Digestive lipases as therapeutic targets in obesity: From Orlistat to next-generation inhibitors

Obesity remains a global pandemic and a major driver of metabolic diseases, with current pharmacotherapies often limited by modest efficacy, systemic side effects, high costs, and weight regain after cessation. Targeting dietary lipid digestion via the inhibition of gastrointestinal lipases offers a mechanistically rational and peripherally acting therapeutic strategy. This review provides an updated, quantitative overview of human gastrointestinal lipolysis, emphasizing the sequential and complementary roles of human gastric lipase and human pancreatic lipase in dietary triglyceride absorption. We critically analyze the clinical proof-of-concept provided by Orlistat, the only approved digestive lipase inhibitor, whose utility is constrained by limited efficacy, significant gastrointestinal intolerance, and rare but severe hepatotoxicity. While next-generation systemic therapies like GLP-1 receptor agonists show superior weight loss, their chronic administration and high cost underscore the need for safer, localized alternatives. We systematically review recent strategies for developing superior digestive lipase inhibitors, including structure-based drug design, in silico screening, and bioguided fractionation of natural products (e.g., flavonoid derivatives). Emphasis is placed on the critical design principles required for next-generation inhibitors, including strict luminal confinement, high selectivity for digestive lipases, and controlled, reversible inhibition to improve tolerability. By bridging biochemical insights with pharmacological challenges, this review outlines a roadmap for the development of safer, more effective lipid-targeted therapies to combat obesity.