Efficacy and Safety of Orlistat in Patients With Overweight/Obese and Hyperuricemia: Results of a Randomized, Double-Blind, Placebo-Controlled Trial

doi:10.21203/rs.3.rs-3887291/v1

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Research Article

Efficacy and Safety of Orlistat in Patients With Overweight/Obese and Hyperuricemia: Results of a Randomized, Double-Blind, Placebo-Controlled Trial

https://doi.org/10.21203/rs.3.rs-3887291/v1

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published 11 Mar, 2024

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Background

Obesity is associated with elevated serum uric acid (SUA) and frequent gout flares. Losing weight can lower SUA and reduce gout flares. The effect of orlistat on SUA and gout flares in patients with overweight/obese and hyperuricemia (HUA) has not been extensively studied. In this study, we investigated the effects of orlistat on SUA and gout flares compared to placebo in overweight or obese patients with HUA.

Methods

A total of 72 Chinese patients with overweight/obese and HUA were randomly divided into placebo group and orlistat group for 12 weeks. The primary endpoints were relative changes in body weight and SUA, as well as gout flares.

Results

72 patients with overweight/obesity and HUA were randomly assigned to placebo group (35, 48.61%) and orlistat group (37, 51.39%). Orlistat was associated with a lower proportion of patients with gout flares (log-rank p = 0.023, hazard rate = 0.31, 95% CI 0.11–0.85). There was no significant difference in SUA level between the two groups. The average weight loss of orlistat group was 2.85kg, which was significantly better than that of control group (P < 0.05).

Conclusions

This study is the first to demonstrate that orlistat has no direct effect on SUA levels in patients with overweight/obese and HUA. The value of orlistat as an adjunct therapy to prevent gout flares during weight loss in patients with HUA was emphasized.

Trial registration:

Clinicaltrials.gov NCT05496075

hyperuricemia

orlistat

uric acid

gout flare

Hyperuricemia (HUA) is a metabolic disease caused by abnormal purine metabolism and/or reduced excretion of uric acid in the body. The prevalence of HUA in China is 13.3% at present, and shows a trend of younger people. With the development of society and change of lifestyle, the prevalence of HUA will further increase(1). Elevated serum uric acid (SUA) may be deposited in articular and non-articular structures to form monosodium uric acid crystals, leading to gout flares(2), manifested by sudden onset of joint pain, erythema, fever, swelling, and dysfunction(3). In addition, HUA is closely associated with metabolic syndrome, type 2 diabetes, hypertension, cardiovascular disease, chronic kidney disease, and is an independent risk factor for premature mortality(4–6).

HUA is considered to be a multifactorial chronic disease related to genetic, environmental and metabolic factors(7). It is particularly emphasized that excess body weight as a major risk factor for the high prevalence of HUA. Epidemiological studies have shown that for every 4 unit increase in body mass index (BMI), SUA can increase by 250 µmol/L, and the risk of HUA increases by 7.49 times(8). Animal study has found that obesity promotes increased uric acid production through the hypoxia mechanism of adipocytes(9). The long-term effects of weight loss can help to lower uric acid and relieve gout flares by reducing obesity(10). Given these findings, weight loss is warranted for patients with overweight/obese and HUA.

Orlistat is a potent and irreversible inhibitor of fatty acid synthase that blocks the absorption of triglycerides from the diet(11). Orlistat has been approved by China National Medical Products Administration for the treatment of obese patients. In clinical trials, orlistat has been shown to be effective in improving obesity and related diseases such as metabolic fatty liver disease(12, 13). However, the effect of orlistat on SUA in obese patients remains controversial. In obese patients with metabolic fatty liver disease, there was no significant difference in the change of SUA between the orlistat group and the control group(13, 14). Orlistat combined with Diane-35 significantly reduced SUA in overweight and obese patients with polycystic ovary syndrome, but there was no significant difference compared with Diane-35 alone(15). Orlistat combined with a low-calorie diet (HCD) significantly improved SUA in patients with type 2 diabetes compared to HCD alone(16). In summary, there is no conclusive evidence for the effect of orlistat on SUA. Studies of orlistat in SUA and gout flares in people with overweight/obese and HUA have not been reported and further research is needed.

The primary objective of our study was to prospectively evaluate the exact effect of orlistat on urate-lowering and gout flares in patients with overweight/obesity and HUA to inform clinicians' treatment choices.

Study design

This study was a prospective, double-blind, randomized controlled trial. This study was designed to compare the efficacy of orlistat and placebo in overweight/obese and HUA populations in China. From August 2022 to December 2023, we recruited 72 subjects with overweight/obese and HUA from the Endocrinology and Metabolism Department of Shanghai Tenth People's Hospital, of whom 55 (76.39%) were gout patients. The primary endpoints were relative change in SUA and gout flares from baseline to week 12. Gout flares are defined as patient-reported pain that requires rescue medication based on joint symptoms and the nature of the flare. This was recorded through a patient diary and by the investigator at follow-up. Secondary endpoints included changes in body weight, waist circumference, body fat composition, glucose metabolism, liver enzymes, insulin, C-peptides, lipid biomarkers, liver fat content, and degree of liver fibrosis from baseline to week 12.

Each participants signed an informed consent prior to entering the program. This study conducted in accordance with the Declaration of Helsinki and the Guidelines for Good Clinical Practice. It was approved by the Clinical Research Ethics Committee of the Tenth People's Hospital Affiliated to Tongji University. The study has been registered in ClinicalTrials.gov with the identification code NCT 05496075.

Eligibility

Inclusion criteria: 1) Age from 18 to 65 years; 2) Male patients with HUA; 3) BMI (weight in kilograms divided by the square of the height in meters) ≥ 25.0 kg/m². The definitions of gout and HUA are based on the American College of Rheumatology/European Alliance of Associations for Rheumatology gout classification criteria(17).

Exclusion criteria: 1) had gout flares in the last two weeks; 2) Severe liver dysfunction, ALT or AST ≥ 2.5 times the upper limit of normal; 3) eGFR < 45ml/min/1.73m²; 4) Obesity caused by secondary diseases such as Cushing's syndrome, pituitary and hypothalamic damage; 5) Use drugs associated with obesity, such as tamoxifen and steroid hormones.

Procedures and Randomization

The study consisted of screening period, washout period, treatment period and follow-up period. At screening, patients receiving urate-lowering therapy stopped treatment and underwent a 2-week washout period. Eligible subjects were then randomly assigned to the control and orlistat groups in a 1:1 ratio. Randomization is achieved by computer generated numbers and distributed in opaque sealed envelopes. Subjects in the control and orlistat groups received 120 mg of placebo and orlistat three times a day within one hour after meals, respectively. Patients in both groups were instructed to maintain their diet, exercise, and rest habits for nearly six months.

Follow-up

All participants had a medical history taken at enrollment, including history of HUA, lifestyle habits (smoking, alcohol and drinking sweetened beverages), comorbidities and family history. Subjects underwent face-to-face visits at our center at weeks 0, 4, 8, and 12 for anthropometric parameter measurements (height, weight, waist circumference and blood pressure) and biochemical tests including glucose, uric acid, lipid levels, alanine aminotransferase (ALT), aspartate aminotransferase (AST), γ-glutamate transpeptidase (γ-GT), creatinine, urea, and estimated glomerular filtration rate (eGFR). All laboratory measurements were performed at our department using standard methodologies. In addition, at each visit, the occurrence of adverse events including oil spots and gout flares was asked and assessed. If the participants had a gout flare during follow-up, 0.5-1.5mg colchicine was given over 24 hours depending on the severity of the flare, or additional treatment is provided at the discretion of the investigator. At baseline, all patients had joint ultrasound assessments of the knee, ankle, metatarsophalangeal joints and their associated tendons, and the semi-quantitative OMERACT scoring system was used to assess double contour signs (DC), tophus (larger crystal deposits) and aggregation (smaller crystal deposits). At weeks 0 and 12, controlled attenuation parameter (CAP) and liver stifness measurement (LSM) were performed by a trained operator using FibroScan 502 (Echosens, Paris, France) to assess changes in liver fat content and degree of liver fibrosis. IOI-353 (Yuseong, South Korea) was used to measure the changes in body fat composition.

Statistical analysis

The Kolmogorov-Smirnov test was used to check the distribution of parameters. Continuous variables with normal and non-normal distributions are expressed as mean ± standard deviation and median (quartile), respectively. Categorical variables are expressed as frequency (percentage). The mean of the normally distributed parameters was compared using the unpaired two-sided Student's t test. In other cases, the Mann-Whitney U test was used for comparison between groups. Categorical variables were analysed using Chi-square tests or Fisher precision tests. Bilateral P values < 0.05 was considered statistically significant. To compare the risk of gout flares between the two groups after initiating orlistat or placebo treatment, we recorded the number of gout flares per month. For the first gout flare analysis, follow-up ended at the first of the following events: the occurrence of the first gout flare or the end of the study. A Cox proportional hazard model was used to estimate the hazard ratio (HR) of the first gout flare and its 95%CI during follow-up. The difference between the two groups was compared by log-rank test. All statistical analyses were performed using SAS 9.4.

Baseline characteristics

Of the 72 enrolled participants with overweight/obese and HUA, 37 were randomly assigned to the orlistat group and 35 to the placebo group (Fig. 1). 2 (5.41%) and 7 (20.00%) patients in the orlistat and placebo groups withdraw from the study, respectively. The most common reasons for discontinuation of treatment are loss of follow-up and withdrawal of consent.

At baseline, the results of demography, biochemical test, FibroScan and joint ultrasound results were balanced in both groups. There was no significant difference between the two groups in history of HUA and lifestyle habits (Table 1).

Table 1

Baseline Demographics and Clinical Characteristics.
Characteristics	Total (n = 72)	Placebo (n = 35)	Orlistat (n = 37)
General data
Age at entry study (years)	37.00 (30.00,41.00)	37.00 (33.00,41.00)	37.00 (29.00,41.00)
BMI (kg/m²)	29.36 (28.38,32.39)	29.22 (27.93,31.41)	30.33 (28.77,33.29)
WC (cm)	102.90 (99.63,108.40)	101.50 (98.80,107.80)	103.60 (100.15,111.40)
Body fat (kg)	27.95 (24.55,30.80)	26.20 (24.05,30.65)	28.15 (25.65,31.18)
Body muscle (kg)	59.80 (56.50,66.23)	59.80 (55.90,66.23)	60.10 (56.70,66.98)
Blood chemistry parameters
TC (mmol/L)	5.29 ± 0.92	5.17 ± 0.87	5.41 ± 0.97
HDL (mmol/L)	1.02 ± 0.15	0.99 ± 0.15	1.04 ± 0.16
LDL (mmol/L)	3.48 ± 0.73	3.34 ± 0.68	3.62 ± 0.77
TG (mmol/L)	2.49 ± 1.09	2.47 ± 0.94	2.52 ± 1.23
Glucose (mmol/L)	5.09 ± 0.49	5.09 ± 0.49	5.09 ± 0.50
HbA1c (%)	5.50 (5.20,5.80)	5.40 (5.18,5.80)	5.50 (5.30,5.90)
FINS (uU/ml)	19.96 (14.81,31.00)	19.50 (13.18,31.00)	21.68 (14.98,33.81)
Fasting C peptide (ng/ml)	3.51 (2.68,4.93)	3.42 (2.64,4.71)	3.55 (2.71,5.03)
HOMA-IR	3.15 (1.64,6.37)	2.86 (1.66,6.19)	3.78 (1.64,6.40)
ALT (U/L)	55.11 ± 33.04	52.82 ± 35.89	57.33 ± 30.35
AST (U/L)	25.20 (19.30,36.20)	20.50 (18.28,34.55)	29.60 (21.65,37.20)
e-GFR (ml/min/1.73m2)	109.85 (93.95,115.13)	105.70 (93.5,115.2)	111.50 (94.05,116.90)
Creatinine (µmol/L)	77.00 (73.00,88.00)	80.00 (76.00,89.00)	75.50 (71.00,84.75)
Urea (mmol/L)	4.45 ± 1.08	4.36 ± 1.22	4.54 ± 0.93
Uric acid (mg/dl)	9.52 ± 1.60	9.51 ± 1.51	9.53 ± 1.81
FibroScan
E (kPa)	5.40 (4.60,6.90)	5.25 (4.60,6.18)	5.50 (4.65,7.65)
CAP (dB/m)	367.00 (316.00,385.00)	341.50 (309.00,382.50)	372.00 (334.00,386.50)
Joint ultrasound
Aggregates	3.67 ± 3.88	3.61 ± 3.90	3.73 ± 3.91
Double contour sign	1.15 ± 2.67	1.10 ± 2.68	1.20 ± 2.71
Tophus	1.15 ± 2.99	1.13 ± 3.00	1.17 ± 3.04
History of HUA
Duration of HUA (years)	6.00 (3.00,10.00)	6.00 (3.00,13.00)	5.50 (2.25,9.75)
The highest uric acid before (µmol/L)	628.01 ± 93.97	630.03 ± 94.57	626.22 ± 94.74
Patients with gout	55 (76.39%)	26 (74.29%)	29 (78.38%)
Duration of gout (years)	5.00 (2.00,13.00)	6.00 (2.00,13.00)	5.00 (2.00,11.00)
The number of gout flares before treatment 1 year (times)	1.00 (1.00,3.00)	1.00 (1.00,3.00)	1.00 (1.00,3.00)
Smoke
No	49 (68.06%)	24 (68.57%)	25 (67.57%)
Yes	23 (31.94%)	11 (31.43%)	12 (32.43%)
Alcohol
No	40 (55.56%)	20 (57.14%)	20 (54.05%)
Yes	32 (44.44%)	15 (42.86%)	17 (45.95%)
Sweet drinks
No	26 (36.11%)	12 (34.29%)	14 (37.84%)
Occasionally	31 (43.06%)	15 (42.86%)	16 (43.24%)
Yes	15 (20.83%)	8 (22.86%)	7 (18.92%)
BMI, body mass index; WC, waist circumference; TC, total cholesterol; HDL, high- density lipoprotein cholesterol; LDL, low-density lipoprotein cholesterol; TG, triglyceride; HbA1c, glycosylated hemoglobin A1c; FINS, fasting insulin; HOMA-IR, homeostasis model assessment of insulin resistance; ALT, alanine aminotransferase; AST, aspartate aminotransferase; e-GFR, estimated glomerular filtration rate; HUA, hyperuricemia.

The average BMI ranged from 29.22 to 30.33kg/m². The mean baseline uric acid was 9.51 to 9.53mg/dl. The mean duration of HUA in each group was 5.5 to 6.0 years. There were 26 (74.29%) and 29 (78.38%) patients with gout in the two groups, respectively (Table 1).

Effect on gout flares

The proportion of patients with gout in the two groups was comparable in the total population and in patients who completed follow-up, ranging from 74.29–78.38%. The average duration of gout ranged from 5.0 to 6.0 years, the average frequency of gout flares in the year prior to enrollment was 1 episode/year, and the mean score of tophus was between 1.13 and 1.17 (Table 1, Table 2).

Table 2

Secondary efficacy endpoints.
Variables	Total (n = 63 )	Placebo (n = 28)	Orlistat (n = 35)	p
General data
Weight (kg)	-1.92 ± 2.59	-0.76 ± 2.37	-2.85 ± 2.37	0.001
BMI (kg/m²)	-0.63 ± 0.83	-0.25 ± 0.75	-0.95 ± 0.77	0.001
WC (cm)	-1.98 ± 2.67	-0.75 ± 2.60	-2.97 ± 2.32	0.001
Body fat (kg)	-1.39 ± 2.11	-0.19 ± 1.69	-2.30 ± 1.95	<0.001
Body muscle (kg)	-0.42 ± 0.89	-0.09 ± 0.87	-0.67 ± 0.83	0.021
Patients with gout	49 (77.78%)	21 (75.00%)	27 (77.14%)	0.843
Blood chemistry parameters
Glucose (mmol/L)	-0.06 ± 0.50	-0.03 ± 0.48	-0.07 ± 0.53	0.776
HbA1c (%)	0.00 (-0.20,0.10)	0.00 (-0.10,0.19)	-0.10 (-0.30,0.10)	0.259
HDL (mmol/L)	-0.05 ± 0.13	0.01 ± 0.13	-0.09 ± 0.10	0.002
LDL (mmol/L)	-0.24 (-0.61,0.21)	0.18 (-0.40,0.44)	-0.55 (-0.67, -0.14)	<0.001
TC (mmol/L)	-0.39 ± 0.75	-0.10 ± 0.64	-0.61 ± 0.76	0.012
TG (mmol/L)	-0.17 (-0.82,0.26)	-0.31 (-0.81,0.13)	-0.14 (-1.11,0.56)	0.268
ALT (U/L)	-4.50 (-21.50,5.00)	-0.85 (-8.33,6.78)	-12.00 (-23.85,2.85)	0.083
AST (U/L)	-1.20 (-7.30,3.20)	0.20 (-2.35,4.20)	-2.80 (-7.85,1.35)	0.172
Urea (mmol/L)	0.20 (-0.40,0.80)	0.30 (-0.43,0.83)	0.10 (-0.35,0.75)	0.609
Creatinine (µmol/L)	0.03 ± 7.38	0.05 ± 7.02	-0.01 ± 7.75	0.983
e-GFR (ml/min/1.73m²)	0.38 ± 9.08	5.03 ± 22.52	0.50 ± 10.44	0.390
FINS (uU/ml)	-3.01 (-7.02,0.72)	-2.34 (-7.89,0.99)	-3.08 (-7.24,1.14)	0.856
Fasting C peptide (ng/ml)	-0.59 (-1.35, -0.10)	-0.60 (-1.00, -0.090)	-0.55 (-1.79, -0.07)	0.980
FibroScan
E (kPa)	-0.57 ± 1.34	-0.12 ± 0.90	-0.88 ± 1.52	0.029
CAP (dB/m)	-21.29 ± 32.66	-7.86 ± 36.82	-30.39 ± 26.42	0.013

During the study period, orlistat was associated with a lower percentage of patients with gout flares (log-rank p = 0.023, HR = 0.31, 95% CI 0.11–0.85; Fig. 2a) in total participants and a lower percentage of patients with recurrent gout flares in participants with gout (log-rank p = 0.012, HR = 0.27, 95% CI 0.10–0.75; Fig. 2b). Gout flares were reported and recorded by the investigator. Gout flares are mostly mild or moderate in severity. A total of 11 (39.29%) in the control group had gout flares, compared with 5 (14.28%) in the orlistat group. The proportion of patients with gout flares per month in the total population over time is shown in Fig. 2c. All of those gout flares occurred in patients with gout, and the proportion of patients with recurrent gout flares per month in the participants with gout is shown in Fig. 2d.

Changes in SUA level

During the study period, there was no significant change in SUA in either the orlistat group or the placebo group. There was no difference in the pattern of SUA change between the two groups (p _time >0.05, p _group*time >0.05) whether in total participants (Fig. 3a) or in participants with gout (Fig. 3b). Among all participants, the changes in SUA levels in the orlistat group at 4, 8, and 12 weeks after treatment were − 0.26, 0.16, and − 0.10mg/dl, respectively. The placebo group was 0.11, 0.12, and 0.23mg/dl, respectively. There was no significant difference in changes in SUA levels between the two groups (Fig. 3c). In participants with gout, there was also no significant difference in changes in SUA levels between the two groups (Fig. 3d).

Changes in obesity and metabolic markers

During the follow-up period, anthropometric indicators showed a downward trend in orlistat group (Tables 2 and Fig. 4). Among these measures, patients in the orlistat group showed greater improvement in body weight, BMI, waist circumference, and body fat content at week 12 compared with those in the placebo group (Fig. 4). In addition, the orlistat group also showed significant improvements in lipid metabolism, liver fat content and liver fibrosis. Absolute changes in biological measures, including liver function, kidney function and glucose metabolism, did not differ over time (Table 2).

Safety

Adverse events and the patient's mental and physical condition were recorded by investigator at each visit. In the orlistat group, 10 (27.03%) participants experienced oil spots, 4 (10.81%) participants experienced mild diarrhea, and 2 (5.41%) participants experienced tolerable loss of appetite and abdominal distension. 2 (5.41%) participants dropped out due to the negative impact of steatorrhea on work and life. No other adverse events were reported in the placebo group except for gout flares (Table S1).

This prospective, randomized, double-blind, controlled study shows that orlistat reduces the rate of gout recurrence in patients with gout. Orlistat was associated with a lower percentage of patients with gout flares (log-rank p = 0.023, HR = 0.31, 95% CI 0.11–0.85) in total participants. In contrast, neither group showed a significant advantage in lowering SUA. As expected, Orlistat group was better than placebo group in improving anthropometric indicators such as body weight, waist circumference, body fat content, lipid metabolism, liver fat content and liver fibrosis.

In the study, patients with overweight/obese and HUA treated with orlistat lost an average of 2.85kg of body weight over a 3-month period, which was significantly higher than that of the control group. This is consistent with previous findings (12, 13).

Obesity has been shown to be associated with increased flares of gout(18), while weight loss can reduce the frequency of gout flares(19). For example, gout patients who lost 7.7 kg of weight through diet management reduced the frequency of gout flares from 2.1 to 0.6 per month(20). Gout patients who underwent bariatric surgery also had significantly lower rates of gout flares one year after surgery(21). In our study, the proportion of patients with gout was similar between the two groups, and the duration of gout, the frequency of gout flares in the year prior to enrollment, and the joint ultrasound signs were all comparable at baseline. However, during the 12-week follow-up, the rate of gout recurrence was significantly lower in the orlistat group than in the control group. This may be because the weight-loss effect of orlistat reduces the frequency of gout flares. In addition, there was a significant decrease in LDL in the orlistat group, which may also account for the lower rate of gout flares. Because previous studies have shown that high LDL is associated with frequent flares of gout(22).

In addition, gout flares are often induced in obese patients in the early stage of weight loss (21, 23). Recurrent gout flares often cause patients to lose confidence in the current treatment, make it difficult to adhere to the treatment, and are not conducive to long-term weight loss. But this phenomenon was not seen in the study. This may be due to orlistat improving the inflammatory response in the body, which suppresses gout flares. There are currently no known direct studies on the effect of orlistat on gout flares. But orlistat has been shown to reduce the body's inflammatory response. In obese rats, orlistat not only has a favorable effect on antioxidant enzymes, but also reduces lipid peroxidation levels, thus alleviating oxidative stress. Moreover, it can inhibit nuclear factor kappa-B, which mediates inflammation, and improve endothelial dysfunction(24). In Polycystic ovarian syndrome (PCOS) rats, orlistat can restore the disturbed metabolism of linoleic acid, arachidonic acid, galactose and glycerol, and thus improve the chronic inflammation in PCOS rats(25). Orlistat has been shown to inhibit the progression of myocardial damage in obese rats by improving oxidative stress, inhibiting the NF-κβ pathway, and caspase-dependent apoptosis(26). Moreover, in obese mice with severe acute pancreatitis, orlistat alleviates adipose tissue necrosis by inhibiting the NLRP3-caspase1 inflammasome pathway of adipose tissue macrophages(27). Activation of the NLRP3 inflammasome also plays a crucial role in the acute symptoms of gout, which leading to the release of IL-1β and other pro-inflammatory cytokines(28). Therefore, Orlistat is likely to reduce the inflammatory response in obese gout patients, thereby suppressing gout flares. The inhibition of gout flares by orlistat during weight loss could be an adjunctive treatment option for obese gout patients to help reduce gout flares induced in the early stages of weight loss.

Weight loss is thought to be directly related to urate-lowering. Therapeutic lifestyle changes and bariatric surgery have both been shown to significantly lower SUA(29). But the effect of orlistat on SUA has been an unresolved and controversial issue in patients with HUA. Our results showed that patients treated with orlistat had an average reduction in SUA levels of 0.10 mg/dl after losing 2.85 kg of weight at 3 months, which is consistent with the dose-response relationship of changes in SUA levels with body weight in other studies(10). Our study demonstrates for the first time that orlistat has no significant urate-lowering effect in patients with overweight/obese and HUA. This may be due to the limited weight loss of orlistat, which is not enough to lower SUA. Orlistat inhibits only about 30% of dietary fat absorption. In 1 year, only 2–5 kg of weight can be lost(30), which is far from the goal of achieving a healthy weight for large weight people.

The study has several advantages. First, we prospectively identified for the first time that orlistat has no direct effect on SUA in overweight/obese patients with HUA. Second, we provide evidence for the potential of orlistat as an adjuvant therapy for the early stages of weight loss. There are several limitations to the study. First, the study period was not long enough to capture the effects of orlistat on weight loss, uric acid-lowering, and gout flares over a longer study period. Second, we included only male patients with HUA and were unable to compare the combined effect of orlistat between male and female patients while excluding gender differences in the results.

In summary, this prospective randomized controlled study demonstrated for the first time that orlistat has no direct effect on SUA levels in patients with overweight/obese and HUA. In addition, we found that orlistat was associated with a lower rate of recurrent gout flare during weight loss, suggesting that orlistat may be used as an adjunctive therapy in the early stage of weight loss. Further pathophysiological mechanism studies are needed to provide sufficient evidence.

Data availability statement

All data generated or analysed during this study are available from the corresponding authors on reasonable request.

Competing interests

The authors declare that they have no conflict of interest.

Funding

This research was funded by the Key Technologies Research and Development Program [grant number: 2019YFA0904500], National Key Research and Development Program of China [2022YFC2503300], and the National Natural Science Foundation of China [grant numbers: 81870606,82170904].

Author’s contribution

Conceptualization, Shuang Liu; Formal analysis, Shuang Liu and Yali Han; Funding acquisition, Haibing Chen; Investigation, Shuang Liu, Xiaojing Lin, Hang Sun, Shaoling Yang and Yining Gao; Methodology, Shuang Liu and Qi Chen; Project administration, Haibing Chen; Software, Shuang Liu and Yali Han; Supervision, Shen Qu and Haibing Chen; Visualization, Shuang Liu; Writing – original draft, Shuang Liu; Writing – review & editing, Shuang Liu and Haibing Chen.

Acknowledgements

We thank the trial staff as well as all people who agreed to participate in this study.

Ethics approval

This study was approved by the Ethics Committee of Shanghai Tenth People's Hospital. It was conducted in accordance with the Declaration of Helsinki and the Guidelines for Good Clinical Practice.

Informed Consent

All participants gave written informed consent before taking part in the study.

Liu R, Han C, Wu D, Xia X, Gu J, Guan H, et al. Prevalence of Hyperuricemia and Gout in Mainland China from 2000 to 2014: A Systematic Review and Meta-Analysis. Biomed Res Int. 2015;2015:762820.
Dalbeth N, Gosling AL, Gaffo A, Abhishek A, Gout. Lancet. 2021;397(10287):1843–55.
Klück V, Jansen T, Janssen M, Comarniceanu A, Efdé M, Tengesdal IW, et al. Dapansutrile, an oral selective NLRP3 inflammasome inhibitor, for treatment of gout flares: an open-label, dose-adaptive, proof-of-concept, phase 2a trial. Lancet Rheumatol. 2020;2(5):e270–e80.
Si K, Wei C, Xu L, Zhou Y, Lv W, Dong B, et al. Hyperuricemia and the Risk of Heart Failure: Pathophysiology and Therapeutic Implications. Front Endocrinol (Lausanne). 2021;12:770815.
Yokose C, McCormick N, Choi HK. The role of diet in hyperuricemia and gout. Curr Opin Rheumatol. 2021;33(2):135–44.
Lee SJ, Oh BK, Sung KC. Uric acid and cardiometabolic diseases. Clin Hypertens. 2020;26:13.
Nakayama A, Matsuo H, Nakaoka H, Nakamura T, Nakashima H, Takada Y, et al. Common dysfunctional variants of ABCG2 have stronger impact on hyperuricemia progression than typical environmental risk factors. Sci Rep. 2014;4:5227.
Palmer TM, Nordestgaard BG, Benn M, Tybjærg-Hansen A, Davey Smith G, Lawlor DA, et al. Association of plasma uric acid with ischaemic heart disease and blood pressure: mendelian randomisation analysis of two large cohorts. BMJ. 2013;347:f4262.
Tsushima Y, Nishizawa H, Tochino Y, Nakatsuji H, Sekimoto R, Nagao H, et al. Uric acid secretion from adipose tissue and its increase in obesity. J Biol Chem. 2013;288(38):27138–49.
Zhu Y, Zhang Y, Choi HK. The serum urate-lowering impact of weight loss among men with a high cardiovascular risk profile: the Multiple Risk Factor Intervention Trial. Rheumatology (Oxford). 2010;49(12):2391–9.
Schcolnik-Cabrera A, Chávez-Blanco A, Domínguez-Gómez G, Taja-Chayeb L, Morales-Barcenas R, Trejo-Becerril C, et al. Orlistat as a FASN inhibitor and multitargeted agent for cancer therapy. Expert Opin Investig Drugs. 2018;27(5):475–89.
Valladales-Restrepo LF, Sánchez-Ramírez N, Usma-Valencia AF, Gaviria-Mendoza A, Machado-Duque ME, Machado-Alba JE. Effectiveness, persistence of use, and safety of orlistat and liraglutide in a group of patients with obesity. Expert Opin Pharmacother. 2023;24(4):535–43.
Feng X, Lin Y, Zhuo S, Dong Z, Shao C, Ye J, et al. Treatment of obesity and metabolic-associated fatty liver disease with a diet or orlistat: A randomized controlled trial. Am J Clin Nutr. 2023;117(4):691–700.
Ye J, Wu Y, Li F, Wu T, Shao C, Lin Y, et al. Effect of orlistat on liver fat content in patients with nonalcoholic fatty liver disease with obesity: assessment using magnetic resonance imaging-derived proton density fat fraction. Th Adv Gastroenterol. 2019;12:1756284819879047.
Song J, Ruan X, Gu M, Wang L, Wang H, Mueck AO. Effect of orlistat or metformin in overweight and obese polycystic ovary syndrome patients with insulin resistance. Gynecol Endocrinol. 2018;34(5):413–7.
Didangelos TP, Thanopoulou AK, Bousboulas SH, Sambanis CL, Athyros VG, Spanou EA, et al. The ORLIstat and CArdiovascular risk profile in patients with metabolic syndrome and type 2 DIAbetes (ORLICARDIA) Study. Curr Med Res Opin. 2004;20(9):1393–401.
Neogi T, Jansen TL, Dalbeth N, Fransen J, Schumacher HR, Berendsen D, et al. 2015 Gout classification criteria: an American College of Rheumatology/European League Against Rheumatism collaborative initiative. Ann Rheum Dis. 2015;74(10):1789–98.
Bajpai R, Muller S, Mallen C, Watson L, Richette P, Hider SL, et al. Onset of comorbidities and flare patterns within pre-existing morbidity clusters in people with gout: 5-year primary care cohort study. Rheumatology (Oxford). 2021;61(1):407–12.
Danve A, Sehra ST, Neogi T. Role of diet in hyperuricemia and gout. Best Pract Res Clin Rheumatol. 2021;35(4):101723.
Dessein PH, Shipton EA, Stanwix AE, Joffe BI, Ramokgadi J. Beneficial effects of weight loss associated with moderate calorie/carbohydrate restriction, and increased proportional intake of protein and unsaturated fat on serum urate and lipoprotein levels in gout: a pilot study. Ann Rheum Dis. 2000;59(7):539–43.
Romero-Talamás H, Daigle CR, Aminian A, Corcelles R, Brethauer SA, Schauer PR. The effect of bariatric surgery on gout: a comparative study. Surg Obes Relat Dis. 2014;10(6):1161–5.
Uhlig T, Karoliussen LF, Sexton J, Kvien TK, Haavardsholm EA, Hammer HB. Lifestyle factors predict gout outcomes: Results from the NOR-Gout longitudinal 2-year treat-to-target study. RMD Open. 2023;9(4).
Kang EH, Lee EY, Lee YJ, Song YW, Lee EB. Clinical features and risk factors of postsurgical gout. Ann Rheum Dis. 2008;67(9):1271–5.
Hamza RZ, Alsolami K. Ameliorative effects of Orlistat and metformin either alone or in combination on liver functions, structure, immunoreactivity and antioxidant enzymes in experimentally induced obesity in male rats. Heliyon. 2023;9(8):e18724.
Yang J, Wang E, Chen W, Xu B, Chen C, Zhang G, et al. TMT-Based Proteomics Analysis of the Intervention Effect of Orlistat on Polycystic Ovary Syndrome Rats Induced by Letrozole Combined with a High-Fat Diet. ACS Omega. 2023;8(28):24831–40.
Othman ZA, Zakaria Z, Suleiman JB, Mustaffa KMF, Jalil NAC, Wan Ghazali WS et al. Orlistat Mitigates Oxidative Stress-Linked Myocardial Damage via NF-κβ- and Caspase-Dependent Activities in Obese Rats. Int J Mol Sci. 2022;23(18).
Xu T, Sheng L, Guo X, Ding Z. Free Fatty Acid Increases the Expression of NLRP3-Caspase1 in Adipose Tissue Macrophages in Obese Severe Acute Pancreatitis. Dig Dis Sci. 2022;67(6):2220–31.
So AK, Martinon F. Inflammation in gout: mechanisms and therapeutic targets. Nat Rev Rheumatol. 2017;13(11):639–47.
Chalès G. How should we manage asymptomatic hyperuricemia? Joint Bone Spine. 2019;86(4):437–43.
Ballinger A, Peikin SR. Orlistat: its current status as an anti-obesity drug. Eur J Pharmacol. 2002;440(2–3):109–17.

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Efficacy and Safety of Orlistat in Patients With Overweight/Obese and Hyperuricemia: Results of a Randomized, Double-Blind, Placebo-Controlled Trial

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Introduction

Patients and Methods

Study design

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Procedures and Randomization

Follow-up

Statistical analysis

Results

Baseline characteristics

Effect on gout flares

Changes in SUA level

Changes in obesity and metabolic markers

Safety

Discussion

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