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LLF580, an FGF21 Analog, Reduces Triglycerides and Hepatic Fat in Obese Adults With Modest Hypertriglyceridemia.
Rader, DJ, Maratos-Flier, E, Nguyen, A, Hom, D, Ferriere, M, Li, Y, Kompa, J, Martic, M, Hinder, M, Basson, CT, et al
The Journal of clinical endocrinology and metabolism. 2022;(1):e57-e70
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Abstract
PURPOSE To evaluate the safety and potential efficacy of LLF580, a genetically engineered variant of human fibroblast growth factor-21, for triglyceride lowering, weight loss, and hepatic fat reduction. METHODS A multicenter, double-blind, parallel design trial in obese, mildly hypertriglyceridemic adults randomized (1:1) to LLF580 300 mg or placebo subcutaneously every 4 weeks for 3 doses. RESULTS Of 64 randomized study participants, 61 (mean ± SD: age 45 ± 11 years, 49% male, 80/15/5% Caucasian/African American/other, body mass index 36.1 ± 3.8 kg/m2) received LLF580 (n = 30) or placebo (n = 31) at 7 research sites in the United States. LLF580 lowered serum triglycerides by 54% (least square mean placebo adjusted change from baseline), total cholesterol 7%, low-density lipoprotein cholesterol 12%, and increased high-density lipoprotein cholesterol 36% compared with placebo (all P < 0.001) over 12 weeks. Substantial reduction of liver fat of 52% over placebo (P < 0.001) was also demonstrated in the setting of improved liver function tests including alanine aminotransferase, aspartate aminotransferase, and alkaline phosphatase, the composite enhanced liver fibrosis score, and N-terminal type III collagen propeptide (all P < 0.05). Insulin and C-peptide levels and insulin resistance by homeostatic model assessment for insulin resistance were all lower, and adiponectin higher with LLF580 treatment compared with placebo, whereas fasting glucose and glycated hemoglobin were unchanged. Reductions in biomarkers of bone formation without differences in markers of bone resorption were observed. LLF580 was generally safe and well tolerated, except for higher incidence of generally mild to moderate gastrointestinal adverse effects. CONCLUSIONS In obese, mildly hypertriglyceridemic adults, LLF580 was generally safe and demonstrated beneficial effects on serum lipids, liver fat, and biomarkers of liver injury, suggesting it may be effective for treatment of select metabolic disorders including hypertriglyceridemia and nonalcoholic fatty liver disease. Assessments of longer term safety and efficacy are warranted. CLINICALTRIALS.GOV IDENTIFIER NCT03466203.
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Omega-3 fatty acids for treatment of non-alcoholic fatty liver disease: design and rationale of randomized controlled trial.
Janczyk, W, Socha, P, Lebensztejn, D, Wierzbicka, A, Mazur, A, Neuhoff-Murawska, J, Matusik, P
BMC pediatrics. 2013;:85
Abstract
BACKGROUND Non-alcoholic fatty liver disease (NAFLD) is a liver manifestation of metabolic syndrome since obesity and insulin resistance are the main pathogenic contributors for both conditions. NAFLD carries increased risk of atherosclerosis and cardiovascular diseases. There is an urgent need to find effective and safe therapy for children and adults with NAFLD. Data from research and clinical studies suggest that omega-3 fatty acids may be beneficial in metabolic syndrome-related conditions and can reduce the risk of cardiovascular disease. METHODS/DESIGN We are conducting a randomized, multicenter, double-blind, placebo-controlled trial of treatment with omega-3 fatty acids in children with NAFLD. Patients are randomized to receive either omega-3 fatty acids containing docosahexaenoic acid (DHA) and eicosapentaenoic acid (EPA) or placebo for 24 weeks. The dose of omega-3 (DHA+ EPA) ranges from 450 to 1300 mg daily. Low calorie diet and increased physical activity are advised and monitored using validated questionnaires. The primary outcome of the trial is the number of patients who decreased ALT activity by ≥ 0,3 of upper limit of normal. The main secondary outcomes are improvement in the laboratory liver tests, liver steatosis on ultrasound, markers of insulin resistance and difference in fat/lean body mass composition after 6 months of intervention. DISCUSSION Potential efficacy of omega-3 fatty acids in the treatment of NAFLD will provide needed rationale for use of this safe diet supplement together with weight reduction therapy in the growing population of children with NAFLD. TRIAL REGISTRATION NCT01547910.
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Pioglitazone versus vitamin E versus placebo for the treatment of non-diabetic patients with non-alcoholic steatohepatitis: PIVENS trial design.
Chalasani, NP, Sanyal, AJ, Kowdley, KV, Robuck, PR, Hoofnagle, J, Kleiner, DE, Unalp, A, Tonascia, J, ,
Contemporary clinical trials. 2009;(1):88-96
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BACKGROUND Non-alcoholic steatohepatitis (NASH) is a common liver disease associated with obesity and diabetes. NASH is a progressive disorder that can lead to cirrhosis and liver failure. Insulin resistance and oxidative stress are thought to play important roles in its pathogenesis. There is no definitive treatment for NASH. OBJECTIVES PIVENS is conducted to test the hypotheses that treatment with pioglitazone, a thiazolidinedione insulin sensitizer, or vitamin E, a naturally available antioxidant, will lead to improvement in hepatic histology in non-diabetic adults with biopsy proven NASH. DESIGN PIVENS is a randomized, multicenter, double-masked, placebo-controlled trial to evaluate whether 96 weeks of treatment with pioglitazone or vitamin E improves hepatic histology in non-diabetic adults with NASH compared to treatment with placebo. Before and post-treatment liver biopsies are read centrally in a masked fashion for an assessment of steatohepatitis and a NAFLD Activity Score (NAS) consisting of steatosis, lobular inflammation, and hepatocyte ballooning. The primary outcome measure is defined as either an improvement in NAS by 2 or more in at least two NAS features, or a post-treatment NAS of 3 or less, and improvement in hepatocyte ballooning by 1 or more, and no worsening of fibrosis. METHODS PIVENS enrollment started in January 2005 and ended in January 2007 with 247 patients randomized to receive either pioglitazone (30 mg q.d.), vitamin E (800 IU q.d.), or placebo for 96 weeks. Participants will be followed for an additional 24 weeks after stopping the treatment. The study protocol incorporates the use of several validated questionnaires and specimen banking. This protocol was approved by all participating center Institutional Review Boards (IRBs) and an independent Data and Safety Monitoring Board (DSMB) which was established for monitoring the accumulated interim data as the trial progresses to ensure patient safety and to review efficacy as well as the quality of data collection and overall study management. (ClinicalTrials.gov number, NCT00063622).
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Efficacy and safety of very-low-calorie diet in Taiwanese: a multicenter randomized, controlled trial.
Lin, WY, Wu, CH, Chu, NF, Chang, CJ
Nutrition (Burbank, Los Angeles County, Calif.). 2009;(11-12):1129-36
Abstract
OBJECTIVE Very-low-calorie diets (VLCDs) are an effective method for weight reduction in Caucasians. This study investigated the efficacy and safety of two different VLCDs (450 or 800kcal/d) in obese Taiwanese. METHODS 132 participants with BMI > or =30kg/m(2) were randomized to two VLCD groups for body weight reduction for 12 weeks. Each group had 66 participants. Anthropometric and metabolic parameters were measured. RESULTS The intention-to-treat analysis revealed that the percentage change in body weight over the 12-week treatment period was -9.14% in the VLCD-450 group and -8.98% in the VLCD-800 group. A total of 27 (40.9%) participants in the VLCD-450 group and 29 (43.9%) participants in the VLCD-800 group achieved 10% or more weight loss at the end of treatment. The body weight, waist circumference, hip circumference, fat mass, blood pressure, triglycerides, and blood glucose were statistically improved from baseline but not between the two groups. The improvement rate of nonalcoholic fatty liver disease (NAFLD) was 41.5% in the VLCD-450 group and 50.0% in the VLCD-800 group. The incidence of adverse events did not differ significantly between the groups and no serious adverse events were reported in either group. CONCLUSION Both the VLCD-450 and 800kcal/d can effectively and safely reduce body weight and improve NAFLD in 12 weeks in obese Taiwanese participants. However, there is no additional benefit in prescribing the more restrictive diet intervention in Taiwanese.
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Effectiveness of Danning Tablet in patients with non-alcoholic fatty liver of damp-heat syndrome type: a multicenter randomized controlled trial.
Ji, G, Fan, JG, Chen, JJ, Lu, LG, Xing, LJ, Zheng, PY, Gu, HG, Wei, HF, You, SF, Zhu, PT
Zhong xi yi jie he xue bao = Journal of Chinese integrative medicine. 2008;(2):128-33
Abstract
OBJECTIVE To evaluate the efficacy and safety of Danning Tablet (DNT) in patients with non-alcoholic fatty liver disease (NAFLD) of damp-heat syndrome type. METHODS A multicenter, randomized, double-blinded and positive drug parallel controlled trial was performed. One hundred and thirty-five patients were enrolled into the study and divided into two groups: DNT-treated group (n=102) and ursodeoxycholic acid (UDCA)-treated group (n=33). Body mass index (BMI), principal symptoms, liver function, blood lipids, iconographic, and compositional parameters were measured before and after treatment, respectively. RESULTS In the two groups, BMI, distress in hepatic region, fatigue, anorexia, liver function, blood lipids and iconographic parameters were significantly improved, and the improvements of BMI, distress in hepatic region were better in DNT-treated group than in UDCA-treated group. The histological study also showed that DNT had positive effect in treatment of NAFLD. CONCLUSION DNT is an effective drug to treat patients with NAFLD of damp-heat syndrome type and is more effective than UDCA.