Continuing Education Activity

Orlistat is a medication used in the management of obesity. Orlistat acts by reversibly inhibiting gastric and pancreatic lipases. The inactivation of lipases prevents the hydrolysis of triglycerides, and thus free fatty acids are not absorbed. The maximum benefit of orlistat occurs when used in conjunction with diet and exercise. This activity reviews the indications, actions, and contraindications of orlistat as a valuable agent in treating obesity. In addition, this activity will highlight the mechanism of action, adverse event profile, and other key factors (e.g., off-label uses, dosing, pharmacodynamics, pharmacokinetics, monitoring, and relevant interactions) pertinent to members of the interprofessional team in the care of patients with obesity.

Objectives:

• Identify the mechanism of action of orlistat.
• Describe the adverse effects of orlistat.
• Outline the appropriate monitoring of patients treated with orlistat.
• Review interprofessional team strategies for optimizing patient education regarding adverse effects and proper administration of orlistat for maximum efficacy.

Indications

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. The 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 the presence of risk factors including hypertension, diabetes, and dyslipidemias
• Reduction of the risk for weight regains after prior weight loss. 

The maximum benefit of orlistat occurs when used in conjunction with diet and exercise. The weight starts to decrease within two weeks of initiation of orlistat. Statistically, significant weight loss occurs when orlistat use is for greater than two months.[1] After six months of orlistat use, the mean weight loss 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] According to a scientific statement from the American Heart Association in 2021, orlistat is safe and effective for treating obesity with heart failure.[5] A study reported that orlistat is safe and effective in lowering serum triglycerides in children with type 1 hyperlipoproteinemia.[6]

Mechanism of Action

Orlistat acts by reversibly inhibiting 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.[7] The primary action of orlistat is local lipase inhibition within the gut. Systemic absorption is not necessary for the activity of orlistat. At the recommended dosage, orlistat inhibits dietary fat absorption (approximately 30%). According to AHA, the percentage change in weight is also associated with a small reduction in blood pressure.[8] 

Research also suggested that orlistat has a beneficial consequence on carbohydrate metabolism.[9] In addition, obesity increases the risk of hyperuricemia and cardiovascular disease. Meta-analysis results indicated that orlistat significantly reduced serum uric acid levels in adult patients.[10]

Pharmacokinetics

• Absorption: Orlistat acts mainly via its local effect in the gut, and systemic exposure to the medication is minimal.
• Distribution: Most (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 excreted in feces.[11]

Administration

Orlistat is available in oral tablets 60 mg (over the counter) and 120 mg (prescription product). The recommended orlistat prescription 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% of calories from fat. If the patient misses the meal, they can omit the orlistat dose. If the patient misses the dose of orlistat and it has been more than 2 hours past the fat-containing meal, then the patient can skip that dose 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 take multivitamin supplements(containing fat-soluble vitamins) daily. Administration of multivitamin supplements should be at a gap of more than 2 hours after the orlistat administration.[12]

Healthcare professionals must rule out organic causes of obesity like hypothyroidism or Cushing syndrome before initiating orlistat therapy.

Use in Specific Patient Population

• Pediatric Population: No research has established safety and efficacy in the pediatric population. However, orlistat is 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 ducts and deranged liver function tests.[13]

• Pregnancy Considerations: Orlistat is contraindicated in pregnancy. It is a former FDA pregnancy category X drug. Patients on orlistat therapy should be counseled regarding the necessity for contraception. According to USPTSF(The United States Preventive Services Task Force), limiting the gestational weight gain(GWG) in pregnancy is associated with a reduced risk of emergency cesarean delivery, gestational diabetes mellitus, and macrosomia. For limiting GWG, behavioral interventions are advised rather than pharmacotherapy.[14][15][16]

• Breastfeeding Considerations: Orlistat is minimally absorbed, and a small amount has been detected in the milk. Orlistat inhibits the absorption of fat-soluble vitamins; breastfeeding mothers should take a multivitamin supplement (containing fat-soluble vitamins). It is doubtful that the infants absorb orlistat in an amount that adversely impacts the breastfed infant.[17] Manufacturer labeling advises caution when orlistat is administered during lactation, and clinical practice guidelines don't recommend weight-management medications during breastfeeding.[18]

Adverse Effects

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.[9] 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).[19] Orlistat inhibits the absorption of fat-soluble vitamins and other fat-soluble nutrients. Patients should use a multivitamin tablet containing vitamins A, D, E, K, and beta-carotene once daily.[20]

• Hepatotoxicity: Cases of hepatotoxicity range from serum enzyme elevations to a few cases of fatal hepatic failure & the requirement for emergency liver transplantation. The proposed mechanism for hepatotoxicity is hypersensitivity, as only a small amount of orlistat is absorbed. However, clinical features of hypersensitivity are absent in orlistat-induced hepatotoxicity.[13]

• 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.[21]

• Musculoskeletal: Theoretically, orlistat can increase the risk of osteoporosis because of impaired absorption of calcium and vitamin D. 

• Oncology: 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. In addition, 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[9]

• Antiepileptics: Orlistat can reduce the absorption of lipophilic antiepileptics like lamotrigine, valproate, vigabatrin, and gabapentin, resulting in a decrease in plasma concentration. In such cases, it is recommended to monitor antiepileptic medication levels.[22]
• Amiodarone: Orlistat can reduce the absorption of amiodarone.[23]
• Cyclosporine: Orlistat can also reduce the absorption of cyclosporine (immunosuppressant). Therefore, the recommendation is that the administration of these two medications should be at a gap of at least 2 hours. Also, the cyclosporine levels require monitoring in patients taking the medication along with orlistat.[24][25]
• Levothyroxine: Orlistat can bind with levothyroxine in the gut and reduce its absorption, leading to decreased plasma concentration of levothyroxine and subsequent hypothyroidism. Thus, clinicians should advise patients to take levothyroxine and orlistat at least 4 hours apart.[26]
• 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.[27]
• 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.[28]

Contraindications

Contraindications to orlistat include the following conditions:

• Hypersensitivity to orlistat or its constituents
• Chronic malabsorption[29][30]
• Cholestasis
• Anorexia and bulimia
• Pregnancy
• Severe renal impairment
• Use with caution in patients with anorexia or bulimia nervosa.[31]

Monitoring

• It is necessary to monitor the body weight, body mass index (BMI), waist circumference, and lipid profile in patients taking orlistat.
• The levels of cyclosporine, antiepileptic, and HIV viral load require monitoring when using orlistat in conjunction with these medications.[9]
• Patients with diabetes might need to adjust the dose of diabetes medicine, as weight loss can affect glycemic control.
• Monitor the impact of Weight loss on Quality of Life-Lite (IWQOL-Lite), a widely used tool in assessing weight-loss interventions in clinical trials.[32]
• According to the (AACE/ACE) American Association of Clinical Endocrinologists, Medical Guidelines & American College of Endocrinology guidelines, patients receiving orlistat should be monitored for cholelithiasis in patients with mild hepatic impairment. In patients receiving orlistat, there is a risk of nephrolithiasis; monitor for flank pain and hematuria.[33]

Toxicity

There is no specific antidote for orlistat overdose. However, if a significant overdose of orlistat occurs, the patient should immediately come to the emergency department and be observed for 24 hours to provide supportive care. There is a report of overdose with 5160 mg orlistat in a 28-month-old baby. The patient did not experience any adverse events and was discharged from the emergency room without any concerns.[34] In a study involving 105 pediatric patients. Orlistat exposures among young children were managed by decontamination and had optimistic outcomes with few gastrointestinal adverse clinical effects.[35]

Enhancing Healthcare Team Outcomes

Obesity and its comorbidities have a significant burden on the healthcare system. According to AHA, Obesity is a multifactorial disease with pathophysiology associated with biological, socioeconomic, psychosocial, and environmental risk factors and leading to adverse health outcomes. Obesity is linked to dyslipidemia, type II diabetes mellitus, hypertension, and sleep disorders. Obesity is also with increased coronary artery calcium score, a marker of coronary atherosclerosis.[5] Obesity also leads to cardiovascular disease and mortality independent of other risk factors.[5] Utilizing pharmacotherapy in the form of orlistat can reduce morbidity and mortality from obesity-related complications but should be employed judiciously.

Orlistat effectively lowers body weight, BMI, cholesterol levels, and waist circumference. It has also been shown to cause a modest decrease in blood pressure and improved glycemic control in patients with diabetes. Gastrointestinal adverse effects are the most common reason for discontinuation of the medication. The drug can be used in the proper clinical setting to achieve weight loss goals and decrease obesity complications.

Clinicians must be vigilant while prescribing orlistat, especially in patients with diabetes, epilepsy, HIV, and blood coagulation disorder. The clinical nurse is required to assist the medical team in educating the patient on the expected gastrointestinal effects of the drug. A specialized pharmacist is a key to optimizing therapy with this drug. The pharmacist should assist the medical team in adjusting doses or timing of other medications when starting the patient on orlistat therapy to ensure their efficacy is not reduced. The pharmacist must educate the patient on proper dosing, timing, and frequency of therapy to minimize adverse outcomes. Dieticians should be involved in patient care, ensuring the patient has direction on a nutritionally balanced, low-calorie diet. For the management of cholelithiasis or nephrolithiasis, surgical consultation may be required. Psychiatrists and psychologist consultations may be necessary for bulimia nervosa.

A coordinated and collaborative interprofessional team of clinicians, pharmacists, nurses, physician assistants, and dieticians can improve the efficacy of orlistat therapy and achieve optimal patient results. According to the AACE/ACE comprehensive clinical practice guidelines for obesity, interprofessional collaboration and communication between clinicians(MD, DO, NP, PA), dietitians, nurses, instructors, physical activity trainers, and clinical psychologists are essential for the effective management of patients with obesity and improving outcomes related to orlistat therapy.[33] [Level 5]