Pancreatic lipase inhibitor was originally discovered and isolated from fermented broth of the Streptomyces toxytricini bacterium in 1981 and named lipstatin. It is a selective and potent irreversible inhibitor of human gastric and pancreatic lipases. Tetrahydrolipstatin, more commonly known as orlistat, is a saturated derivative produced by hydrogenation. It was developed in 1983 by Hoffmann-La Roche and is a more simple and stable compound than lipstatin. For that reason orlistat was chosen over lipstatin for development as an anti-obesity drug. It is the only available FDA-approved oral lipase inhibitor and is known on the market as Xenical and Alli.
Initially orlistat was developed as a treatment for dyslipidemia, not as an anti-obesity agent. When researchers found out that it promotes less energy uptake, the focus was switched to obesity.
Orlistat has a few adverse effects. Most reported side effects are gastrointestinal; including liquid stools, steatorrhea and abdominal pain. More severe and serious are interactions between orlistat and anticoagulants when given in combination. It can increase INR which can lead to insufficient anticoagulant treatment and bleeding. These adverse effects of orlistat are more common early in the therapy but usually decrease with time. Pancreatic lipases do not only affect the hydrolysis of triglycerides but are also necessary for hydrolysis of fat soluble vitamins. Due to this, the absorption of fat-soluble vitamins may decrease. Therefore, it is recommended to take a multiple-vitamin supplement during orlistat therapy.
Cetilistat, a new lipase inhibitor, is an experimental drug for obesity. In October 2016 the drug was still in clinical trials.
Cetilistat was developed to overcome the adverse effects on the gastrointestinal tract of orlistat. It has a different structure but similar inhibition activity to the gastrointestinal lipase. However cetilistat interacts differently with the fat micelles from digested food, therefore it has less side effects and better tolerability.