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Combination Therapy Potential of HTD1801 (Berbe-rine Ursodeoxycholate) in MASLD/MASH and Cardiovascular-Kidney-Metabolic Disease

Submitted:

08 September 2026

Posted:

09 September 2026

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Abstract

Background: Metabolic dysfunction-associated steatotic liver disease (MASLD) and steatohepatitis (MASH) are central to the cardiovascular-kidney-metabolic (CKM) continuum, where metabolic injury, hepatocellular stress, and systemic inflammation converge. These features represent key markers across the MASLD and CKM continuum. In this context, HTD1801, an ionic complex of berberine and ursodeoxycholic acid (UDCA), has shown improvements in glycemic control, LDL cholesterol, hepatic fat, and liver enzymes in clinical trials. The evidence base remains limited, with trials conducted in China and the United States and no biopsy-confirmed histologic outcomes yet reported. Main body: This review summarizes the mechanistic profile of HTD1801 and examines potential intersections with therapies commonly used in MASLD/MASH and CKM disease. Metformin is currently the only partner supported by Phase 3 randomized data demonstrating efficacy of HTD1801 as add-on therapy. For GLP-1 receptor agonists, statins, and SGLT2 inhibitors, combination rationale is biologically plausible but rests on mechanistic, preclinical, or comparative evidence rather than randomized human combination trials. Combinations with PPAR agonists or resmetirom remain hypothetical pending direct combination data and published biopsy-based efficacy results for HTD1801. Conclusions: HTD1801 occupies an intermediate position between metabolic and liver-directed therapy. Its role is promising but not yet fully defined. Publication of biopsy-based results from the completed CENTRICITY Phase 2b trial, and dedicated combination trials will be the primary requirement to determine whether HTD1801 can bridge metabolic and hepatic treatment strategies within the CKM spectrum, with geographic validation serving as a secondary consideration.

Keywords: 
HTD1801
;  
berberine ursodeoxycholate
;  
combination therapy
;  
metabolic dysfunction-associated steatotic liver disease
;  
metabolic dysfunction-associated steatohepatitis
;  
type 2 diabetes mellitus
;  
cardiovascular-kidney-metabolic syndrome
Subject: 
Medicine and Pharmacology  -   Medicine and Pharmacology

Background

Metabolic dysfunction-associated steatotic liver disease (MASLD) and its inflammatory subtype, metabolic dysfunction-associated steatohepatitis (MASH), are closely associated with obesity and type 2 diabetes mellitus (T2DM) [1,2], and their global burden has increased substantially in recent years [3,4]. Rather than representing isolated liver disorders, MASLD and MASH should be viewed within the broader cardiovascular–kidney–metabolic (CKM) syndrome framework, in which metabolic dysfunction, chronic kidney disease, cardiovascular disease, and hepatic steatosis are interrelated and mutually reinforcing [5]. Accordingly, management of MASH in individuals with T2DM should extend beyond liver-directed care alone and address the broader metabolic and cardiorenal context [6]. Treating MASLD or MASH as purely hepatic disorders overlooks the close interactions among metabolic, cardiovascular, renal, and hepatic pathways.
Although current guidelines recommend effective therapies for individual components of CKM syndrome, no single agent comprehensively addresses metabolic, hepatic, and cardiorenal risk simultaneously. This review therefore focuses on six therapeutic classes—metformin, glucagon-like peptide-1 (GLP-1) receptor agonists, statins, sodium–glucose cotransporter-2 (SGLT2) inhibitors, peroxisome proliferator-activated receptor (PPAR) agonists, and resmetirom. These classes were selected because each has published human clinical evidence relevant to at least one metabolic or cardiorenal outcome and one hepatic outcome, allowing comparison of their respective strengths and limitations across the CKM spectrum.
GLP-1 receptor agonists and SGLT2 inhibitors provide important cardiovascular and renal benefits, including reductions in major adverse cardiovascular events, cardiovascular death, and progression of chronic kidney disease [7,8]. For example, in EMPA-REG OUTCOME, empagliflozin reduced three-point major adverse cardiovascular events by 14% and cardiovascular death by 38% in patients with T2DM and established atherosclerotic cardiovascular disease [8]. Semaglutide has also demonstrated histologic benefit in MASH [9]. Nevertheless, the extent to which incretin-based therapies provide durable fibrosis regression and comprehensive hepatic benefit across the broader CKM syndrome continuum remains under investigation [7]. Conversely, liver-directed therapies such as PPAR agonists and resmetirom can improve histologic endpoints [10,11], but definitive evidence of major cardiovascular or kidney outcome benefits remains limited. Foundational therapies, including metformin and statins, remain essential for glycemic and cardiovascular risk management but rarely reverse established liver injury.
HTD1801 was developed as an ionic salt of berberine and ursodeoxycholic acid (UDCA), intended to integrate their potentially complementary pharmacologic actions within a single therapeutic entity rather than as a simple physical mixture. Ionic complexation has also been proposed as a formulation strategy to improve the solubility and oral bioavailability of berberine, whose clinical utility is limited by poor intestinal absorption and extensive first-pass elimination [12]. This review examines the mechanistic profile of HTD1801 and its potential intersections with the six therapeutic classes discussed above.

Methods

For this narrative review, we examined literature indexed in PubMed/MEDLINE through August 9 2026, focusing on studies that directly evaluated HTD1801 or its individual components, berberine and ursodeoxycholic acid (UDCA). Because HTD1801 has a relatively limited evidence base, the search strategy was intentionally broad. Keywords included “HTD1801,” “berberine ursodeoxycholate,” “BUDCA,” “berberine,” “ursodeoxycholic acid,” “MASLD,” “MASH,” and “type 2 diabetes,” along with names of therapeutic classes commonly used in MASLD/MASH and CKM disease: metformin, GLP-1 receptor agonists, statins, SGLT2 inhibitors, PPAR agonists, and resmetirom.
We also reviewed ClinicalTrials.gov, last checked on 9 August 2026, to identify ongoing, completed, or unpublished studies. Abstracts from recent ADA, EASL, and ERA meetings were incorporated when they provided mechanistic or early clinical insights not yet available in peer-reviewed publications. Sponsor-released materials were used sparingly and only when they clarified trial design, regulatory status, or endpoints; such evidence is identified as preliminary or non-peer-reviewed.
Because the available studies differ substantially in design, duration, and patient characteristics, and because published human biopsy-based efficacy results for HTD1801 were unavailable at the search cutoff, a formal meta-analysis or structured risk-of-bias assessment was not appropriate. Instead, we adopted a narrative approach, interpreting each study within its own context rather than forcing heterogeneous data into a single analytical framework. Findings from berberine or UDCA monotherapy were included only when they helped explain mechanistic pathways relevant to HTD1801; these component-level insights are distinguished from HTD1801-specific evidence throughout the review.
Conference abstracts and other non-peer-reviewed sources were treated as preliminary signals. They can provide useful early information, but they require cautious interpretation until full peer-reviewed data become available. This approach allowed the review to remain current without overstating the certainty of early findings.

Mechanisms of Action

HTD1801 dissociates in the gastrointestinal tract into berberine and ursodeoxycholic acid (UDCA), and much of what is currently known about its biology comes from studies of these individual components rather than the intact ionic complex.
Berberine’s metabolic actions have been characterized for decades. By inhibiting mitochondrial complex I, berberine increases the intracellular AMP:ATP ratio and activates AMP-activated protein kinase (AMPK) [13]. Activation of AMPK suppresses hepatic gluconeogenesis, slows de novo lipogenesis [14,15], and promotes autophagy [16]. These pathways help explain why berberine consistently reduces hepatic fat and improves systemic metabolic balance. Although these mechanisms are well documented for berberine monotherapy, they have not yet been directly confirmed for HTD1801 itself.
UDCA acts primarily on the hepatocellular stress axis. It reduces endoplasmic reticulum stress, prevents mitochondrial permeability transition pore opening, and interferes with Bax-mediated apoptosis [17]. In broad terms, berberine tends to correct metabolic dysfunction, whereas UDCA protects hepatocytes under cellular stress. In a phase 2 clinical trial of HTD1801, the clearest evidence of improved insulin homeostasis was observed for the homeostatic model assessment of insulin resistance (HOMA-IR), with a numerically greater reduction at the higher dose: least-squares mean changes from baseline were −0.3 (SE, 0.3) with 500 mg twice daily and −0.9 (SE, 0.3) with 1000 mg twice daily, compared with +0.5 (SE, 0.3) with placebo (P=.13 and P=.006, respectively; n=33–34 per group) [18]. While encouraging, HOMA-IR reflects systemic insulin sensitivity and cannot be taken as direct evidence of hepatic AMPK activation.
Berberine has also been associated with anti-inflammatory effects in preclinical models, particularly through suppression of NF-κB and NLRP3 inflammasome signaling, resulting in reductions in proinflammatory cytokines such as tumor necrosis factor-α (TNF-α), interleukin-6 (IL-6), and interleukin-1β (IL-1β) [19,20]. Whether HTD1801 reproduces these anti-inflammatory effects in humans remains uncertain. UDCA may exert additional anti-inflammatory effects by modulating Kupffer cells, the liver-resident macrophages that play a central role in NAFLD pathogenesis, potentially promoting an anti-inflammatory M2-like phenotype and reducing the production of proinflammatory cytokines, including TNF-α and IL-6. [21].
In the 12-week trial by Ji et al. [18], high-sensitivity C-reactive protein (hsCRP) declined modestly in all three groups—placebo, HTD1801 500 mg, and HTD1801 1000 mg (LS mean change: −1.3 [SE 0.3], −1.5 [SE 0.3], and −1.3 [SE 0.3] mg/L, respectively)—with no significant between-group differences (500 mg vs placebo, P=.70; 1000 mg vs placebo, P=.90). Because hsCRP is a broad and nonspecific marker, these results do not clarify whether HTD1801 meaningfully modulates NLRP3 or NF-κB pathways in humans.
Another mechanistic thread involves the incretin axis, the gut-hormone system in which intestinally derived hormones such as glucagon-like peptide-1 (GLP-1) are released after nutrient intake to stimulate insulin secretion and enhance glycemic control. UDCA activates the bile acid receptor TGR5 on intestinal L cells (enteroendocrine cells that secrete GLP-1 in response to luminal nutrients), increasing endogenous GLP-1 secretion. Evidence from small human studies suggests this effect: a sequential pre–post study in healthy volunteers by Murakami et al. [22] and a pilot randomized, controlled add-on trial in patients with T2DM and chronic liver disease by Shima et al. [23]. Berberine may also enhance GLP-1 release: in diet-induced obese mice, high-fat feeding caused mitochondrial stress (cristae loss, membrane rupture, and swelling) in colonic enterocytes—the site of GLP-1-producing L cells—and this mitochondrial dysfunction was associated with reduced GLP-1 expression; berberine treatment attenuated the mitochondrial stress and restored GLP-1 expression, an effect attributed to protection of enterocyte mitochondria rather than to changes in gut microbiota [24]. These studies evaluated free UDCA (Murakami [22], Shima [23]) or free berberine (Sun et al. [24]) rather than HTD1801, and no HTD1801 trial has measured endogenous GLP-1 directly. Whether the ionic complex preserves this UDCA-mediated GLP-1 secretory mechanism remains unknown. Overall, the proposed mechanisms of HTD1801, including AMPK activation, attenuation of hepatocellular stress, modulation of inflammatory signaling, and potential enhancement of endogenous GLP-1 secretion, provide a biologically plausible framework for its observed metabolic and hepatic effects. However, current mechanistic understanding remains largely extrapolated from studies of berberine and UDCA individually, as HTD1801-specific mechanistic evidence is still lacking.
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Figure 1. Mechanisms of action of HTD1801. HTD1801 dissociates into berberine and ursodeoxycholic acid (UDCA) in the gastrointestinal tract. (A) Berberine inhibits mitochondrial complex I, raises the adenosine monophosphate:adenosine triphosphate (AMP:ATP) ratio, and activates AMP-activated protein kinase (AMPK), thereby reducing gluconeogenesis, lipogenesis, and nuclear factor kappa B (NF-κB)/NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3)-mediated inflammation. (B) UDCA activates Takeda G protein-coupled receptor 5 (TGR5) on intestinal L-cells to stimulate endogenous glucagon-like peptide-1 (GLP-1) secretion and exerts hepatoprotective effects by attenuating endoplasmic reticulum (ER) stress, preventing mitochondrial permeability transition pore (mPTP) opening, and inhibiting Bax translocation. (C) These complementary component-level pathways could contribute to observed effects on glycemic control, lipid metabolism, inflammation, and hepatic integrity. The proposed mechanisms are primarily derived from component-level studies, with limited direct evidence for the HTD1801 complex. Created with BioRender.com.
Figure 1. Mechanisms of action of HTD1801. HTD1801 dissociates into berberine and ursodeoxycholic acid (UDCA) in the gastrointestinal tract. (A) Berberine inhibits mitochondrial complex I, raises the adenosine monophosphate:adenosine triphosphate (AMP:ATP) ratio, and activates AMP-activated protein kinase (AMPK), thereby reducing gluconeogenesis, lipogenesis, and nuclear factor kappa B (NF-κB)/NOD-, LRR- and pyrin domain-containing protein 3 (NLRP3)-mediated inflammation. (B) UDCA activates Takeda G protein-coupled receptor 5 (TGR5) on intestinal L-cells to stimulate endogenous glucagon-like peptide-1 (GLP-1) secretion and exerts hepatoprotective effects by attenuating endoplasmic reticulum (ER) stress, preventing mitochondrial permeability transition pore (mPTP) opening, and inhibiting Bax translocation. (C) These complementary component-level pathways could contribute to observed effects on glycemic control, lipid metabolism, inflammation, and hepatic integrity. The proposed mechanisms are primarily derived from component-level studies, with limited direct evidence for the HTD1801 complex. Created with BioRender.com.
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Combination Potential

HTD1801’s broad metabolic and hepatic actions naturally prompt consideration of how it might interact with therapies commonly used in MASLD/MASH and CKM disease. The aim is not to suggest synergy where none has been demonstrated, but to identify areas where biological plausibility and early clinical signals justify further exploration.

Htd1801 Clinical Evidence: an Integrated Summary

Before evaluating potential combination strategies, it is useful to outline what HTD1801 achieves as monotherapy. Across seven completed studies with publicly reported results, from Phase 1b dose escalation work through Phase 3 trials, HTD1801 has shown a consistent pattern of benefit, including improvements in glycemic control, LDL-C, hepatic fat fraction, and liver enzymes. These effects have appeared across varied study designs, durations, and patient populations, which strengthens confidence in the overall signal.
The phase 1b study evaluated the safety, pharmacokinetics, and pharmacodynamic effects of HTD1801 over 28 days in participants with hypercholesterolemia [25]. At steady state, plasma exposures of both berberine and UDCA appeared broadly dose-proportional across the evaluated dose range. Beyond the pharmacokinetic findings, HTD1801 was generally well tolerated and was associated with dose-dependent reductions in LDL-C and total cholesterol; at the highest dose (2000 mg/day), LDL-C decreased by 10.4% and total cholesterol by 8.2% versus placebo at day 28. However, because the trial did not include a direct comparator group receiving co-administered free berberine and UDCA, it characterizes the pharmacokinetics and short-term pharmacodynamic effects of HTD1801 but does not establish whether the ionic complex confers pharmacokinetic or clinical advantages over its individual components. Although complex formation has been proposed as a strategy to address the poor oral bioavailability of berberine, direct comparative pharmacokinetic and clinical studies are needed.
Table 1. Summary of completed clinical trials of HTD1801: study designs, endpoints, and key findings. The overall pattern is clear: HTD1801 reliably improves metabolic and hepatic markers, and several studies demonstrate dose-responsive effects.
Table 1. Summary of completed clinical trials of HTD1801: study designs, endpoints, and key findings. The overall pattern is clear: HTD1801 reliably improves metabolic and hepatic markers, and several studies demonstrate dose-responsive effects.
Trial ID / Reference / Evidence Level Population / Design N / Duration; nation Primary endpoint Key results Notable secondary findings
NCT03656744 (Phase 2a)
Harrison et al. [12]


Level 1b 		MASH + T2DM; 1:1:1 double-blind (DB): HTD1801 500 mg BID vs 1000 mg BID vs placebo N=100; 18 wks; USA MRI-PDFF (magnetic resonance imaging–proton density fat fraction) hepatic fat reduction 1000 mg: −4.8% vs placebo −2.0% (P=0.011); MRI response 52% vs 24% ALT/AST improvement; LDL-C reduction; HbA1c improvement; dose-dependent HOMA-IR reduction
NCT06411275 (Phase 2)
Ji et al. [18]


Level 1b 		T2DM inadequately controlled with diet/exercise; 1:1:1 DB RCT: HTD1801 500 mg BID vs 1000 mg BID vs placebo N=113; 12 wks; China HbA1c reduction 500 mg: −0.4% vs placebo (P=0.04); 1000 mg: −0.7% vs placebo (P<0.001); HbA1c <7%: 55.9% vs 15.2% LDL-C −11.2 mg/dL; ALT/AST improvement; hs-CRP decline not significant (NS)
NCT06350890 (Phase 3)
SYMPHONY-1, ADA 2025 [26]


Level 1b 		T2DM inadequately controlled with diet/exercise; 2:1 DB RCT + OLE: HTD1801 1000 mg BID vs placebo N≈400; 24 wks + OLE ; China HbA1c reduction vs placebo 1000 mg: LS mean −1.26% vs placebo −0.61% (P<0.0001); HbA1c <7%: 42% (placebo % not publicly reported) LDL-C, hs-CRP improvement; sustained HbA1c reduction at 52 wks
NCT06353347 (Phase 3)
SYMPHONY-2, NEJM Evid 2026 [27]


Level 1b 		T2DM inadequately controlled with metformin; 2:1 DB RCT + OLE: HTD1801 1000 mg BID (add-on to metformin) vs placebo N=549; 24 wks + OLE ; China HbA1c reduction vs placebo (add-on to metformin) 1000 mg: LS mean −1.21% vs placebo −0.68% (P<0.0001); HbA1c <7%: 33% vs 11% LDL-C/non-HDL-C reduction; GGT improvement; eGFR increase in mild CKD

NCT06415773 (Phase 3)
HARMONY, ADA 2026 [28]


Level 1b 		T2DM inadequately controlled with metformin; 1:1 DB RCT, head-to-head: HTD1801 N=369; 24 wks; China HbA1c non-inferiority vs dapagliflozin (margin 0.4%) 1000 mg: −1.12% vs dapagliflozin −0.93% (LS mean difference −0.20%; 95% CI −0.37 to −0.03; P<0.001), statistically superior LDL-C superior; eGFR increase (HTD1801 only); lower statin initiation
ChiCTR2500110932 (Phase 1b)
Mai et al. [29]


Level 2b 		T2DM + MASLD; dose-escalation (treatment-naïve) + metformin add-on cohort; DB RCT N=48; 4 wks; China Safety/tolerability; PK of berberine and UDCA Well tolerated; no SAEs; berberine saturation kinetics, UDCA linear kinetics Dose-dependent improvement in glucose, lipids, liver enzymes; in metformin cohort (1000 mg) FPG −1.271 vs +0.423 mmol/L, LDL-C −0.623 vs +0.290 mmol/L
NCT03381287 (Phase 1b/2a)
Di Bisceglie et al. [25]


Level 2b 		Hypercholesterolemia (LDL-C >2.59 mmol/L), overweight/obesity; dose-escalation (3:1 active:placebo); DB RCT N=50; 4 wks; Australia Safety/tolerability; PK of berberine and UDCA Well tolerated at all doses incl. 2000 mg/day; no significant AEs; dose-dependent LDL-C reduction At highest dose (2000 mg/day) vs placebo at day 28: total cholesterol −8.2% (P=0.0004), LDL-C −10.4% (P=0.0006); no significant change in TG or HDL-C
Footnote: Evidence levels assigned according to the Oxford Centre for Evidence-Based Medicine (CEBM) 2011 Levels of Evidence for therapy/prevention questions [30]. Level 1b, individual randomized controlled trial with adequate blinding and control; Level 2b, individual trial with methodological limitations (e.g., small sample size, non-efficacy primary endpoint).
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; BID, twice daily; CKD, chronic kidney disease; DB, double-blind; eGFR, estimated glomerular filtration rate; FPG, fasting plasma glucose; GGT, gamma-glutamyl transferase; HbA1c, glycated hemoglobin; HDL-C, high-density lipoprotein cholesterol; HOMA-IR, homeostatic model assessment of insulin resistance; hs-CRP, high-sensitivity C-reactive protein; LDL-C, low-density lipoprotein cholesterol; LS, least-squares (mean); MASH, metabolic dysfunction-associated steatohepatitis; MASLD, metabolic dysfunction-associated steatotic liver disease; OLE, open-label extension; PK, pharmacokinetics; RCT, randomized controlled trial; SAEs, serious adverse events; T2DM, type 2 diabetes mellitus; UDCA, ursodeoxycholic acid.
Two limitations, however, should be acknowledged. First, the completed Phase 3 T2DM trials have been conducted in China [27,28], while the earlier MASH/T2DM Phase 2 trial was conducted in the United States [12]. This does not diminish the value of the findings, but metabolic disease varies across ethnic backgrounds, and broader geographic validation will be essential. Second, no published human study has yet reported biopsy-confirmed histologic efficacy outcomes for HTD1801. The CENTRICITY Phase 2b trial (NCT05623189) was completed with biopsy-based histologic endpoints, but results have not been posted on ClinicalTrials.gov or published as of 9 August 2026 [31]. A 2025 secondary analysis combined preclinical histology with human noninvasive markers rather than human biopsy outcomes [32], and subsequent commentary highlighted the limits of inferring histologic benefit from surrogate markers [33]. Improvements in ALT, AST, or MRI-PDFF remain encouraging but cannot substitute for direct histologic confirmation of MASH resolution or fibrosis improvement. Until such data are available, HTD1801’s position among liver-directed therapies will remain provisional.
These considerations help clarify where HTD1801 currently stands and what questions remain open as its potential role alongside other agents is evaluated.

Metformin

Both metformin and berberine inhibit mitochondrial complex I, raise the AMP:ATP ratio, and activate AMPK, thereby suppressing hepatic gluconeogenesis [13,34,35]. This shared mechanism produces partial overlap. Berberine monotherapy has also been shown to increase glucose disposal rate on hyperinsulinemic-euglycemic clamp testing, consistent with improved insulin sensitivity [36]. In addition, both agents enhance peripheral glucose uptake via AMPK-mediated GLUT4 translocation [37]. UDCA may complement these effects by stimulating TGR5-dependent GLP-1 secretion and exerting direct hepatoprotective actions; in KK-Ay mice (a genetic mouse model of obesity-associated type 2 diabetes), UDCA improved hepatic insulin sensitivity without affecting peripheral parameters [38]. Because these findings derive from studies of the individual components rather than the HTD1801 complex, they provide only indirect support for combination therapy (Figure 2).
In high-fat diet mouse models and HepG2 hepatocyte cultures, co-administration of berberine and metformin yielded greater reductions in steatosis, inflammation, and hepatocyte ballooning than either agent alone through an AMPK-dependent pathway [39]. Although these combination studies did not include UDCA, and therefore inform HTD1801 pharmacology only indirectly, they provide supportive mechanistic rationale for targeting complementary metabolic pathways.
Clinical evidence supporting this rationale comes from the Phase 3 SYMPHONY-2 trial, which evaluated HTD1801 as add-on therapy in patients with type 2 diabetes inadequately controlled on metformin [27]. Over 24 weeks, add-on HTD1801 achieved a significantly greater reduction in HbA1c compared with placebo (adjusted least-squares mean difference, −0.5%; 95% CI, −0.7 to −0.4; P < 0.0001). A greater proportion of patients receiving HTD1801 achieved HbA1c < 7.0% (33% vs. 11%), accompanied by improvements in LDL-C and GGT. SYMPHONY-2 was designed to assess overall therapeutic efficacy rather than to isolate individual mechanistic contributions.
Among the combination strategies evaluated to date, HTD1801 plus metformin has the most mature clinical evidence, supported by Phase 3 randomized trial data. This combination may be particularly relevant for patients with T2DM inadequately controlled on metformin, especially those with concurrent MASLD, dyslipidemia, or elevated liver enzymes. Beyond glycemic improvement, the potential hepatic and metabolic benefits of HTD1801 make this combination an attractive area for further investigation in high-risk metabolic populations [27].

Glp-1 Receptor Agonists

GLP-1, released from intestinal L-cells, lowers blood glucose by stimulating insulin secretion and suppressing glucagon in a glucose-dependent manner, while also delaying gastric emptying and reducing appetite [40,41]. GLP-1 receptor agonists continuously activate the GLP-1 receptor independently of endogenous hormone levels. By comparison, the components of HTD1801 act further upstream: UDCA stimulates endogenous GLP-1 secretion through TGR5 activation on L-cells, whereas berberine has been shown in diet-induced obese mice to restore GLP-1 secretion by protecting colonic enterocytes from mitochondrial overheating [22,23,24]. Because HTD1801 enhances endogenous GLP-1 availability whereas GLP-1 receptor agonists directly activate the receptor, these therapies act at different levels of the GLP-1 pathway and may therefore provide complementary therapeutic effects rather than redundant ones (Figure 3).
Support for this combination comes primarily from translational animal models. In a diet-induced obesity mouse study presented at the 2026 ADA Scientific Sessions, combining HTD1801 with semaglutide or tirzepatide produced greater weight loss than either GLP-1 receptor agonist alone, primarily through additional reductions in fat mass while largely preserving lean mass [42]. Following semaglutide discontinuation, HTD1801 also attenuated body-weight regain, improved body composition by maintaining a lower fat-mass ratio and a higher lean-mass ratio, and reduced glucose rebound. Although these findings are currently available only in a conference abstract and await peer-reviewed quantitative confirmation, they suggest a potential role for HTD1801 in supporting weight maintenance and preserving favorable body composition.
HTD1801 may represent a rational combination partner for patients with obesity-associated MASLD who continue to exhibit hepatic steatosis or dyslipidemia despite GLP-1 receptor agonist-induced weight loss. GLP-1 receptor agonists improve hepatic outcomes primarily through systemic weight reduction, whereas UDCA directly protects hepatocytes by attenuating endoplasmic reticulum stress, preventing mitochondrial permeability transition pore opening, and inhibiting Bax-mediated apoptosis (Figure 1) [17]. These mechanistic differences raise the possibility that HTD1801 may help address persistent hepatocellular injury independently of weight loss. This hypothesis warrants evaluation in early-phase clinical combination studies.

Statins

Statins remain the cornerstone of LDL-C-lowering therapy, reducing cardiovascular risk primarily by inhibiting HMG-CoA reductase and upregulating LDL receptor transcription through SREBP-2 [43,44]. Despite their proven efficacy, many patients do not achieve guideline-recommended LDL-C targets with statin monotherapy, leaving substantial residual cardiovascular risk [45]. Berberine offers a distinct complementary mechanism by stabilizing LDLR mRNA and suppressing PCSK9 transcription [46,47,48,49]. Because statin therapy also induces a compensatory increase in circulating PCSK9 levels, partially limiting its LDL-C-lowering effect, berberine-mediated PCSK9 suppression may counteract this adaptive response [50] (Figure 4). These complementary mechanisms support further clinical evaluation of HTD1801 in combination with statins to improve lipid control.
In high-fat diet-fed rats, co-administration of berberine (90 mg/kg/day) and simvastatin (6 mg/kg/day) reduced serum LDL-C by 46.2%, exceeding the reductions achieved with simvastatin (28.3%) or berberine (26.8%) alone (P < 0.01 for both). This combined effect was comparable to high-dose simvastatin monotherapy (12 mg/kg/day; 43.4%) and was accompanied by an approximately 1.6-fold increase in hepatic LDLR mRNA expression [51].
In monocyte-derived macrophages, berberine (0.1-100 nM) combined with atorvastatin (100 nM) dose-dependently suppressed LOX-1 expression through an endothelin-1 receptor-mediated mechanism [52]. Although these studies evaluated berberine rather than HTD1801 directly, Phase 2 clinical trials have demonstrated that HTD1801 independently lowers LDL-C, providing indirect clinical support for further evaluation of this combination strategy [12,18].
HTD1801 may represent a potential add-on option for patients with MASLD or T2DM who continue to exhibit atherogenic dyslipidemia despite optimized statin therapy. The complementary mechanisms of statin-mediated cholesterol synthesis inhibition and berberine-mediated stabilization of hepatic LDL receptors provide a biological rationale for combination therapy. Whether this mechanistic complementarity translates into additional clinical benefit remains to be established in dedicated prospective combination trials [45].

Sglt2 Inhibitors: Comparative, Not Combination, Evidence

SGLT2 inhibitors lower blood glucose through glucosuria and confer robust cardiorenal protection via mechanisms distinct from those of HTD1801 [53,54,55,56]. Although certain downstream pathways, such as AMPK activation and NLRP3 inflammasome suppression, may partially overlap with the pharmacological actions of berberine or ursodeoxycholic acid (UDCA), the two therapies primarily act through distinct physiological mechanisms.
Although combination therapy with SGLT2 inhibitors has not yet been formally evaluated, head-to-head clinical data provide indirect evidence relevant to future combination strategies. The Phase 3 HARMONY trial (NCT06415773) compared HTD1801 directly with dapagliflozin as monotherapies [28]. At week 24, sponsor-reported and conference-presented data indicated a greater HbA1c reduction with HTD1801 than with dapagliflozin (−1.12% vs. −0.93%; least-squares mean difference, −0.20%; 95% CI, −0.37 to −0.03; reported P < 0.001), with a higher proportion of patients achieving HbA1c < 7.0%. HTD1801 treatment was also associated with an increase in eGFR during the study period, whereas dapagliflozin did not demonstrate a comparable increase. These findings remain preliminary until full peer-reviewed results are available.
Patients with cardiovascular-kidney-metabolic (CKM) syndrome, particularly those with concomitant MASLD and early chronic kidney disease, may represent an appropriate population for future combination studies. The established cardiorenal benefits of SGLT2 inhibitors and the hepatic and glycemic effects of HTD1801 suggest complementary therapeutic roles. Whether these complementary mechanisms translate into additional clinical benefit should be evaluated in prospective combination trials [5,57].

Low-Evidence Candidates: Ppar Agonists and Resmetirom

PPAR agonists and resmetirom act through mechanisms distinct from the AMPK- and TGR5-mediated actions of HTD1801. PPAR agonists improve insulin sensitivity while attenuating inflammatory and fibrotic pathways, whereas resmetirom selectively enhances mitochondrial fatty-acid oxidation through thyroid hormone receptor-β (THRβ) activation [58]. Clinically, lanifibranor demonstrated histologic efficacy in the Phase 2b NATIVE trial [59], and resmetirom achieved biopsy-confirmed histologic improvements in pivotal Phase 3 studies [11].
Although these distinct mechanisms provide a theoretical rationale for combination therapy, no preclinical or clinical studies have evaluated HTD1801 in combination with either PPAR agonists or resmetirom. While HTD1801 consistently improves hepatic fat fraction, liver transaminases, and systemic lipid profiles, its clinical positioning relative to histology-proven therapies such as resmetirom or pan-PPAR agonists remains uncertain because published human biopsy-confirmed histologic efficacy data are not yet available. Among the drug classes reviewed, evidence supporting combination therapy with PPAR agonists or resmetirom remains limited and largely theoretical.

Discussion

Current evidence provides several rationales for combining HTD1801 with established therapies, yet the strength of clinical support varies widely across drug classes. Metformin is the only partner backed by Phase 3 randomized data demonstrating the efficacy of HTD1801 as add-on therapy (SYMPHONY-2) [27]. GLP-1 receptor agonists and statins act through complementary pathways that make combination therapy biologically plausible [22,46,48], but no clinical combination studies have been conducted. For SGLT2 inhibitors, the available data come mainly from head-to-head comparisons, while evidence for PPAR agonists and resmetirom is still largely mechanistic [10,11]. In short, mechanistic insights have advanced faster than clinical validation. The documented ability of UDCA to stimulate GLP-1 via TGR5 [22,23] and the consistent LDL-C reductions seen with HTD1801 monotherapy [12,18] offer a reasonable foundation for testing combinations with GLP-1 receptor agonists and statins in future trials.
HTD1801 improves glycemic control and lipid profiles and produces favorable trends in hepatic and renal biomarkers, which supports its further evaluation in the context of CKM syndrome [5,60]. Several important limitations, however, must be kept in mind. No published human MASH trial has reported biopsy-confirmed histologic efficacy results for HTD1801, direct comparisons with other liver-directed agents are lacking, and the Phase 3 T2DM studies to date have been conducted in China [27,28], although the earlier MASH/T2DM Phase 2 trial was conducted in the United States [12]. In addition, much of the mechanistic understanding still rests on studies of berberine or UDCA alone rather than the ionic complex itself [13,17]. A substantial portion of the clinical data also comes from sponsor-affiliated reports or conference abstracts that have not yet undergone full peer review.
Beyond its effects on glucose, HTD1801 has been linked to improvements in several cardiometabolic markers: reductions in hepatic fat (−4.8% on MRI-PDFF), ALT, AST, LDL-C, and GGT, as well as increases in eGFR, particularly in patients with mild chronic kidney disease [12,18,26,27,28]. A pooled post-hoc analysis of SYMPHONY-1 and SYMPHONY-2 presented at the 2026 ERA Congress showed that patients with baseline eGFR of 60-90 mL/min/1.73 m2 had a mean eGFR increase of +3.08 mL/min/1.73 m2 at week 52 (95% CI 0.46-5.70), without signs of hyperfiltration or fluid retention [61]. Taken together, these observations raise the possibility that HTD1801 could help address residual risks such as dyslipidemia, hepatic steatosis, and early renal impairment even after glycemic targets are met. Because the trials were not designed or powered to assess hard cardiometabolic outcomes, however, this interpretation remains exploratory [12,18].
Both SYMPHONY trials stratified randomization by a baseline HbA1c threshold of 8.5%, yet peer-reviewed subgroup analyses examining differential treatment response by glycemic severity have not been published. It remains uncertain whether HTD1801 is best positioned as add-on therapy for patients inadequately controlled on metformin or whether it may also have a role earlier in treatment. Prospective studies with predefined HbA1c strata will be needed to clarify this question.
Patients with MASLD and T2DM frequently exhibit overlapping features of CKM syndrome, making it unlikely that any single pathway agent can fully address the combined metabolic, hepatic, cardiovascular, and renal abnormalities [5]. This context supports further evaluation of HTD1801 in combination with agents such as GLP-1 receptor agonists [62,63], SGLT2 inhibitors, and resmetirom. In March 2026, China’s National Medical Products Administration accepted HighTide Therapeutics’ first New Drug Application for HTD1801, based on three Phase 3 trials that met their primary and multiple secondary endpoints in T2DM, a notable regulatory milestone toward potential commercialization [64].
Immediate research priorities include the pending biopsy-based histologic results from the completed CENTRICITY Phase 2b trial (NCT05623189), early clinical combination studies with GLP-1 receptor agonists and statins, and confirmation of efficacy in more diverse populations. Based on current evidence, HTD1801 appears most promising as add-on therapy for patients who continue to carry residual cardiometabolic risk despite metformin, although this positioning will require confirmation in adequately powered trials.
Combination strategies are likely to be most effective when guided by patient phenotype rather than drug class alone. Individuals with obesity-associated MASLD may be particularly suitable for evaluating HTD1801 together with GLP-1 receptor agonists [65,66], whereas patients with persistent dyslipidemia despite statin therapy [45] or those with CKM syndrome and early CKD [5,57] may be better candidates for statin or SGLT2 inhibitor-based combinations. At present, metformin remains the only partner supported by Phase 3 randomized clinical evidence for HTD1801 add-on therapy [27]. Although these concepts are still exploratory, a phenotype-guided approach may improve both trial design and patient selection in future combination studies. Table 2 summarizes the current mechanistic, preclinical, and clinical evidence for each candidate partner.

Safety Considerations

When evaluating HTD1801 in combination with other therapies, the main safety considerations involve overlapping adverse effects and potential pharmacokinetic interactions. In SYMPHONY-2, diarrhea was the most frequently reported adverse event with HTD1801 add-on therapy (23.8% vs. 1.1% with placebo, including three severe cases) [27]. Because metformin commonly causes gastrointestinal intolerance, this overlap is particularly relevant for the combination with the strongest supporting evidence. Even so, no unexpected safety signals emerged in that trial [27].
UDCA can stimulate endogenous GLP-1 secretion through TGR5 activation, raising the possibility of increased gastrointestinal intolerance when HTD1801 is paired with GLP-1 receptor agonists; however, this combination has not yet been evaluated clinically [22,67,68]. Resmetirom has shown an acceptable safety profile in Phase 3 studies [11], but its concomitant use with HTD1801 remains unexplored. PPAR agonists such as lanifibranor are associated with diarrhea, nausea, peripheral edema, anemia, and weight gain [59], making gastrointestinal tolerability a potential concern if used together with HTD1801.
Whether these adverse effects interact with HTD1801’s metabolic or hepatic actions is unknown. SGLT2 inhibitors promote osmotic diuresis and increase the risk of genital infections; although their mechanisms differ from those of HTD1801, combined therapy may require monitoring of volume status and renal function in susceptible individuals [69].
Repeated berberine administration has been reported to inhibit CYP3A4 and CYP2D6 activity in humans [70], and preclinical work has raised concern about combined CYP3A4 inhibition and hERG channel effects when berberine is used with selected statins [71]. This creates a theoretical interaction concern for statins that depend substantially on CYP3A4 metabolism, including simvastatin and atorvastatin [72]. However, these findings have not been established specifically for HTD1801 in prospective drug-drug interaction studies. Direct HTD1801 interaction data are needed before preferential statin selection, routine ECG monitoring, or other combination-specific monitoring strategies can be recommended. Clinically meaningful CYP-mediated interactions are less expected with metformin, GLP-1 receptor agonists, or SGLT2 inhibitors, but dedicated HTD1801 studies remain limited.
Gradual titration of incretin-based therapies may help improve gastrointestinal tolerability. Routine monitoring of liver enzymes and lipid profiles is appropriate during treatment, and MRI-PDFF, when available, may offer additional insight into hepatic response [6]. Completed clinical studies have not identified unexpected safety concerns with HTD1801, but combination-specific safety data remain limited. Future trials designed to evaluate combination therapy should incorporate dedicated safety assessments.

Conclusions

HTD1801 engages multiple pathways involved in metabolic dysfunction, hepatic injury, and dyslipidemia. Across completed clinical studies, it has consistently improved glycemic control, LDL-C, hepatic fat content, and liver enzyme profiles. These findings support continued evaluation of HTD1801 as an adjunctive therapy for patients with MASLD/MASH or CKM syndrome who continue to carry residual cardiometabolic risk despite standard treatment.
Several evidence gaps still shape its current positioning. Published human biopsy-based histologic efficacy has not yet been demonstrated, all completed Phase 3 T2DM trials have been conducted exclusively in Chinese cohorts [27,28], and no dedicated human combination studies have assessed HTD1801 with GLP-1 receptor agonists, statins, resmetirom, or PPAR agonists. In addition, although HTD1801 was developed as an ionic complex of berberine and UDCA, it remains uncertain whether the complex provides pharmacokinetic or clinical advantages beyond co-administration of the two components because direct comparative studies are lacking.
The role HTD1801 ultimately occupies in MASH and CKM care will depend on publication of the biopsy-based outcomes from the completed CENTRICITY trial and on confirmation of efficacy and safety in more diverse populations. Favorable results would strengthen the case for incorporating HTD1801 into phenotype-guided combination strategies within the CKM framework.

Author Contributions

Conceptualization, B.K. and K.K.; methodology, B.K.; formal analysis, B.K.; investigation, B.K.; validation, J.K. and G.K.; writing—original draft preparation, B.K.; writing—review and editing, K.K., J.K. and G.K.; supervision, K.K.; project administration, K.K. All authors have read and agreed to the published version of the manuscript.

Funding

Open access publication fees will be supported in part by the MDPI–University of California agreement that offers APC support for UC corresponding authors.

Institutional Review Board Statement

Not applicable.

Data Availability Statement

No new data were created or analyzed in this study. Data sharing is not applicable to this article.

Acknowledgments

During the preparation of this work, the authors used ChatGPT (OpenAI) to improve the English-language quality and linguistic clarity of the manuscript. BioRender (BioRender.com) was used to create the schematic figures. The authors reviewed and edited all AI-assisted content and take full responsibility for the scientific accuracy and integrity of the final manuscript.

Conflicts of Interest

The authors declare no conflicts of interest.

Abbreviations

ADA, American Diabetes Association; ALT, alanine aminotransferase; AMPK, AMP-activated protein kinase; AST, aspartate aminotransferase; BID, twice daily; BUDCA, berberine ursodeoxycholate; CKD, chronic kidney disease; CKM, cardiovascular-kidney-metabolic; CYP, cytochrome P450; CYP2D6, cytochrome P450 2D6; CYP3A4, cytochrome P450 3A4; DB, double-blind; eGFR, estimated glomerular filtration rate; ER, endoplasmic reticulum; FPG, fasting plasma glucose; FXR, farnesoid X receptor; GGT, gamma-glutamyl transferase; GLP-1, glucagon-like peptide-1; GLP-1RA, glucagon-like peptide-1 receptor agonist; GLUT4, glucose transporter type 4; HbA1c, glycated hemoglobin; HDL-C, high-density lipoprotein cholesterol; HOMA-IR, homeostatic model assessment of insulin resistance; hs-CRP, high-sensitivity C-reactive protein; IL-1β, interleukin-1 beta; IL-6, interleukin-6; LDL-C, low-density lipoprotein cholesterol; LDLR, low-density lipoprotein receptor; LOX-1, lectin-like oxidized LDL receptor-1; LS, least-squares (mean); MASH, metabolic dysfunction-associated steatohepatitis; MASLD, metabolic dysfunction-associated steatotic liver disease; MRI-PDFF, magnetic resonance imaging proton density fat fraction; NF-κB, nuclear factor kappa B; NLRP3, NOD-, LRR- and pyrin domain-containing protein 3; OLE, open-label extension; PCSK9, proprotein convertase subtilisin/kexin type 9; PGC-1α, peroxisome proliferator-activated receptor gamma coactivator 1-alpha; PK, pharmacokinetics; PPAR, peroxisome proliferator-activated receptor; RCT, randomized controlled trial; SAEs, serious adverse events; SGLT2i, sodium-glucose cotransporter-2 inhibitor; T2DM, type 2 diabetes mellitus; TGR5, Takeda G protein-coupled receptor 5; THRβ, thyroid hormone receptor beta; TNF-α, tumor necrosis factor-alpha; UDCA, ursodeoxycholic acid.

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Figure 2. Mechanistic rationale for combining HTD1801 with metformin. (A) Both berberine and metformin inhibit mitochondrial complex I, elevate the adenosine monophosphate:adenosine triphosphate (AMP:ATP) ratio, and activate AMP-activated protein kinase (AMPK), resulting in reduced hepatic gluconeogenesis (partial mechanistic overlap). (B) Both agents enhance peripheral glucose uptake via AMPK-mediated glucose transporter type 4 (GLUT4) translocation in skeletal muscle and adipose tissue. (C) Ursodeoxycholic acid (UDCA) complements these actions through Takeda G protein-coupled receptor 5 (TGR5)-mediated glucagon-like peptide-1 (GLP-1) secretion and direct hepatoprotection (reduced endoplasmic reticulum stress and lipid accumulation), and may improve hepatic insulin sensitivity. Created with BioRender.com.
Figure 2. Mechanistic rationale for combining HTD1801 with metformin. (A) Both berberine and metformin inhibit mitochondrial complex I, elevate the adenosine monophosphate:adenosine triphosphate (AMP:ATP) ratio, and activate AMP-activated protein kinase (AMPK), resulting in reduced hepatic gluconeogenesis (partial mechanistic overlap). (B) Both agents enhance peripheral glucose uptake via AMPK-mediated glucose transporter type 4 (GLUT4) translocation in skeletal muscle and adipose tissue. (C) Ursodeoxycholic acid (UDCA) complements these actions through Takeda G protein-coupled receptor 5 (TGR5)-mediated glucagon-like peptide-1 (GLP-1) secretion and direct hepatoprotection (reduced endoplasmic reticulum stress and lipid accumulation), and may improve hepatic insulin sensitivity. Created with BioRender.com.
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Figure 3. Complementary mechanisms of HTD1801 and glucagon-like peptide-1 (GLP-1) receptor agonists. (A) Ursodeoxycholic acid (UDCA) stimulates endogenous GLP-1 secretion via Takeda G protein-coupled receptor 5 (TGR5) activation on intestinal L-cells. (B) Berberine may further support GLP-1 secretion by protecting colonic enterocytes from mitochondrial overheating. In contrast, GLP-1 receptor agonists act directly on the GLP-1 receptor. (C) Both pathways converge on GLP-1 receptor activation, driving multi-organ metabolic effects. Because HTD1801 acts upstream to increase endogenous ligand availability while GLP-1 receptor agonists act downstream at the receptor, the two approaches are potentially complementary rather than fully redundant, although clinical evidence for the combination remains limited. Created with BioRender.com.
Figure 3. Complementary mechanisms of HTD1801 and glucagon-like peptide-1 (GLP-1) receptor agonists. (A) Ursodeoxycholic acid (UDCA) stimulates endogenous GLP-1 secretion via Takeda G protein-coupled receptor 5 (TGR5) activation on intestinal L-cells. (B) Berberine may further support GLP-1 secretion by protecting colonic enterocytes from mitochondrial overheating. In contrast, GLP-1 receptor agonists act directly on the GLP-1 receptor. (C) Both pathways converge on GLP-1 receptor activation, driving multi-organ metabolic effects. Because HTD1801 acts upstream to increase endogenous ligand availability while GLP-1 receptor agonists act downstream at the receptor, the two approaches are potentially complementary rather than fully redundant, although clinical evidence for the combination remains limited. Created with BioRender.com.
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Figure 4. Mechanistic rationale for combining HTD1801 with statins. (A) Statins inhibit 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, activate sterol regulatory element-binding protein 2 (SREBP-2), and increase low-density lipoprotein receptor (LDLR) gene transcription. (B) Berberine stabilizes LDLR mRNA and suppresses proprotein convertase subtilisin/kexin type 9 (PCSK9) transcription, thereby prolonging LDLR half-life on the hepatocyte surface. (C) The combined actions enhance low-density lipoprotein cholesterol (LDL-C) clearance through mechanistically distinct pathways, supporting a mechanistic rationale for prospective evaluation of statins with HTD1801. Created with BioRender.com.
Figure 4. Mechanistic rationale for combining HTD1801 with statins. (A) Statins inhibit 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase, activate sterol regulatory element-binding protein 2 (SREBP-2), and increase low-density lipoprotein receptor (LDLR) gene transcription. (B) Berberine stabilizes LDLR mRNA and suppresses proprotein convertase subtilisin/kexin type 9 (PCSK9) transcription, thereby prolonging LDLR half-life on the hepatocyte surface. (C) The combined actions enhance low-density lipoprotein cholesterol (LDL-C) clearance through mechanistically distinct pathways, supporting a mechanistic rationale for prospective evaluation of statins with HTD1801. Created with BioRender.com.
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Table 2. Evidence-gap map and prioritization of HTD1801 combination strategies. Evidence levels are categorized as (a) evidence exists, (b) partial or indirect evidence, and (c) no evidence, reflecting a qualitative synthesis of mechanistic, preclinical, and clinical data intended for comparative interpretation rather than formal grading. Research priority denotes the author’s qualitative assessment of combinations most suitable for near-term investigation, based on evidence maturity and mechanistic complementarity.
Table 2. Evidence-gap map and prioritization of HTD1801 combination strategies. Evidence levels are categorized as (a) evidence exists, (b) partial or indirect evidence, and (c) no evidence, reflecting a qualitative synthesis of mechanistic, preclinical, and clinical data intended for comparative interpretation rather than formal grading. Research priority denotes the author’s qualitative assessment of combinations most suitable for near-term investigation, based on evidence maturity and mechanistic complementarity.
Drug Class Mechanistic
Rationale 		Clinical Evidence
for Combination 		Overall
Evidence
Level 		Research
Priority
Metformin (a) Partial AMPK overlap (a) Confirmed: SYMPHONY-2 Phase 3 RCT
(combination benefit shown)		 Confirmed (Phase 3) Highest
GLP-1RA
(semaglutide,
tirzepatide)		 (a) TGR5-GLP-1 non-overlap (b) Preclinical only (ADA 2026);
no human combination RCT
Mechanistic +
Preclinical		 High
Statins (a) LDLR/PCSK9 non-overlap (b) HTD1801 monotherapy signal only;
no combination RCT
Mechanistic +
Preclinical		 High
SGLT2i
(dapagliflozin)		 (b) Downstream convergence (a) HARMONY head-to-head RCT
(comparator only, not combination)
Comparative
only		 Medium
PPAR Agonists
(lanifibranor)		 (b) Partial AMPK- PPAR overlap (c) Each has monotherapy data;
no combination or head-to-head data
Mechanistic
only		 Low
Resmetirom (b) THRβ-mediated pathway, distinct from AMPK/TGR5 (c) No combination or
head-to-head data exist		 No direct evidence Lowest
Abbreviations: ALT, alanine aminotransferase; AMPK, AMP-activated protein kinase; AST, aspartate aminotransferase; BUDCA, berberine ursodeoxycholate; CKM, cardiovascular-kidney-metabolic syndrome; eGFR, estimated glomerular filtration rate; GLP-1, glucagon-like peptide-1; GLP-1RA, glucagon-like peptide-1 receptor agonist; IL-1β, interleukin-1 beta; IL-6, interleukin-6; LDL-C, low-density lipoprotein cholesterol; LDLR, low-density lipoprotein receptor; LOX-1, lectin-like oxidized LDL receptor-1; MASLD, metabolic dysfunction-associated steatotic liver disease; MASH, metabolic dysfunction-associated steatohepatitis; NF-κB, nuclear factor kappa B; NLRP3, NOD-, LRR- and pyrin domain-containing protein 3; PCSK9, proprotein convertase subtilisin/kexin type 9; PPAR, peroxisome proliferator-activated receptor; RCT, randomized controlled trial; SGLT2i, sodium-glucose cotransporter-2 inhibitor; T2DM, type 2 diabetes mellitus; TGR5, Takeda G protein-coupled receptor 5; THRβ, thyroid hormone receptor-β; TNF-α, tumor necrosis factor-alpha; UDCA, ursodeoxycholic acid.
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