Orlistat (tetrahydrolipstatin) is a United States Food and Drug Administration (FDA) approved anti-obesity medication. It is a saturated derivative of endogenous lipstatin isolated from Streptomyces toxytricini. FDA approved indications of orlistat include: 

• Patients with obesity with a body mass index (BMI) of over 30 kg/m
• Patients with a BMI greater than 27 kg/m and presence of risk factors including hypertension, diabetes, and dyslipidemias

The maximum benefit of orlistat occurs when used in conjunction with diet and exercise. The weight starts to decrease within 2 weeks of initiation of orlistat. Statistically, significant weight loss occurs when orlistat use is for greater than 2 months.[1] The mean weight loss after 6 months of orlistat use is around 5.6 kg compared to 2.4 kg in the placebo group. Orlistat also causes a significant reduction in BMI, waist circumference, total cholesterol, and LDL levels.[2][3] In the XENDOS trial, orlistat has been found to have a statistically significant impact in reducing the incidence of diabetes in patients with impaired glucose tolerance.[4]

Orlistat acts by reversibly inhibiting the gastric and pancreatic lipases. These lipases have an important role in the digestion of dietary fat. They work by breaking down the triglycerides into absorbable free fatty acids and monoglycerides. Orlistat covalently binds to the serine residues of active sites of lipases and inactivates them. The inactivation of lipases prevents the hydrolysis of triglycerides, and thus free fatty acids are not absorbed.[5] The primary action of orlistat is local lipase inhibition within the gut. Systemic absorption is not necessary for the activity of orlistat. At its recommended dosage, it inhibits dietary fat absorption by approximately 30%.

The recommended orlistat dose is 120 mg capsule orally thrice daily. The administration should be during or within 1 hour after the fat-containing meal. Doses of more than 120 mg have not shown any additional benefit. The recommendation is that the patient adheres to a nutritionally balanced, low-calorie diet with less than 30% calories from fat. If the patient misses the meal, they can omit the dose of orlistat. If the patient misses the dose of orlistat and it has been more than 2 hours past the fat-containing meal, then that dose can be skipped since by that time most of the fat absorption has already occurred, and the medication would not work effectively. Since orlistat reduces the absorption of fat-soluble vitamins, patients should also take multivitamin supplements once daily, but their administration should be at a gap of more than 2 hours after the orlistat administration.

Also, healthcare professionals need to rule out organic causes of obesity like hypothyroidism or Cushing syndrome before initiating orlistat therapy.

Pharmacokinetics

• Absorption: Orlistat acts mainly via its local effect in the gut, and systemic exposure to the medication is minimal.
• Distribution: The majority (more than 99%) of the drug is bound to the plasma proteins (lipoproteins and albumin are the major binding proteins).
• Metabolism: Orlistat metabolism is primarily within the intestinal wall.
• Elimination: 95 to -97% of the medication is unabsorbed and gets excreted in feces.

The utility of orlistat in specific patient population groups:

• Pregnancy: Orlistat should not be used in pregnant and breastfeeding mothers. It is a pregnancy category B drug.
• Pediatric population: No research has established safety and efficacy in the pediatric population. However, orlistat has been found to be safe and effective in adolescent patients with obesity.
• Renal impairment: Orlistat is safe in patients with renal impairment
• Hepatobiliary disease: Orlistat use requires caution in patients with obstructed bile duct and deranged liver function tests.

The side effects of orlistat include the following:

• Gastrointestinal: The most common side effect of orlistat use is steatorrhea, which occurs because of the impaired absorption of dietary fat. Other side effects include fecal spotting, diarrhea, abdominal pain, and anal fissures. The gastrointestinal adverse effects decrease with ongoing orlistat therapy.  These adverse effects can be minimized by following a hypocaloric and low-fat diet with less than 30% of the calories from fats.[6] Rarely, orlistat correlates with cholelithiasis, pancreatitis, and acute cholestatic hepatitis. However, orlistat has been shown to reverse steatosis in patients with non-alcoholic fatty liver disease (NAFLD).[7] Orlistat inhibits the absorption of fat-soluble vitamins and other fat-soluble nutrients. Patients should use a multivitamin tablet containing vitamin A, D, E, K, and beta-carotene once daily.[8]
• Renal: Orlistat can increase the risk of acute kidney injury; this occurs because the unabsorbed fat binds with calcium in the intestinal lumen resulting in excessive oxalate, which is absorbed and deposited in the kidney leading to oxalate nephropathy and increased risk of renal stones.[9]
• Musculoskeletal: Theoretically, orlistat can increase the risk of osteoporosis because of impaired absorption of calcium and vitamin D. 
• Cancer: Animal studies have shown an increased risk of colorectal cancer with orlistat. However, in humans, no such association has been elucidated. Orlistat is known to inhibit the synthesis of fatty acid synthase (Fas) enzyme, which increases tumor growth. Orlistat has been shown to have anti-neoplastic activity in ovarian cancer cells, breast cancer cells, and prostate cancer cells in various animal studies.

Few case reports have illustrated the association of orlistat use with hypertension, diabetic ketoacidosis, depression, cutaneous vasculitis, lichenoid eruptions, and vaginitis. However, a causal relationship between orlistat and these adverse effects remains unproven.

Drug interactions[6]

• Antiepileptics: Orlistat can reduce the absorption of lipophilic antiepileptics like lamotrigine, valproate, vigabatrin, and gabapentin, resulting in a decrease in their plasma concentration. In such cases, it is recommended to monitor antiepileptic medication levels.[10]
• Amiodarone: Orlistat can reduce the absorption of amiodarone.[11]
• Cyclosporine: Orlistat can also reduce the absorption of cyclosporine (immunosuppressant), and therefore, the recommendation is that the administration of these two medications should be with a gap of at least 2 hours. Also, the cyclosporine levels require monitoring in patients taking the medication along with orlistat.[12][13]
• Levothyroxine: Orlistat can bind with levothyroxine in the gut and reduce its absorption leading to a decrease in plasma concentration of levothyroxine and subsequent hypothyroidism. Thus, clinicians should advise patients to take levothyroxine and orlistat at least 4 hours apart.[14]
• Warfarin: Using orlistat along with warfarin can result in prolonged prothrombin time and INR because orlistat reduces the absorption of vitamin K. Therefore, coagulation parameters require monitoring in patients taking these two medications together.[15]
• Antiretroviral medications: Orlistat also reduces the absorption of antiretroviral drugs; monitoring of HIV viral load is necessary. If the HIV viral load increases, orlistat should be discontinued.

Contraindications to orlistat include the following conditions:

• Hypersensitivity to orlistat or its constituents
• Chronic malabsorption
• Cholestasis
• Anorexia and bulimia