Comparison of effectiveness between phentermine/topiramate and liraglutide in obese patients with nonalcoholic fatty liver disease

doi:10.21203/rs.3.rs-4183955/v1

Anti-obesity drugs improve hepatic inflammation in patients with nonalcoholic fatty liver disease (NAFLD). We aimed to compare the effects of phentermine/topiramate and liraglutide in obese NAFLD patients. This retrospective study included 411 obese NAFLD patients (body mass index [BMI] > 25 and detection of fatty liver on ultrasound) who received phentermine/topiramate (n = 303) or liraglutide (n = 108) for more than 12 months. Steatosis was assessed using the hepatic steatosis index (HSI) and controlled attenuation parameter (CAP). Fibrosis was assessed using the fibrosis index based on four factors (FIB-4), the NAFLD fibrosis score (NFS), and liver stiffness (LS). Improvements in steatosis and fibrosis were defined as ≥ 5% decreases in CAP and LS values, respectively, at 12 months compared with baseline values. Values for baseline mean body weight (phentermine/topiramate vs. liraglutide, 82.3 vs. 81.2 kg) and BMI (30.1 vs. 29.8 kg/m²) were similar between the two groups. Both groups showed significant reductions in steatosis (phentermine/topiramate: CAP, 319→290 dB/m; HSI, 40.6→37.0; liraglutide: CAP, 306→286 dB/m; HSI, 40.3→39.3,all p < 0.001) and fibrosis (phentermine/topiramate: NFS, − 2.5→−2.6; LS, 6.7→5.3kpa; liraglutide: NFS, − 2.4→−2.6, LS, 6.0→5.3kpa,all p < 0.05) after 12 months of treatment compared with baseline values. The Phentermine/topiramate group showed significantly greater weight loss and steatosis reduction than the liraglutide group (Δweight, − 7.5 vs. −4.5 kg, p = 0.001; ΔCAP: −29 vs. −8 dB/m,p < 0.001). Phentermine/topiramate treatment was an independent predictor of steatosis improvemement (odds ratio, 3.817;95% confidence interval,1.618–9.006;p = 0.002). Phentermine/topiramate or liraglutide treatment significantly ameliorated liver steatosis and fibrosis, however, phentermine/topiramate treatment resulted in better steatosis improvement.

Health sciences/Diseases

Health sciences/Gastroenterology

fibrosis

liraglutide

nonalcoholic fatty liver disease

phentermine/topiramate

steatosis

Nonalcoholic fatty liver disease (NAFLD) is a highly prevalent disease affecting approximately 25–40% of the general population worldwide.^1,2 The prevalence is higher among patients with metabolic syndrome, obesity, or type 2 diabetes mellitus (T2DM).^3–7 NAFLD comprises a spectrum of pathological conditions ranging from simple steatosis to nonalcoholic steatohepatitis (NASH) and cirrhosis.^8,9 There is a risk of hepatocellular carcinoma (HCC) in each stages of NAFLD.^10,11 Additionally, NAFLD is the most common cause of chronic liver disease in industrialized countries and often constitutes the main causes of liver transplantation.¹²

Considering that obesity, T2DM, and NAFLD share many complex pathogenetic pathways centered around insulin resistance, a recent proposal suggested renaming NAFLD to ‘metabolic-associated steatotic liver disease’.^13,14 Currently, lifestyle modification based on exercise and calorie restriction is the only proven treatment for NAFLD.^15,16 However, most patients with NAFLD maintain their dietary habits and fail to achieve long-term weight loss goals. Therefore, drugs targeting multifaceted pathophysiology of NAFLD are the focus of active investigation. Among them, anti-obesity drugs improve liver inflammation and/or fibrosis by reducing fat mass via weight loss. Glucagon-like peptide-1 receptor agonists (GLP-1 RAs) constitute a class of subcutaneous glucose-lowering drugs initially approved for the treatment of T2DM.¹⁷ Since their introduction, these drugs have also been approved for the treatment of obesity.¹⁸ Several randomized controlled trials have investigated the beneficial effects of these drugs on NASH,¹⁹ with conflicting results. The Liraglutide Efficacy and Action in NASH (LEAN) multicenter, double-blind, placebo-controlled, randomized trial, involving 48 weeks of liraglutide treatment in patients with biopsy-confirmed NASH, showed that liraglutide met the primary endpoint of NASH resolution in 39% of patients.²⁰ Compared with placebo, once-daily administration of the GLP-1 RA semaglutide led to better NASH resolution with no worsening of fibrosis²¹; conversely, once-weekly administration of semaglutide did not lead to significant improvements in fibrosis, nor did it result in NASH resolution.²²

The combination of phentermine and topiramate was approved by the Food and Drug Administration in 2012 as an anti-obesity agent.^22,23 According to a systematic review and meta-analysis of the effects of anti-obesity drugs on weight loss, as well as adverse events associated with those drugs, phentermine/topiramate was associated with the highest odds of achieving at least 5% weight loss among six drugs; it had the third lowest incidence of side effects.²⁴ Although phentermine/topiramate appears to induce greater weight loss than other anti-obesity agents, relevant data are limited regarding improvements in steatosis and fibrosis among NAFLD patients. Moreover, no studies have directly compared the effects of phentermine/topiramate and liraglutide on NAFLD in a real-world setting.

Liver biopsy is regarded as the gold standard for evaluating the endpoints of NAFLD (i.e., NASH resolution and no worsening or improvement of fibrosis). However, liver biopsy can be inaccurate due to sampling error, and it is difficult to obtain consistent results due to significant intra-/inter- observer variation, and repeated measurements are difficult due to its invasive nature.²⁵ Thus, many non-invasive serum biomarkers and radiologic tests have been utilized to evaluate liver steatosis and fibrosis.^16,26 In this study, we utilized the hepatic steatosis index (HSI) and controlled attenuation parameter (CAP) for steatosis assessment; we used the fibrosis index based on four factors (FIB-4), the NAFLD fibrosis score (NFS), and liver stiffness (LS) for fibrosis assessment. We sought to compare the effects of phentermine/topiramate and liraglutide on improvements in steatosis and fibrosis among NAFLD patients in a real-world setting.

Study design and patients

This retrospective observational study included obese NAFLD patients who received either phentermine/topiramate or liraglutide for > 12 consecutive months between January 2012 and March 2022 in CHA Bundang Medical Center, CHA University college of Medicine (Seongnam, Korea). Obesity was defined as a body mass index (BMI) > 25 kg/m².^27,28 NAFLD was defined as fatty liver detection by ultrasound within 6 months of the index date. Patients with chronic liver disease (e.g., viral hepatitis, autoimmune hepatitis, or primary biliary cholangitis) or severe alcohol drinking behavior were excluded, depending on their laboratory test results and medical history. Liraglutide was administrated subcutaneously one daily and increased by 0.6 mg every 7 days from a starting dose of 0.6 mg daily until the maximal dose of 3.0 mg daily was achieved, and maintenance dose was determined at the discretion of the physician. Phentermine/topiramate was administered orally once daily with starting dose of 3.75 mg/23 mg for 2 weeks, and treated with 7.5 mg/46 mg for next 12 weeks, and maintained with either 7.5 mg/46 mg, 11.25 mg/69 mg, or 15 mg/92 mg depending upon the clinical judgement. The exclusion criteria were as follows: (1) age < 19 years, (2) cessation of anti-obesity medication for > 1 month during 12 months of treatment, (3) combination treatment with other anti-obesity medication or herbal treatment for obesity, (4) start of liraglutide for the purpose of treating diabetes rather than treating obesity, (5) lack of laboratory or anthropometric indices necessary for steatosis or fibrosis formula at baseline or at 12 months, and (6) absence of a transient elastography (TE) measurement at baseline or at 12 months. This study was conducted in accordance with the Declaration of Helsinki; the protocol was reviewed and approved by the Institutional Review Board of CHA Bundang Medical Center (IRB no. 2021-10-016). The requirement for informed consent was waived due to the retrospective nature of the analyses.

Data collection and anthropometric measurements

Baseline demographic characteristics, clinical findings, and laboratory data were retrieved from the hospital’s electronic database. Laboratory data included aspartate aminotransferase (AST) level, alanine aminotransferase (ALT) level, serum albumin level, and platelet count. Baseline anthropometric indices (height, body weight [BW], and body fat) were measured using the InBody test. BMI was calculated as weight/height (kg/m²). Anthropometric indices were recorded every 3 months with the InBody test; they were also measured at random intervals depending on the researchers’ judgement. Body fat was automatically calculated during the InBody test. Changes in values were determined by subtracting the value at baseline from the value at the end of treatment (ΔBW = BW at 12 months − BW at baseline).

Outcome measurements

The primary outcomes were improvements in liver steatosis and fibrosis from baseline to the end of treatment. Steatosis was assessed using the HSI and CAP. Fibrosis was assessed using the FIB-4, the fibrosis NFS, and LS.

Baseline steatosis and fibrosis measurements were performed on the same day or within 1 month prior to the initiation of anti-obesity drugs. TE was used to simultaneously acquire LS and CAP values. Specifically, the operator obtained LS and CAP values by positioning the probe on the right lobe of the liver through the intercostal spaces while the patient rested in the dorsal decubitus position with his/her right arm in maximal abduction.²⁹ LS values were expressed in units of kPa; they were considered reliable when ≥ 10 valid shots were recorded, all of which satisfied the interquartile range-to-median ratio of ≤ 0.3. CAP values were expressed in units of dB/m; 10 valid shots were needed for the analysis. Initially, the M probe was used routinely; however, the XL probe was utilized in cases of M probe failure or if the patient’s BMI exceeded 28 kg/m². LS stages were defined according to the following cut-offs: F1 ≥ 5.5 kPa, F2 ≥ 7.5 kPa, F3 ≥ 9.5 kPa, and F4 ≥ 11.0 kPa. CAP stages were classified as S1 ≥ 238 dB/m, S2 ≥ 260 dB/m, and S3 ≥ 330 dB/m. HSI, FIB-4, and NFS were calculated according to the following formulas: HSI < 30.0 (or > 36.0) was used to rule in (out) hepatic steatosis³⁰; FIB-4 < 1.30 (or > 2.67) was considered to rule in (out) advanced fibrosis³¹; NFS <-1.455 (or > 0.676 ) was used to rule in (out) advanced fibrosis.³²

Hepatic steatosis index

HSI = 8 × ALT / AST ratio + BMI (+ 2, if diabetes; +2, if female).

FIB-4

FIB–4 = age (years) × AST [U/L] / (platelets [10⁹/L] × (ALT [U/L])^1/2).

NAFLD fibrosis score

NFS = (–1.675 + 0.037 × age (years) + 0.094 × BMI (kg/m²) + 1.13 × impaired fasting glucose / diabetes (yes = 1, no = 0) + 0.99 × AST / ALT ratio – 0.013 × platelet count (×10⁹/L) – 0.66 × albumin [g/dL])

Improvement in steatosis was defined as a ≥ 5% decrease in CAP value at 12 months compared with baseline. Improvement in fibrosis was defined as a ≥ 5% decrease in LS value at 12 months compared with baseline.

Statistical analysis

Data are presented as mean ± standard deviation, or number (%), as appropriate. Differences among continuous and categorical variables were compared using Student’s t-test and the chi-squared test, respectively. Univariate logistic regression analysis was performed to investigate predictors of improvements in steatosis and fibrosis; odds ratios (ORs) and 95% confidence internals (CIs) were also calculated. Subsequently, multivariate regression analyses were performed to assess independent associations of the univariate predictors and improvements in steatosis and fibrosis, respectively. All statistical analyses were conducted using SPSS software (version 22.0; Chicago, IL, USA) and R software (version 3.2.3; R Foundation for Statistical Computing, Vienna, Austria). Two-sided p-values < 0.05 were considered statistically significant.

Baseline characteristics

Among 523 obese NAFLD patients receiving either liraglutide or phentermine/topiramate for >12 consecutive months who met the eligibility criteria, 112 patients were excluded. Ultimately, 411 patients receiving either liraglutide (n=108) or phentermine/topiramate (n=303) were included in the study (Supplementary Figure 1). The baseline characteristics of the 411 patients are summarized in Supplementary Table 1. The mean age of the patients (301 women and 101 men) was 42.9 years. The mean BMI was 30.0 kg/m2, and 20.7% of the patients had T2DM. The mean HSI and CAP values were 40.535 and 314 dB/m, respectively. The mean FIB-4, NFS, and LS values were 0.885, −2.481, and 6.4 kPa, respectively. The proportion of patients with T2DM was significantly greater in the liraglutide group than in the phentermine/topiramate group (31.5% vs. 16.8%, p=0.002). Other baseline variables were similar between the two groups.

Changes in anthropometric parameters during the 12 months of anti-obesity treatment

Changes in BW, BMI, and body fat over a 3-month interval are depicted in Figure 1. After 12 months of treatment, phentermine/topiramate and liraglutide induced mean weight loss values of 7.5 and 4.5 kg, respectively (Figure 1A). Mean BMI values were reduced by 2.6 kg/m2 in the phentermine/topiramate group and 1.5 kg/m2 in the liraglutide group (Figure 1B). Mean body fat percentage were reduced by 3.7% and 5.4% in the phentermine/topiramate and liraglutide groups, respectively (Figure 1C). Although the greatest weight loss and BMI reduction occurred during the first 3 months of the treatment period in both groups, body fat percentage decreased at a similar rate over the 12-month period.

Changes in steatosis and fibrosis indices during the 12 months of anti-obesity treatment

HSI (40.634→37.080 in phentermine/topiramate; 40.267→39.347 in liraglutide) and CAP values (319→290 dB/m in phentermine/topiramate; 306→286 in liraglutide) continuously decreased during the 12-month treatment period in both groups; the greatest decrease occurred in the first 3 months of treatment (Figure 2A, 2B). NFS (−2.516 → −2.624 in phentermine/topiramate; −2.386 → −2.580 in liraglutide) and LS (6.7→5.3 kPa in phentermine/topiramate; 6.0→5.3 kPa in liraglutide) showed significant decreases from baseline to 12 months at the 3-month interval in both treatment groups (Figure 2C, 2D). The FIB-4 index significantly decreased in the liraglutide group but did not significantly change in the phentermine/topiramate group during the 12 months of treatment (Figure 2E).

Changes in steatosis and fibrosis indices after 12 months of anti-obesity treatment

In the phentermine/topiramate group, the mean BW decreased by −7.5 kg (from 82.3 to 74.8 kg; −9.1%) and the mean BMI decreased by −2.6 kg/m2 (from 30.1 to 27.5 kg/m2; −8.6%) after 12 months (Table 1). Body fat, AST, and ALT values also significantly decreased. HSI (40.634 vs. 37.080; p<0.001) and CAP (319 vs. 290 dB/m; p<0.001) showed significant decreases at 12 months compared with baseline. Although NFS (−2.516 vs. −2.624; p=0.013) and LS (6.7 vs. 5.3 kPa; p<0.001) values were lower at 12 months, the FIB-4 index at 12 months was similar to the baseline value.

In the liraglutide group, the mean BW decreased by −4.5 kg (from 81.2 to 76.7 kg; −5.5%) and the mean BMI decreased by −2.6 kg/m2 (from 29.8 to 28.3 kg/m2; −5.0%) after 12 months (Table 2). Body fat, AST, and ALT values also decreased at 12 months compared with baseline. HSI (40.267 vs. 39.347; p=0.036) and CAP (306 vs. 286 dB/m; p< 0.001) showed significant decreases at 12 months. The FIB-4 index (0.838 vs. 0.717; p<0.001), NFS (−2.386 vs. −2.580; p=0.016), and LS (6.0 vs. 5.3 kPa; p=0.002) values were significantly lower at 12 months.

Comparison of changes according to anti-obesity drugs

Reductions of BW (−7.5 vs. −4.5 kg; p<0.001) and BMI (−2.6 vs. −1.5 kg/m2; p<0.001) from baseline to 12 months were significantly greater in the phentermine/topiramate group than in the liraglutide group (Table 3). Although statistically insignificant, the liraglutide group showed a greater reduction in body fat. Steatosis reduction, as determined by HSI (−3.554 vs. −0.937; p<0.001) or CAP (−29 vs. −8 dB/m; p<0.001), was significantly greater in the phentermine/topiramate group than in the liraglutide group. Fibrosis reduction, as measured by LS (−1.5 vs. −0.5; p=0.024), was significantly greater in the phentermine/topiramate group; however, NFS reduction did not show any difference between the two treatment groups. Fibrosis reduction, as indicated by FIB-4, was only significant in the liraglutide group.

Predictors of improvement in steatosis

Twelve-month steatosis improvement occurred in 66.7% (274/411) of patients. Univariate analysis indicated that ΔBMI, ΔHSI, and treatment group (phentermine/topiramate vs. liraglutide) were associated with steatosis improvement (all p<0.05). In a subsequent multivariate analysis, ΔBMI and Δ HSI were analyzed in a sperate model due to multicollinearity. After adjusting for ΔBMI, phentermine/topiramate treatment was the only predictor of steatosis improvement after 12 months of anti-obesity treatment (OR, 3.647; 95% CI, 1.248–8.586; p=0.024; Table 4). In another multivariable model adjusting for ΔHSI, phentermine/topiramate treatment was also a predictor of steatosis improvement (OR, 2.627; 95% CI, 1.018–7.232; p=0.014; Table 4)

Predictors of improvement in fibrosis

Two-hundred forty-seven (60.1%) patients showed fibrosis improvement at 12 months. Baseline LS value was the only predictor of fibrosis improvement (Table 5).

Safety profiles

Drug-related adverse events (AEs) are listed in Supplementary Table 2; 148 (48.9%) patients in the phentermine/topiramate group and 67 (62.0%) patients in the liraglutide experienced at least one side effect, without a statistical difference in the occurrence rate between groups (p=0.492). Most AEs were manageable, and neither drug caused serious AEs. The most common AEs in the phentermine/topiramate group were paresthesia (20.8%), dry mouth (14.9%), and depression (14.9%); in the liraglutide group, the most common AEs were vomiting (16.7%), nausea (14.8%), and insomnia (11.1%). Paresthesia was significantly more frequent in the phentermine/topiramate group than in the liraglutide group (20.8% vs. 0.9%, p<0.001). Nausea and vomiting were more frequent in the liraglutide group than in the phentermine/topiramate group (all p<0.05). The most common AEs of grade 3 or higher were palpitation in the phentermine/topiramate group and gastrointestinal disturbance in the liraglutide group.

Phentermine/topiramate or liraglutide treatment for 12 months led to significant weight loss and reductions in BMI and body fat in both treatment groups. Subsequently, phentermine/topiramate or liraglutide treatment significantly ameliorated liver steatosis and phentermine/topiramate treatment resulted in better steatosis improvement. Fibrosis markers, as determined by LS and NFS, also showed a significant decrease in both groups; however, the difference between treatment groups was negligible. To our knowledge, this is the first study to compare the effects of phentermine/topiramate and liraglutide on improvements in steatosis and fibrosis among patients with NAFLD in a real-world setting.

In the LEAN study investigating the efficacy of liraglutide in patients with NAFLD, liraglutide provided a mean absolute weight loss of − 5.3 kg and a mean percent weight loss of − 5.5% after 12 months of treatment; these values correspond to − 4.5 kg and − 5.5%, respectively, in our study.²⁰ In the EQUIP study concerning the efficacy of weight loss in morbidly obese patients using phentermine/topiramate, low to top doses of phentermine/topiramate resulted in weight loss values of − 6.7% to − 14.4% after 12 months of treatment.²³ In the current study, mean weight loss of − 9.1% was achieved. Although the baseline characteristics and study settings differed, the present study showed that anti-obesity treatment for 12 months induced a numerically similar degree of weight loss compared with randomized controlled trials. Additionally, our findings are consistent with the results of a meta-analysis, which showed that phentermine/topiramate treatment produced a greater weight loss effect compared with five other anti-obesity drugs including liraglutide.²⁴ The degree of weight loss in NAFLD is regarded as a significantly independent predictor of improvements in steatosis, inflammation, and fibrosis.³³ Therefore, the improvements in steatosis and fibrosis in our study may be associated with the considerable weight reduction effects of the two drugs. The findings that steatosis improvement was more prominent in the phentermine/topiramate group, and that the use of phentermine/topiramate rather than liraglutide was an independent predictor of improvement in steatosis, probably resulted from quantitatively a greater degree of weight reduction in the phentermine/topiramate group.

Thus far, it is unclear whether the benefits of treatment with phentermine/topiramate or liraglutide are direct or mediated by drug-induced weight loss. The beneficial effects of phentermine/topiramate on NAFLD in terms of steatosis, inflammation, and fibrosis improvement (according to studies of liver histology and molecular pathogenesis) have not been determined. Some studies have shown that patients receiving phentermine/topiramate exhibit reduced high-sensitivity C-reactive protein levels and increased insulin-sensitizing adipokine adiponectin.³⁴ Our study is the first to investigate longitudinal changes in liver steatosis and fibrosis improvement during treatment with phentermine/topiramate. The mechanism of action through which GLP-1 RAs influence NAFLD may be multifactorial. Other than effects mediated by BW reduction and improved glycemic control, other pharmacological mechanisms may be involved. In the LEAN study, changes in BW and hemoglobin A1c did not differ between patients who did and did not achieve NASH resolution, suggesting that the hepatic effects of liraglutide are independent of weight loss or improved insulin sensitivity.²⁰ In an animal study, reductions in hepatic steatosis and endoplasmic reticulum oxidative stress occurred regardless of BW loss among mice treated with liraglutide.³⁵ The mechanisms by which GLP-1 RAs ameliorate steatosis and inflammation may include anti-inflammatory and anti-oxidative effects, reduction of the endoplasmic reticulum stress response, and amelioration of hepatocyte apoptosis.^36,37 It remains unclear whether liraglutide contributes to fibrosis regression, and no molecular mechanism has been established. A recent study showed that semaglutide inhibited de novo collagen production in a mouse model, indicating potential prevention of liver fibrosis progression.³⁸ Further research is needed to elucidate the pharmacological mechanisms by which liraglutide and phentermine/topiramate influence improvements in steatosis, inflammation, and fibrosis in NAFLD.

Considering that significant fibrosis regression is anticipated several years after hepatitis C virus eradication or among chronic hepatitis B patients with virological response during antiviral treatment,^39,40 1 year may be insufficient to re-evaluate the fibrosis burden. A longer follow-up period will likely be needed to assess fibrosis regression after weight loss. Because the number of patients with high baseline fibrosis burden (> significant fibrosis; FIB-4 > 2.67, 4.3%; NFS > 0.676, 1.9%; LS > 8 kPa, 14.6%) was small in our study, it was difficult to evaluate fibrosis regression in patients with a higher fibrotic burden. Inevitably, among patients with improved LS, reduced inflammation may have been regarded as fibrosis regression in part. Therefore, future studies should focus on long-term follow-up of additional patients with advanced fibrosis and cirrhosis.

The most common side effects were paresthesia in the phentermine/topiramate group and gastrointestinal disturbance in the liraglutide group. The types and frequencies of AEs were similar to findings in clinical trials.^20,23,34 However, because this study only included patients who tolerated anti-obesity drugs for > 12 months, the actual rates and severities of AEs may have been higher in the entire cohort, including patients who had stopped drugs within 1 year. Among patients who began taking anti-obesity drugs, the proportion who received treatment for > 12 months was very high in the phentermine/topiramate group (Supplementary Fig. 1). The higher compliance rate in the phentermine/topiramate group was presumably related to the convenient administration route (oral vs. subcutaneous) and lower price.

This study had several limitations. First, we did not perform liver biopsies, which are regarded as gold standard to assess changes in steatosis, inflammation, and fibrosis. Second, we did not examine or control for patient exercise habits. Third, we did not investigate indicators of insulin resistance or T2DM. Finally, we did not perform baseline matching between the two treatment groups. The number of patients in each group was very small after matching, and there were no significant differences in baseline characteristics (other than T2DM prevalence) in the raw data set. Despite these limitations, this study is the first to longitudinally present the effects of two anti-obesity medications on improvements in steatosis and fibrosis among patients with NAFLD using non-invasive tests and to provide a comparison between two treatment groups.

Phentermine/topiramate or liraglutide treatment significantly ameliorated liver steatosis and fibrosis; however, phentermine/topiramate treatment resulted in better steatosis improvement. Future long-term follow-up studies are needed to determine whether anti-obesity drugs lead to significant and sustainable improvements in fibrosis in addition to steatosis. Additionally, clarification is needed regarding whether obesity medications contribute to NAFLD improvement through mechanisms other than weight loss.

NAFLD

nonalcoholic fatty liver disease

BMI

body mass index

HIS

hepatic steatosis index

CAP

controlled attenuation parameter

FIB-4

fibrosis index based on four factors

NFS

NAFLD fibrosis score

LS

liver stiffness

T2DM

type 2 diabetes mellitus

NASH

nonalcoholic steatohepatitis

HCC

hepatocellular carcinoma

GLP-1 RA

glucagon-like peptide-1 receptor agonist

TE

transient elastography

AST

aspartate aminotransferase

ALT

alanine aminotransferase

BW

body weight

OR

odds ratio

CI

confidence interval

AE

adverse event.

Author Contribution

1) Young Eun Chon takes responsibility for the integrity of the work, from inception to the published article.2) Specific author contributions: Conception: Sung Jun Park, and Young Eun Chon; Study design: Sung Jun Park, and Young Eun Chon; Contribution to data acquisition: Sung Jun Park, Yeonjung Ha, Joo Ho Lee, Kwank Sik Lee, and Young Eun Chon; Statistical analysis: Sung Jun Park, Yeonjung Ha and Young Eun Chon; Writing papers: Sung Jun Park, and Young Eun Chon.3) All authors have reviewed the paper and approved the final version.

Acknowledgments:

None

Financial support: None

Conflict of interest: None

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Table 1. Clinical characteristics of patients receiving phentermine/topiramate for 12 months (n=303)
Variables	Baseline	End of treatment	P-value
Age, years	43.2 ± 10.9
Male gender	73 (24.1)
Body weight (kg)	82.3 ± 18.4	74.8 ± 16.5	<0.001
Body mass index (kg/m²)	30.1 ± 5.6	27.5 ± 4.8	<0.001
Body fat (%)	38.5 ± 6.7	34.8 ± 7.3	<0.001
Diabetes mellitus	51 (16.8)	53 (17.5)	0.255
Hypertension	52 (17.2)	55 (18.2)	0.153
Dyslipidemia	43 (14.2)	44 (14.5)	0.956
Aspartate aminotransferase (IU/L)	28 ± 20	23 ± 16	<0.001
Alanine aminotransferase (IU/L)	32 ± 31	23 ± 17	<0.001
Serum albumin (g/dL)	4.5 ± 0.3	4.5 ± 0.3	0.417
Platelet count (×10⁹/L)	280 ± 64	277 ± 69	0.170
Hepatic Steatosis Index	40.634 ± 7.531	37.080 ±6.187	<0.001
FIB-4	0.902 ± 0.723	0.923 ± 0.956	0.592
NAFLD fibrosis score	-2.516 ± 1.338	-2.624 ± 1.346	0.013
CAP (dB/m)	319 ± 37	290 ± 38	<0.001
LS (kPa)	6.7 ± 3.7	5.3 ± 2.5	<0.001
Variables are expressed as median (range), mean ± (SD), or n (%).

FIB-4, fibrosis index based on four factors; CAP, controlled attenuation parameter; LS, liver stiffness.

Table 2. Clinical characteristics of patients receiving liraglutide for 12 months (n=108)
Variables	Baseline	End of treatment	P-value
Age, years	42.2 ± 14.0
Male gender	28 (25.9)
Body weight (kg)	81.2 ± 18.5	76.7± 15.7	<0.001
Body mass index (kg/m²)	29.8 ± 4.7	28.3 ± 4.6	<0.001
Body fat (%)	39.6 ± 6.0	34.2 ± 6.5	<0.001
Diabetes mellitus	34 (31.5)	37 (34.3)	0.510
Hypertension	26 (24.1)	27 (25.0)	0.946
Dyslipidemia	21 (19.4)	25 (23.1)	0.705
Aspartate aminotransferase (IU/L)	29 ± 22	21 ± 10	<0.001
Alanine aminotransferase (IU/L)	31 ± 26	23 ± 14	<0.001
Serum albumin (g/dL)	4.5 ± 0.3	4.5 ± 0.3	0.901
Platelet count (×10⁹/L)	275 ± 58	277 ± 62	0.613
Hepatic Steatosis Index	40.267 ± 6.467	39.347 ± 6.546	0.036
FIB-4	0.838 ± 0.419	0.717 ± 0.360	<0.001
NAFLD fibrosis score	-2.386 ± 1.223	-2.580 ± 1.250	0.016
CAP (dB/m)	306 ± 37	286 ± 34	<0.001
LS (kPa)	6.0 ± 2.6	5.3 ± 2.5	0.002
Variables are expressed as median (range), mean ± (SD), or n (%).

FIB-4, fibrosis index based on four factors; CAP, controlled attenuation parameter; LS, liver stiffness.

Table 3. Comparison of changes between baseline and 12 months according to anti-obesity drugs
Changes between baseline and 12 months	Phentermine/topiramate (n=303)	Liraglutide (n=108)	P-value
Body weight (kg)	-7.5 ± 5.9	-4.5 ± 8.8	0.001
Body mass index (kg/m²)	-2.6 ± 2.5	-1.5 ± 3.3	0.001
Body fat (%)	-2.7 ± 7.7	-4.3 ± 6.1	0.048
Aspartate aminotransferase (IU/L)	-5 ± 16	-8 ± 19	0.084
Alanine aminotransferase (IU/L)	-9 ± 24	-9 ± 20	0.852
Serum albumin (g/dL)	0.0 ± 0.3	0.0 ± 0.4	0.670
Platelet count (×10⁹/L)	-3 ± 40	2 ± 39	0.256
Hepatic Steatosis Index	-3.554 ± 4.302	-0.937 ± 4.482	<0.001
FIB-4	0.021 ± 0.673	-0.120 ± 0.314	0.036
NAFLD fibrosis score	-0.021 ± 0.673	-0.196 ± 0.829	0.300
CAP (dB/m)	-29 ± 20	-8 ± 17	<0.001
LS (kPa)	-1.5 ± 3.4	-0.5 ± 1.6	0.024
Variables are expressed as median (range), mean ± (SD), or n (%).

FIB-4, fibrosis index based on four factors; CAP, controlled attenuation parameter; LS, liver stiffness.

Table 4. Predictors of improvement in steatosis after 12 months of treatment
	Univariate			Multivariate 1	Multivariate 2
Variables	P-value	OR (95% CI)	P-value	OR (95% CI)	P-value	OR (95% CI)
Age, years	0.703
Male gender	0.674
Body weight (kg)	0.541
Δ Body weight	0.054
Body mass index (kg/m²)	0.287
Δ Body mass index	0.025	0.829 (0.703−0.977)	0.298	0.794 (0.640−1.273)
Body fat (%)	0.618
Δ Body fat	0.434
Diabetes mellitus	0.881
Hypertension	0.785
Dyslipidemia	0.690
Aspartate aminotransferase (IU/L)	0.760
Δ Aspartate aminotransferase	0.538
Alanine aminotransferase (IU/L)	0.643
Δ Alanine aminotransferase	0.436
Serum albumin (g/dL)	0.063
Δ Serum albumin	0.059
Platelet count (×10⁹/L)	0.613
Δ Platelet count	0.642
Hepatic Steatosis Index	0.736
Δ Hepatic Steatosis Index	0.045	0.907 (0.824−0.998)			0.943	1.042 (0.875−1.231)
FIB-4	0.393
Δ FIB-4	0.77
NAFLD fibrosis score	0.681
CAP (dB/m)	0.245
LS (kPa)	0.333
Δ LS	0.132
Liraglutide vs. phentermine/topiramate	<0.001	4.261 (1.924−9.439)	0.024	3.647 (1.428−8.586)	0.014	2.627 (1.018−7.232)
Variables are expressed as median (range), mean ± (SD), or n (%).
Changes in values were determined by subtracting the value at baseline from the value at the end of treatment
(Δ Body weight = Body weight at 12 months – Body weight at baseline).

Table 5. Predictors of improvement in fibrosis after 12 months of treatment
		Univariate
Variables	P-value		OR (95% CI)
Age, years	0.134
Male gender	0.141
Body weight (kg)	0.934
Δ Body weight	0.560
Body mass index (kg/m²)	0.750
Δ Body mass index	0.114
Body fat (%)	0.628
Δ Body fat	0.944
Diabetes mellitus	0.138
Hypertension	0.326
Dyslipidemia	0.265
Aspartate aminotransferase (IU/L)	0.533
Δ Aspartate aminotransferase	0.346
Alanine aminotransferase (IU/L)	0.556
Δ Alanine aminotransferase	0.935
Serum albumin (g/dL)	0.827
Δ Serum albumin	0.840
Platelet count (×10⁹/L)	0.967
Δ Platelet count	0.473
Hepatic Steatosis Index	0.714
Δ Hepatic Steatosis Index	0.356
FIB-4	0.712
Δ FIB-4	0.185
NAFLD fibrosis score	0.928
CAP (dB/m)	0.635
Δ CAP	0.421
LS (kPa)	<0.001		1.790 (1.313−2.440)
Liraglutide vs. phentermine/topiramate	0.784
Variables are expressed as median (range), mean ± (SD), or n (%).
Changes in values were determined by subtracting the value at baseline from the value at the end of treatment
(Δ Body weight = Body weight at 12 months – Body weight at baseline).

No competing interests reported.

Supplementaryfilesnew.docx

Comparison of effectiveness between phentermine/topiramate and liraglutide in obese patients with nonalcoholic fatty liver disease

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Abstract

Figures

Introduction

Methods

Study design and patients

Data collection and anthropometric measurements

Outcome measurements

Hepatic steatosis index

FIB-4

NAFLD fibrosis score

Statistical analysis

Results

Discussions

Abbreviations

Declarations

Author Contribution

Acknowledgments:

References

Tables

Additional Declarations

Supplementary Files

Status:

Version 1