Orlistat


Article Author:
Agam Bansal


Article Editor:
Yasir Al Khalili


Editors In Chief:
Melissa Max
Danyae Lee
Manouchkathe Cassagnol


Managing Editors:
Avais Raja
Orawan Chaigasame
Carrie Smith
Abdul Waheed
Khalid Alsayouri
Frank Smeeks
Kristina Soman-Faulkner
Radia Jamil
Patrick Le
Sobhan Daneshfar
Anoosh Zafar Gondal
Saad Nazir
William Gossman
Pritesh Sheth
Hassam Zulfiqar
Navid Mahabadi
Steve Bhimji
John Shell
Matthew Varacallo
Heba Mahdy
Ahmad Malik
Mark Pellegrini
James Hughes
Beata Beatty
Nazia Sadiq
Hajira Basit
Phillip Hynes
Tehmina Warsi


Updated:
5/25/2019 5:09:51 PM

Indications

Orlistat (tetrahydrolipstatin) is an FDA approved anti-obesity medication. It is a saturated derivative of endogenous lipstatin isolated from Streptomyces toxytricini. FDA approved indications of orlistat include: 

  • Obese patients with BMI over 30 kg/m
  • Patients with a BMI greater than 27 kg/m and presence of risk factors including hypertension, diabetes, and dyslipidemias

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]

Mechanism of Action

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 prevent 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%.

Administration

The recommended orlistat dose is 120 mg capsule orally thrice daily. The capsule should be taken 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 they should be taken at a gap of more than 2 hours after the orlistat administration.

Also, it is important for healthcare professionals 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: Safety and efficacy have not been established in the pediatric population. However, orlistat has been found to be safe and effective in obese adolescent patients.
  • 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.

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.[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 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 these two medications should be taken at 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, patients should be advised 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

Contraindications to orlistat include the following conditions:

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

Monitoring

Monitor body weight, body mass index (BMI), waist circumference, and lipid profile in patients taking orlistat. The levels of cyclosporine, antiepileptics, and HIV viral load require monitoring when using orlistat in conjunction with these medications.

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 with the provision of supportive care.

Enhancing Healthcare Team Outcomes

Obesity and its comorbidities have a significant burden on the healthcare system. Utilizing pharmacotherapy in the form of orlistat can reduce morbidity and mortality from obesity-related complications. Orlistat is effective in lowering body weight, BMI, cholesterol levels, waist circumference, and has also been shown to cause a  modest decrease in blood pressure and improve glycemic control in diabetic patients. Gastrointestinal adverse effects are the most common reason for discontinuation of the medication. The healthcare personnel should educate the patients regarding the importance of adherence to the medication and its indications, adverse effects, and contraindications. The dieticians should be involved in patient care, ensuring the patient has direction on a nutritionally balanced, low-calorie diet. Emphasis as to when and how to take the medication is also crucial for therapeutic success. The physicians should also take an appropriate medication history to prevent drug interactions with orlistat.

As can be seen above, orlistat therapy requires an interprofessional team approach, including physicians, specialists, specialty-trained nurses, dieticians, and pharmacists, all collaborating across disciplines to achieve optimal patient results. [Level V]


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Orlistat - Questions

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A 43-year old male presents to the emergency department complaining of progressive colicky left lower quadrant pain radiating to the groin for the past 2 weeks. His past medical history is significant for hypertension and obesity for which he is taking enalapril and orlistat, respectively. The patient mentions that he has changed his diet and consumes a lot of spinach and nuts. There is no history of hematuria. His BMI is 31 kg/m2. The general physical examination is normal without any costovertebral tenderness. Urinalysis reveals 3-4 RBCs. Abdominal CT is performed which reveals the presence of renal stone. Which of the following could explain the patient's symptoms?



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A 35-year old female presents to the office for a regular health examination. She mentions that she is frustrated about her body weight. For the past 3 months, she has been strictly following a low-calorie, low-fat diet. She also goes to the gym 5 days a week and does a significant amount of workout. Despite this, she has been unable to lose substantial weight and requests the physician to add on a medication to help her achieve the goal. The physician decides to start a medication that acts by inhibiting lipases. What should be the physician's advice to the patient?



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A 52-year old obese female presents to the emergency department with complaints of right upper quadrant abdominal pain from the last two weeks. The pain is colicky in nature and worsens after meals. It is associated with nausea and vomiting. She has also noticed that her stools have become pale. Her past medical history is significant for hypertension, diabetes, and chronic kidney disease (baseline serum creatinine 2.3 mg/dl). She also requests the physician to provide her with a medication to lose weight. Her current weight is 90 kg and height is 168 cm. Her physical examination reveals icteric sclera and tenderness in RUQ abdomen. Laboratory values reveal the following: serum creatinine 2.4 mg/dl, direct bilirubin 1.4 mg/dl, ALT 40 U/l, AST 30 U/l, ALP 56 U/l. Abdominal ultrasound reveals an incidental hepatic adenoma and cholelithiasis with cholestasis. Which of the following would prevent the patient from being started on orlistat?



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A 46-year old female patient presents to the office with complaints of oily stools and flatulence for the past 2 weeks. Her past medical history is significant for diabetes, for which she is taking metformin for the last 2 years. She was started on orlistat medication 120 mg thrice daily 3 weeks back for her obesity, and she has been compliant to the medication. Her diet has been irregular, and she prefers a high-fat diet. Her weight is 85 kg and height is 160 cm. Which of the following should be advised to relieve patient's symptoms?



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A 46-year old female presents to the office with complains of constipation, dry hair, and fatigue for the past 2 weeks. Her past medical history is significant for hypothyroidism diagnosed 3 years back. She is taking levothyroxine for her hypothyroidism and orlistat for her obesity, which was started 1 month back. Her family history is significant for hypothyroidism in her mother. She has been strictly adhering to her low-fat, low-calorie diet since the past 1 month. On physical examination, hair is coarse, and deep tendon reflexes are delayed. Her laboratory investigations reveal the following: TSH 7 mU/l and FT4 0.2 ng/dl. Which of the following should be advised to the patient?



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A 49-year old male presents to the office for excessive daytime sleepiness and snoring for the past month. His past medical history is significant for diabetes mellitus diagnosed 4 years back. His family history is also notable for obesity. He tells the physician that he walks 1 hour daily and has tried to limit his caloric intake. He is currently taking metformin. The patient requests the physician to add a medication which could help him lose weight. His current weight is 102 kg and height is 172 cm. His blood pressure is 122/72 mm Hg, and the pulse is 80/min. The physician initiates a medication for his weight loss. This medication acts by which of the following mechanism?



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A patient would like more information on the drug orlistat that she recently started on per provider prescription for obesity. What are the facts about this medication? Select all that apply.



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Orlistat - References

References

Torgerson JS,Hauptman J,Boldrin MN,Sjöström L, XENical in the prevention of diabetes in obese subjects (XENDOS) study: a randomized study of orlistat as an adjunct to lifestyle changes for the prevention of type 2 diabetes in obese patients. Diabetes care. 2004 Jan;     [PubMed]
Jain SS,Ramanand SJ,Ramanand JB,Akat PB,Patwardhan MH,Joshi SR, Evaluation of efficacy and safety of orlistat in obese patients. Indian journal of endocrinology and metabolism. 2011 Apr;     [PubMed]
Hollywood A,Ogden J, Taking Orlistat: Predicting Weight Loss over 6 Months. Journal of obesity. 2011;     [PubMed]
Sjöström L,Rissanen A,Andersen T,Boldrin M,Golay A,Koppeschaar HP,Krempf M, Randomised placebo-controlled trial of orlistat for weight loss and prevention of weight regain in obese patients. European Multicentre Orlistat Study Group. Lancet (London, England). 1998 Jul 18;     [PubMed]
Guerciolini R, Mode of action of orlistat. International journal of obesity and related metabolic disorders : journal of the International Association for the Study of Obesity. 1997 Jun;     [PubMed]
MacWalter RS,Fraser HW,Armstrong KM, Orlistat enhances warfarin effect. The Annals of pharmacotherapy. 2003 Apr;     [PubMed]
Nägele H,Petersen B,Bonacker U,Rödiger W, Effect of orlistat on blood cyclosporin concentration in an obese heart transplant patient. European journal of clinical pharmacology. 1999 Nov;     [PubMed]
Asberg A, Interactions between cyclosporin and lipid-lowering drugs: implications for organ transplant recipients. Drugs. 2003;     [PubMed]
Zhi J,Moore R,Kanitra L,Mulligan TE, Effects of orlistat, a lipase inhibitor, on the pharmacokinetics of three highly lipophilic drugs (amiodarone, fluoxetine, and simvastatin) in healthy volunteers. Journal of clinical pharmacology. 2003 Apr;     [PubMed]
Bigham S,McGuigan C,MacDonald BK, Reduced absorption of lipophilic anti-epileptic medications when used concomitantly with the anti-obesity drug orlistat. Epilepsia. 2006 Dec;     [PubMed]
Humayun Y,Ball KC,Lewin JR,Lerant AA,Fülöp T, Acute oxalate nephropathy associated with orlistat. Journal of nephropathology. 2016 Apr;     [PubMed]
Wang H,Wang L,Cheng Y,Xia Z,Liao Y,Cao J, Efficacy of orlistat in non-alcoholic fatty liver disease: A systematic review and meta-analysis. Biomedical reports. 2018 Jul;     [PubMed]
Filippatos TD,Derdemezis CS,Gazi IF,Nakou ES,Mikhailidis DP,Elisaf MS, Orlistat-associated adverse effects and drug interactions: a critical review. Drug safety. 2008;     [PubMed]
Skelin M,Lucijanić T,Amidžić Klarić D,Rešić A,Bakula M,Liberati-Čizmek AM,Gharib H,Rahelić D, Factors Affecting Gastrointestinal Absorption of Levothyroxine: A Review. Clinical therapeutics. 2017 Feb;     [PubMed]
McDuffie JR,Calis KA,Booth SL,Uwaifo GI,Yanovski JA, Effects of orlistat on fat-soluble vitamins in obese adolescents. Pharmacotherapy. 2002 Jul;     [PubMed]

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