Efficacy of orlistat in obese patients with nonalcoholic fatty liver disease: a systematic review and meta-analysis of randomized controlled trials.
Proceedings (Baylor University. Medical Center)
Nonalcoholic fatty liver disease (NAFLD) or metabolic dysfunction-associated steatotic liver disease (MASLD) is a significant contributor to chronic liver disease worldwide. Orlistat blocks intestinal fat absorption, leading to decreased liver fat content. Therefore, it is a viable option for NAFLD management. We performed a systematic review and metaanalysis using randomized controlled trials (RCTs). We used mean difference (MD) to pool continuous outcomes presented with the corresponding confidence interval (CI). We included four RCTs with a total of 379 patients. Orlistat was effective in reducing liver fat content (MD: -5.02, 95% CI [-7.23, -2.82], = 0.00001), alanine transferase (MD: -10.03, 95% CI [-17.80, -2.26], = 0.01), aspartate transferase (MD: -4.29, 95% CI [-7.59, -0.99], = 0.01), waist circumference (MD: -3.18, 95% CI [-4.25, -2.10], = 0.00001), body mass index (MD: -1.03, 95% CI [-1.34, -0.73], = 0.00001), total cholesterol (MD: -3.75, 95% CI [-4.02, -3.49], = 0.00001), and low-density lipoprotein (MD: -3.83, 95% CI [-4.05, -3.61], = 0.00001). However, orlistat was associated with increased serum triglycerides (MD: 7.46, 95% CI [6.48, 8.44], = 0. 00001). Orlistat is a viable option for NAFLD management; however, it increases triglyceride levels. Larger RCTs are required.
10.1080/08998280.2024.2335829
Effectiveness of pharmacological interventions for managing obesity in children and adolescents: A systematic review and meta-analysis framed using minimal important difference estimates based on GRADE guidance to inform a clinical practice guideline.
Pediatric obesity
OBJECTIVE:To summarize the literature on pharmacotherapy for managing paediatric obesity. METHODS:A systematic review and meta-analysis were conducted of randomized controlled trials (RCTs) with <18-year-olds of pharmacotherapeutic agents published up to November 2022. Estimates of effect for outcomes were presented relative to minimal important differences and GRADE certainty of evidence. We examined data on patient/proxy-reported outcome measures (PROMs), cardiometabolic risk factors, anthropometry and adverse events (AEs). RESULTS:Overall, 35 RCTs were included. Trials examined metformin (n = 26), glucagon-like peptide-1 receptor agonists (GLP1RAs) (n = 7) and a lipase inhibitor (orlistat; n = 2). Intervention duration varied (3-24 months). Metformin had little to no benefit on PROMs (e.g., health-related quality of life [HRQoL]; 6 RCTs), moderate reductions in triglycerides, a moderate decline in insulin resistance, a small to moderate decline in BMI z-score (BMIz) and a moderate increase in mild to moderate gastrointestinal AEs. Response to GLP1RAs was heterogeneous and results of subgroup analysis demonstrated variability of impact. Liraglutide (2 RCTs) resulted in a small reduction in HOMA-IR and BMIz, but little to no benefit on other outcomes. Exenatide (4 RCTs) had a moderate reduction on blood pressure and a small decrease in BMIz with little to no benefit on other outcomes. Semaglutide (1 RCT) had a small benefit on HRQoL, a small reduction on SBP, a moderate reduction on total cholesterol and LDL-cholesterol, a large reduction on triglyceride, and a very large decline in BMIz accompanied by a small increase in mild to moderate gastrointestinal AEs. Orlistat had a moderate reduction in DBP and little to no benefit in other outcomes measured, but had a very large increased risk of mild to moderate gastrointestinal AEs. Serious AEs were rare and for interventions with sufficent AE reporting, were considered not likely attributable to the interventions. CONCLUSION:Few studies examined the impact of pharmacotherapy on PROMs. There is evidence that metformin and GLP1RAs lead to important improvements in cardiometabolic and anthropometric outcomes while accompanied by mild to moderate AEs. Long-term effectiveness and safety of GLP1RAs remain to be evaluated.
10.1111/ijpo.13169
Targeting obesity with plant-derived pancreatic lipase inhibitors: A comprehensive review.
Rajan Logesh,Palaniswamy Dhanabal,Mohankumar Suresh Kumar
Pharmacological research
The prevalence of obesity is alarmingly increasing in the last few decades and leading to many serious public health concerns worldwide. The dysregulated lipid homeostasis due to various genetic, environmental and lifestyle factors is considered one of the critical putative pathways mediating obesity. Nonetheless, the scientific advancements unleashing the molecular dynamics of lipid metabolism have provided deeper insights on the emerging roles of lipid hydrolysing enzymes, including pancreatic lipase. It is hypothesized that inhibiting pancreatic lipase would prevent the breakdown of triglyceride and delays the absorption of fatty acids into the systemic circulation and adipocytes. Whilst, orlistat is the only conventional pancreatic lipase enzyme inhibitor available in clinics, identifying the safe clinical alternatives from plants to inhibit pancreatic lipase has been considered a significant advancement. Consequently, plants which have shown significant potential to combat obesity are now revisited for its abilities to inhibit pancreatic lipase. In this regard, our review surveyed the potential of medicinal plants and its phytoconstituents to inhibit pancreatic lipase and to elicit anti-obesity effects. Thus, the review collate and critically appraise the potential of medicinal plants and phyto-molecules inhibiting pancreatic lipase enzyme and consequently modulating triglyceride absorption in gut, and discuss its implications in the development of novel therapeutic strategies to combat obesity.
10.1016/j.phrs.2020.104681
Computational approaches for the discovery of natural pancreatic lipase inhibitors as antiobesity agents.
Almasri Ihab M
Future medicinal chemistry
Obesity is becoming one of the greatest threats to global health in the 21st century and therefore the development of novel antiobesity drugs is one of the top priorities of global drug research. An important treatment strategy includes the reduction of intestinal fat absorption through the inhibition of pancreatic lipase (PL). Natural products provide a vast pool of PL inhibitors with novel scaffolds that can possibly be developed into clinical products. Computational drug design methods have become increasingly invaluable in the drug discovery process. In recent years, the discovery of new antiobesity PL inhibitors has been facilitated by the application of computational methods. This review highlights some computer-aided drug design techniques utilized in the discovery of natural PL inhibitors.
10.4155/fmc-2019-0284
Pancreatic lipase inhibitors: The road voyaged and successes.
Kumar Ashwani,Chauhan Shilpi
Life sciences
Human pancreatic lipase (triacylglycerol acyl hydrolase EC3.1.1.3) is the most widely studied member of the human lipase superfamily related to carboxyl esterase. It is secreted from the acinar cell of pancreas and has strong preference for triacylglycerides over cholesterol esters, phospholipids, and galactolipids. Apart from the hydrolysis of triacylglycerides, pancreatic lipase may cause the hydrolysis of retinyl esters in vivo. So, it is very much evidenced that pancreatic lipase with its cofactor colipase has prominent role in efficient digestion of dietary fat. Hence, the modulation of human pancreatic lipase may represent a new insight in the discovery of a number of therapeutics that can inhibit the absorption of fat in body and can be used in obesity and other related metabolic disorders. Even, the only Food and drug administration (FDA) approved antiobesity drug, orlistat, is also an inhibitor of pancreatic lipase. This review summarizes studies about structure, mechanistic approach of pancreatic lipase enzyme while emphasizing on the various synthetic pancreatic lipase inhibitors with their structure activity relationship (SAR).
10.1016/j.lfs.2021.119115
Pancreatic lipase and its related proteins: where are we now?
Drug discovery today
Obesity is a disease of epidemic proportions, with a worrisome upward trend. The high consumption of lipids, a major energy source, leads to obesity because of their high calorific value. Pancreatic lipase (PTL), produced by pancreatic acinar cells, hydrolyzes 50-70% of triacylglycerol (TAG) from food. PTL-related protein 1 (PLRP1) and 2 (PLRP2) are also produced by these cells. In vertebrates, PLRP1 has relatively less lipolytic activity, whereas PLRP2 has an essential role in lipid digestion, especially in infants. In this review, we summarize the structure and function of PTL, PLRP1, and PLRP2, and the metabolic fate of PTL inhibitors. We also discuss the current status of clinical trials on orlistat and its combinations for obesity treatment.
10.1016/j.drudis.2023.103855
Anti-Obesity Therapeutic Targets Studied In Silico and In Vivo: A Systematic Review.
International journal of molecular sciences
In the age of information technology and the additional computational search tools and software available, this systematic review aimed to identify potential therapeutic targets for obesity, evaluated in silico and subsequently validated in vivo. The systematic review was initially guided by the research question "What therapeutic targets have been used in in silico analysis for the treatment of obesity?" and structured based on the acronym PECo (P, problem; E, exposure; Co, context). The systematic review protocol was formulated and registered in PROSPERO (CRD42022353808) in accordance with the Preferred Reporting Items Checklist for Systematic Review and Meta-Analysis Protocols (PRISMA-P), and the PRISMA was followed for the systematic review. The studies were selected according to the eligibility criteria, aligned with PECo, in the following databases: PubMed, ScienceDirect, Scopus, Web of Science, BVS, and EMBASE. The search strategy yielded 1142 articles, from which, based on the evaluation criteria, 12 were included in the systematic review. Only seven these articles allowed the identification of both in silico and in vivo reassessed therapeutic targets. Among these targets, five were exclusively experimental, one was exclusively theoretical, and one of the targets presented an experimental portion and a portion obtained by modeling. The predominant methodology used was molecular docking and the most studied target was Human Pancreatic Lipase (HPL) (n = 4). The lack of methodological details resulted in more than 50% of the papers being categorized with an "unclear risk of bias" across eight out of the eleven evaluated criteria. From the current systematic review, it seems evident that integrating in silico methodologies into studies of potential drug targets for the exploration of new therapeutic agents provides an important tool, given the ongoing challenges in controlling obesity.
10.3390/ijms25094699