.5394 to − 0.0367, indicating no clear dose-exposure relationship. In contrast, baseline-corrected and total UDCA showed a linear relationship with dose. The regression coefficients ranged from 1.0522 to 1.2590 for baseline-corrected UDCA and from 1.1050 to 1.3602 for total UDCA.

Pharmacodynamics

Glycemic improvement

After 28 days of treatment, all HTD1801 groups exhibited dose-dependent reductions in blood glucose levels following a standardized meal, with improvements observed in 2-h postprandial glucose and AUEC_0−4 h in the 1,000 mg groups. Additionally, the group receiving 1,000 mg of HTD1801 in combination with a stable dose of metformin demonstrated a greater reduction in glucose levels than the group receiving 1,000 mg of HTD1801 monotherapy (Fig. 1).

Fig. 1.

Changes in glycemic parameters from baseline after 28 days of treatment across different dose groups. (A) Fasting plasma glucose (FPG); (B) 2-h postprandial blood glucose (2hPG); (C) Area under the effect curve for glucose from 0 to 4 h (AUEC0–4 h); and (D) Area under the effect curve for glucose from 0 to 24 h (AUEC0–24 h). Values are expressed as mean changes from baseline

The mean changes in fasting blood glucose were as follows: HTD1801 1000 mg monotherapy: − 0.602 mmol/L (p = 0.2485); Monotherapy placebo: +0.727 mmol/L (p = 0.2859); HTD1801 1000 mg + metformin: − 1.271 mmol/L (p = 0.2294); and Combined placebo: +0.423 mmol/L (p = 0.4613).

The mean changes in 2-h post-meal blood glucose were as follows: HTD1801 1000 mg monotherapy: − 2.356 mmol/L (p = 0.0159); Monotherapy placebo: +0.462 mmol/L(p=0.6416); HTD1801 1000 mg + metformin: − 4.167 mmol/L (p = 0.0063); and Combined placebo: +0.290 mmol/L (p = 0.8905).

Insulin and c-peptide levels

After 28 days of treatment, HTD1801 had minimal impact on both fasting and postprandial insulin and C-peptide levels.

Lipid improvement

After 28 days of treatment, low-density lipoprotein cholesterol (LDL-C), triglyceride (TG), total cholesterol (TC), and non-high-density lipoprotein cholesterol (non-HDL-C) levels decreased from baseline in all HTD1801 dose groups, with reductions showing a dose-dependent trend. The 750 mg and 1000 mg HTD1801 monotherapy groups, as well as the 1000 mg HTD1801 + metformin group, exhibited greater reductions compared to the placebo group. The combination group showed better results than the 1000 mg monotherapy group.

Liver-associated enzyme improvement

Gamma-glutamyltranspeptidase (γ-GGT) decreased from baseline in all dose groups, with greater reductions observed at higher doses (Fig. 2). The average γ-GGT reduction after 28 days in each group and the extent of reduction appeared to be correlated with the dosage administered, which included HTD1801 1000 mg monotherapy: − 9.99 U/L (p = 0.0208); HTD1801 1000 mg + metformin: − 9.28 U/L (p = 0.0269); and placebo: − 0.06 U/L (monotherapy, p = 0.9879), − 4.43 U/L (combination group, p = 0.4014). The levels of alanine aminotransferase (ALT), aspartate aminotransferase (AST), and total bilirubin (TBIL) remained unchanged.

Fig. 2.

Blood glucose concentration–time curves during the standard meal test. The HTD1801 arm and the HTD1801 + Metformin arm. Blood glucose levels were measured at specified time points after meals to assess the glycemic response

The results of above evaluated indicators are shown in Table 5.

Table 5.

Pharmacodynamics parameters of mean changes from D28 to baseline (Mean)

	The HTD1801 arm				The HTD1801 + metformin arm
	500 mg (N = 9)	750 mg (N = 9)	1000 mg (N = 9)	Placebo (N = 9)	HTD1801 1000 mg/metformin (N = 9)	Placebo/metformin (N = 3)
Glucose
Fasting glucose (mmol/L)	0.352	-0.229	-0.602	0.727	-1.271	0.423
2-h postprandial (mmol/L)	0.431	-1.739	-2.356*	0.462	-4.167**	0.290
AUEC0−4 h (h*mmol/L)	0.6711	-5.48788*	-8.0424*	2.8173	-12.1813*	0.6183
AUEC0–24 h (h*mmol/L)	-2.1535	-32.3292	-30.8209	14.0778	-45.3649	8.6861
Insulin
Fasting (pmol/L)	5.623	13.428	8.426	14.872	9.918*	8.767
2-h postprandial (pmol/L)	32.654	63.053*	5.303	-6.894	-23.012	55.033*
AUEC0−4 h (h*pmol/L)	39.6893	154.5396	-3.0471	26.8434	-11.7365	97.7085
c-peptide
Fasting (pmol/L)	73.6	40.4	92.4	121.2	80.1	109.3
2-h postprandial (pmol/L)	104.4	223.1	60.2	0.0	-73.3	348.7*
AUEC0−4 h (h*pmol/L)	165.30	532.38	95.25	259.20	-86.90	847.75*
HbA1c (%)	-0.17	-0.07	-0.42	-0.12	-0.23	-0.33
LDL-C (mmol/L)	-0.194	-0.464**	-0.593**	0.120	-0.623***	0.290
HDL-C (mmol/L)	0.073*	0.059*	0.013	0.092	-0.037	0.163
TG (mmol/L)	-0.037	-0.646	-0.934	-0.538	-1.286***	-2.073
TC (mmol/L)	-0.253	-0.675*	-0.933***	-0.029	-1.090**	0.023
Non-HDL-C (mmol/L)	-0.327	-0.831*	-0.947***	-0.121	-1.053***	-0.140
ALT (U/L)	-0.29	0.74	-4.64	-4.76	0.27	2.10
AST (U/L)	0.01	1.96	0.50	-0.98	0.96	3.03
GGT (U/L)	-1.88	-4.59	-9.99*	-0.06	-9.28*	-4.43
TBIL (µmol/L)	1.27	1.83	0.17	2.79**	0.93	8.07*

*p < 0.05, **p < 0.01, ***p < 0.001

Discussion

Side effects

BUDCA is a novel compound formed by combining two known agents, BBR and UDCA, into a single salt formulation [22]. In this study, BUDCA was found to be safe and well-tolerated when administered for up to 28 days in patients with type 2 diabetes and nonalcoholic fatty liver disease. No episodes of hypoglycemia or hepatotoxicity were observed. Most adverse events (AEs) were mild in severity and occurred at comparable rates in both the BUDCA and placebo groups.

A total of 22 subjects experienced at least one drug-related adverse event: 7 subjects (58.3%) in the placebo group and 15 subjects (41.7%) in the BUDCA group. Except for one case of high triglycerides in the placebo group, all side effects (TEAEs) were of mild to moderate severity (grade 1 or 2).

In previous studies, the most commonly reported TEAEs associated with BUDCA (also referred to as HTD1801) in patients with hyperlipidemia included headache and gastrointestinal symptoms such as diarrhea, abdominal pain, and nausea, with an overall incidence of approximately 67%, consistent with the present findings. No headaches were reported in the current study; however, gastrointestinal AEs, including diarrhea and vomiting, were observed. Diarrhea occurred exclusively in the BUDCA groups, with an incidence of 11.1% (1/9) in each dose group, and did not exhibit a dose-dependent pattern [18].

Pharmacokinetic (PK) profile

Following oral administration, BUDCA is expected to dissociate in the gastrointestinal tract into its active components, BBR and UDCA. Peak plasma concentrations of UDCA were approximately 1,000 to 2,000 times higher than those of BBR, and UDCA appeared in circulation 1 to 2 h earlier than BBR.

The blood levels of BBR did not increase with higher doses, possibly due to its tendency to accumulate inside cells [27].

The pharmacokinetic (PK) profile of BBR from HTD1801 showed signs of saturation, while UDCA followed a linear PK pattern (Fig. 3). Both drugs were efficiently absorbed with T_max values of 3–6 h for BBR, 2.00–3.00 h for UDCA, and 2.00–4.00 h for total UDCA. BBR was cleared from the blood relatively quickly, as were UDCA and total UDCA. Their average half-lives (t_1/2) were 8.97–17.56 h (BBR), 6.38–10.31 h (UDCA), and 12.31–15.61 h (total UDCA). Mild accumulation was observed, with mean Rac values ranging from 0.9673 to 2.6659, supporting the use of HTD1801 twice daily [18].

Fig. 3.

Changes in lipid metabolism markers and liver-associated enzyme levels from baseline after 28 days of treatment across different dose groups. Parameters include low-density lipoprotein cholesterol (LDL-C), non-high-density lipoprotein cholesterol (non-HDL-C), triglyceride (TG), total cholesterol (TC),and γ-glutamyl transpeptidase (γ-GGT). Values are presented as mean changes from baseline

Plasma exposure levels of HTD1801 and UDCA were similar between patients with hyperlipidemia and those with diabetes and fatty liver [18]. For instance, in the 1000 mg group, the C_max was 3370 ng/mL in patients with hyperlipidemia versus 3863.39 ng/mL in diabetic patients. The absorption (T_max) and elimination (t_1/2) rates of both BBR and UDCA were also similar between the two groups. However, after repeated dosing, BBR and UDCA showed approximately 4-fold and 2-fold accumulation, respectively, in hyperlipidemia patients, which were higher than in diabetic and fatty liver patients [18].

At steady state, the ratios of BBR, UDCA, and total UDCA exposure (C_{max, ss} and AUC_{tau, ss}) in the HTD1801 1000 mg + metformin group compared to the HTD1801 1000 mg monotherapy group were 1.11–1.15, 0.99–1.03, and 0.92–0.99, respectively. These results suggest that metformin does not affect HTD1801 exposure, and there is no drug-drug interaction between them at a steady state [28].

Pharmacodynamics

After 28 days of treatment, HTD1801 significantly reduced blood glucose, LDL-C, non-HDL-C, and γ-GGT levels in a dose-dependent manner in patients with type 2 diabetes and nonalcoholic fatty liver disease.

Although the exact mechanism of BUDCA’s lipid-lowering effect is not fully understood, both of its components, berberine (BBR) and ursodeoxycholic acid (UDCA), have known lipid-lowering properties that may act additively or synergistically. UDCA, a secondary bile acid, is used in the treatment of primary biliary cholangitis for its choleretic, anti-inflammatory, and cholesterol-lowering effects [11–13, 29]. In this setting, UDCA may reduce cholesterol by suppressing its synthesis in the liver. Berberine lowers serum cholesterol by upregulating LDL receptor expression via a post-transcriptional mechanism, thereby enhancing LDL clearance [11, 12]. A meta-analysis of 18 studies (n = 1788) reported that berberine reduced LDL-C by 0.46 mmol/L, total cholesterol by 0.48 mmol/L, and triglycerides by 0.34 mmol/L [29].

There is a clinical need for cholesterol-lowering agents that also benefit insulin resistance, diabetes, and fatty liver disease, especially for patients with hypercholesterolemia who cannot tolerate statins. In such cases, alternatives such as ezetimibe or benzodiazic acid are used, and agents such as BUDCA may offer additional therapeutic value [7, 8].

In this study, the higher 1000 mg dose of HTD1801 resulted in a rapid and sustained reduction in total cholesterol, LDL-C, and non-HDL-C by day 8, lasting through day 28. The 1000 mg HTD1801 monotherapy group showed greater reductions in LDL-C, TG, TC, and non-HDL-C than the 500 mg, 750 mg, or placebo groups, highlighting a clear pharmacological advantage (Fig. 2). Both HTD1801 1000 mg monotherapy and its combination with metformin produced similar lipid-lowering effects: LDL-C decreased by ~ 0.6 mmol/L, and TG, TC, and non-HDL-C by ~ 1.0 mmol/L, greater than the reductions typically observed with berberine alone [30].

Compared with a prior study in hyperlipidemia patients treated with HTD1801 1000 mg BID for 28 days, the lipid-lowering effects of HTD1801 in T2D patients with fatty liver were slightly better [18, 31, 32]. For example, LDL-C was reduced by 0.593 mmol/L in this study compared to 0.41 mmol/L previously, and TC by 0.933 mmol/L than 0.49 mmol/L [18].

Fasting blood glucose levels decreased with increasing doses and longer treatment durations, particularly in the 750 mg and 1000 mg groups (see Fig. 4), with the most pronounced effects observed in the combination therapy group. Prior studies in patients with suspected nonalcoholic steatohepatitis (NASH) and T2D treated with HTD1801 at doses of 500 mg and 1000 mg twice daily for 18 weeks similarly demonstrated significant reductions in HbA1c levels [33]. Given that HTD1801 does not stimulate insulin secretion, its glucose-lowering effects are likely mediated through activation of AMPK and anti-inflammatory pathways [31, 32].

Fig. 4.

Mean plasma concentration-time profiles for each treatment group. (A) Baseline-corrected ursodeoxycholic acid (UDCA) plasma concentrations; (B) Berberine (BBR) plasma concentrations. Data are presented as mean values over the sampling period

Conclusion

Treatment with HTD1801 for 28 days resulted in significant reductions in blood glucose, LDL-C, non-HDL-C, and γ-GGT levels in patients with T2DM and fatty liver disease. The compound was well tolerated throughout the study period. These findings support continued investigation of HTD1801 as a therapeutic option for T2DM with fatty liver and potentially for NASH.

Supplementary Information

Below is the link to the electronic supplementary material.

Abbreviations

T2DM

Type 2 diabetes mellitus

MASLD

Metabolic dysfunction-associated steatotic liver disease

BBR

Berberine

UDCA

Ursodeoxycholic acid

LDL-C

Low-density lipoprotein cholesterol

TG

Triglyceride

TC

Total cholesterol

non-HDL-C

Non-high-density lipoprotein cholesterol

PCSK9

Proprotein convertase subtilisin/kexin type 9

BUDCA

Berberine ursodeoxycholate

GUDCA

Glycoursodeoxycholic acid

TUDCA

Tauroursodeoxycholic acid

PK

Pharmacokinetics

PD

Pharmacodynamics

NAFLD

Nonalcoholic fatty liver disease

HBA1c

Hemoglobin A1c

G6PD

Glucose-6-phosphate dehydrogenase

TEAEs

Treatment-emergent adverse events

NCI-CTCAE

National Cancer Institute Common Terminology Criteria for Adverse Events

MedDRA

Medical Dictionary for Regulatory Activities

C_max

Maximum plasma concentration

T_max

Time to reach

AUC

Area under the concentration–time curve

AUC₀_–t

AUC from time 0 to the last measurable point

AUC₀_–∞

AUC from time 0 to extrapolated to infinity

t_1/2

Terminal elimination half-life

CL

Clearance

V

Volume of distribution

Rac

Accumulation ratio

AEs

Adverse events

ALT

Alanine aminotransferase

AST

Aspartate aminotransferase

γ-GGT

Gamma-glutamyltranspeptidase

TBIL

Total bilirubin

NASH

Nonalcoholic steatohepatitis

Author contributions

J.M. performed the research wrote the manuscript and researched data. Y.D. contributed to discussion and reviewed/edited the manuscript. G.W. reviewed/edited the manuscript. H.Z. researched data and contributed to discussion. M.W., M.Y., and K.L. reviewed/edited the manuscript. All authors read and approved the final manuscript.

Funding

No Funding.

Data availability

The datasets generated during and/or analyzed during the current study are available from the corresponding author upon reasonable request.

Declarations

Ethics approval and consent to participate

The study protocol was prepared per the principles of the Declaration of Helsinki and approved by the Institutional Review Board of the First Hospital of Jilin University (21Y345-001). All recruited patients provided written informed consent before participating in any study-related procedures.

Consent for publication

Not applicable.

Competing interests

The authors declare no competing interests.