Drugs for Obesity

April 2, 2020 Rima Pharmacology 0

What is obesity? Is it a serious health problem?

  • Obesity is defined as a condition of abnormal or excessive accumulation of adipose tissue, to the extent that health may be impaired. Obesity increases chances of serious health complications like hypertension, heart disease, type 2 diabetes, stroke, osteoarthritis etc. The prevalence of obesity is increasing exponentially worldwide. According to WHO, present obesity pandemic is a consequence of increasing imbalance between energy intake and expenditure, specially the effect of high energy dietary intake and relative physical inactivity (World Health Organization, 2004).
  • Clinically, overweight and obesity are assessed in terms of Body Mass Index (BMI = Body weight in Kg/Height in meter2) and waist circumferences. The normal value of BMI in adults is 18.5 to 24.9. An individual is said to be overweight if his BMI is of 25 to 29.9; and obese if BMI is 30 or higher. BMI of 35 or more means severe obesity. Asians develop hypertension, IHD and type 2 diabetes mellitus at lower level of BMI than their western counterparts if their waist circumference is higher than normal. Thus, according to the new Asian criteria, a person with a BMI > 23 is considered as obese.
  • Alternatively, obesity is diagnosed even with normal BMI if the waist circumference exceeds 102 cm in men and 88 cm in women in the western countries; for Asians, the corresponding figures are 90 cm and 80 cm, respectively.

When is drug therapy indicated for treatment of obesity?

  • Weight-loss medications are indicated for patients having BMI (Body Mass Index) of at least 30 kg/m2 or who have obesity associated comorbidities and BMI of at least 27 kg/m2. However, these medications are not magic pills and help to lose only about 10-25 pounds in patient. They should be used in adjuvant with diet, exercise and other lifestyle changes.

Figure: General recommendation for obesity management

  • Weight-loss surgery is a safe and effective option for patients with a BMI of at least 40 kg/m2 or, with comorbidities, a BMI of at least 35 kg/m2.

History of weight-loss drugs

  • Many drugs were introduced in market for weight loss and later withdrawn due to their serious health complications. The serotonin (5-HT)-releasing agents, fenfluramine, dexfenfluramine and combination fenfluramine/phentermine, were withdrawn from the market in 1997 due to cardiovascular safety concerns, specifically increased risk of primary pulmonary hypertension and valvular regurgitation.
  • Sibutramine, a dual monoamine (noradrenaline and serotonin) reuptake inhibitor was approved for weight loss in 1997. Increase in heart rate and blood pressure were observed in initial trial and then post marketing studies found an increase in non-fatal cardiovascular and cerebrovascular events in those with preexisting cardiovascular disease and diabetes mellitus. Based on these results it was withdrawn in 2010 from US and European market.
  • Rimonabant, a selective endocannabinoid (CB1) receptor inverse agonist that act by suppressing appetite, was approved in 2006 and subsequently withdrawn in 2008 owing to concerns related to serious psychiatric sequelae, including suicide and depression.

Current pharmacotherapy for obesity

Current pharmacotherapy for obesity includes both monotherapy and combination therapy indicated for either short-term or long-term use.

Classification of drugs used for obesity

1. Centrally acting appetite suppressants (Anorexiants)

  • Adrenergic agents e.g. Benzamphetamine, Phentermine, Mazindol, Phendimetrazine, Diethylpropion.
  • 5-HT agonists e.g. Fenfluramine, Dexfenfluramine, Fluoxetine, Lorcaserin.
  • Drugs acting on both adrenergic and 5-HT systems e.g. Sibutramine
  • Cannabinoid receptor antagonists e. g. Rimonabant.

2. Drugs acting in the GI tract

  • Bulk anorexiants e.g. Dietary fiber, Methylcellulose, Guar gum.
  • Non-absorbable fat substitutes e.g. Olestra
  • Lipase inhibitors e.g. Orlistat

3. Drug combinations: e.g. Phenteramine + Topiramate, Bupropion + Naltrexon

4. Miscellaneous e.g. Metformin, Liraglutide

Following are the description of drugs used for weight loss which are approved by FDA.

1. Centrally acting appetite suppressants (Anorexiants)

Phenteramine:

  • It got its FDA approval in 1959 for short term use as an adjuvant to lifestyle for treating obesity and  acts by stimulating β2 adrenergic receptors to induce appetite suppression. It is prescribed at an oral dose of 15, 30 or 37.5 mg daily either before or 1-2 hour after breakfast.
  • Common adverse effect includes dry mouth, insomnia which tend to wane with continued use. Phenteramine was believed to increase blood pressure and pulse rate so was contraindicated in patients with cardiovascular diseases. However more recent studies have concluded that it is not associated with any serious side effects. Other contraindications include hyperthyroidism, glaucoma, history of drug abuse, pregnancy, breastfeeding and recent use of monoamine oxidase inhibitor.

Lorcaserin:

  • It is selective serotonin 2C receptor agonist that acts on hypothalamus to suppress appetite. It got its FDA approval  in 2012 for long term weight management. The recommended dose is 10 mg twice daily.
  • Common adverse effects include dry mouth, gastrointestinal disturbances, headache. Patients with type 2 diabetes mellitus should be monitored for hypoglycemia. It should be used with extra caution in patients taking other serotonergic agents. It should be contraindicated in pregnancy, patients having severe renal insufficiency or severe hepatic impairment.
  • A pilot study that added penteramine to lorcaserin yielded double weight loss than lorcaserine alone. This drug combination needs more investigation to be approved.

2. Drugs acting in the GI tract

Orlistat

  • It got its approval as prescription drug in 1999 and over the counter drug in 2007. It acts by inhibiting pancreatic and gastric lipase and also reduces metabolism and absorption of dietary fat thereby inhibiting hydrolysis of triglycerides into fatty acids and monoglycerides thus increasing fecal fat excretion by about 30 %.
  • Orlistat is a good choice for weight loss therapy due to its safe cardiovascular risk profile and beneficial effects on lipid level. However, its long-term effect on weight is only modest. The prescribed dose is 120 mg 2-3 times daily with low-fat diet for maximum of 2 years. To prevent potential deficiencies of fat-soluble vitamins, a daily multivitamin supplement is recommended.
  • Adverse effects observed are gastrointestinal disturbance due to high content of undigested fat in stool, hepatotoxicity and oxalate induced nephropathy. It is reported to interfere with lipophilic drugs so drugs like warfarin, cyclosporine, certain antiepileptic drugs should be monitored while taking orlistat.

3. Drug combinations

Phenteramine+ Topiramate:

  • This combination was approved by FDA in 2012 and available under brand name Qsymia. Topiramate is used for seizure disorder and prophylactic treatment of migraine. It is not approved as monotherapy for obesity. The exact mechanism of action of topiramate in weight loss is still unknown.
  • Phenteramine-topiramate therapy is advantageous over monotherapy as low dose of each can be used to achieve same benefit and avoid dose related adverse effects. Phentermine-topiramate is available in capsules containing 3.75-23, 7.5-46, 11.25-69, and 15-92 mg. The recommended starting dosage is 3.75-23 mg/day for 14 days, increasing to 7.5-46 mg/day. If patients do not lose at least 3% of their body weight after 12 weeks, the dose can be increased to 11.25-69 mg daily for 14 days, followed by 15-92 mg daily.
  • This combination therapy was well tolerated in the trials. The most commonly reported adverse reactions were dry mouth, dizziness, constipation, insomnia, dysgeusia, paresthesia, and increased resting heart rate. Acute myopia and angle-closure glaucoma also have been reported with topiramate.
  • Patients having this therapy should be monitored for resting heartrate, blood chemistry panel, depression screening. It is not recommended in those with recent or unstable vascular disease, significant depression or active suicidal ideation and is contraindicated in those with glaucoma and hyperthyroidism. As topiramate has teratogenic potential, women of reproductive age should be informed of possible teratogenic risks, undergo pregnancy testing before initiating therapy, monthly thereafter and use effective contraception.

Naltrexone- Bupropion:

  • It is available in market under brand name Contrave and got its FDA approval  in 2014. Naltrexone is mu-opioid receptor antagonist indicated to treat alcohol and opioid dependence. Bupropion is dopamine-norepinephrine reuptake inhibitor and is approved to treat depression and to help with smoking cessation.
  • Combination of these drugs act on 2 areas of brain that control food intake i.e. hypothalamus (appetite) and mesolimbic dopamine circuit (reward system). Naltrexone mediate suppression of an auto-inhibitory effect of β-endorphin (an endogenous opioid) within the hypothalamus. β-endorphin has also been implicated in reward pathways associated with ingestion of palatable food and it has therefore been suggested that decreasing b-endorphin via naloxone influences the mesolimbic dopaminergic reward system leading to modulation of hedonic food reward pathways and enhanced control of eating behavior.
  • Naltrexone- bupropion is available as an extended-release tablet of 8/90 mg. The recommended dose is 8/90 mg for 7 days; then twice a day for 7 days; then 2 tablets in morning and 1 tablet in the evening    for 7 days, followed by 2 tablets twice a day.  Discontinue if < 5% weight    loss at   12 weeks. Dose should be adjusted in hepatic and renal impairment.
  • Most common adverse effects include constipation, vomiting, dizziness, headache, insomnia, dry mouth. It is contraindicated in patients with uncontrolled hypertension, seizure disorder, eating disorder, in pregnancy and in those who have been treated with monoamine oxidase inhibitor within 14 days.

4. Miscellaneous

Liraglutide:

  • It was already licensed for treatment of type 2 diabetes and was approved for treating obesity in 2014 by FDA. Its precise mechanism of action in therapy of obesity is not clear. It is GLP-1 (glucagon like peptide-1 receptor) agonist which acts by stimulating glucose dependent insulin release, slowing gastric emptying and thus may reduce food intake.
  • It is given through injection in abdomen, thigh or arm once daily. The starting dose is 0.6 mg/day up to 1 week and then increase by 0.6 mg weekly to reach daily target dose of 3mg. If there is less than 4 % weight loss at 16 weeks, therapy can be discontinued.
  • The most common adverse effects are nausea, vomiting, hypoglycemia, renal impairment, suicidal thoughts, pancreatitis and gall bladder disease. According to FDA, it is contraindicated in those with a personal or family history of medullary thyroid cancer or multiple endocrine neoplasia (MEN) syndrome type 2, because of an increased incidence of thyroid C-cell tumors in rodents.

               Figure- Mechanism of action of FDA approved weight-loss drugs

Choosing a drug for obese patient

  • When lifestyle modification doesn’t bring desired weight loss, medications are prescribed. Phentermine-topiramate and liraglutide were most likely to produce at least a 5% weight loss, while liraglutide and naltrexone-bupropion were most likely to be discontinued because of adverse events. Combination drugs may have the advantages of synergistic effects on weight loss and fewer adverse reactions.
  • Response to therapy should be evaluated at 12 weeks on the maintenance dose. If less than 5% weight loss has been achieved, the medication should be discontinued. Physician should consider factors like adverse-effect profiles, drug interactions, abuse, misuse, and overdose potential when prescribing these drugs. Weight-loss drugs are contraindicated in pregnancy as they offer no potential benefit to a pregnant woman and may harm the fetus.
  • Only taking these drugs will not be effective therapy for weight loss. Some other points which should be considered during therapy are;
    • Intake of proper diet which is nutritionally adequate and contains low calorie
    • Fat intake below 25% of total calorie prescribed
    • Liberal use of fiber containing foods
    • Regular exercise
    • Restriction of alcohol
    • Behavioral therapy for change in lifestyle.

References

  1. US Department of Health and Human Services. National Institute of Diabetes and Digestive and Kidney Diseases. Overweight and obesity statistics.
  2. Jensen MD, Ryan DH, Apovian CM, et al; American College of Cardiology/American Heart Association Task Force on Practice Guidelines; Obesity Society. 2013 AHA/ACC/TOS guideline for the management of overweight and obesity in adults: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Obesity Society. J Am Coll Cardiol 2014; 63:2985–3023.
  3. Wadden TA, Berkowitz RI, Womble LG, et al. Randomized trial of lifestyle modification and pharmacotherapy for obesity. N Engl J Med 2005; 353:2111–2120.
  4. Mechanick JI, Youdim A, Jones DB, et al. Clinical practice guidelines for the perioperative nutritional, metabolic, and nonsurgical support of the bariatric surgery patient, 2013 update: cosponsored by American Association of Clinical Endocrinologists, the Obesity Society, and American Society for Metabolic and Bariatric Surgery. Surg Obes Relat Dis 2013; 9:159–191.
  5. Kim SH, Lee YM, Jee SH, et al. Effect of sibutramine on weight loss and blood pressure: a meta-analysis of controlled trials. Obes Res 2003; 11:1116–1123
  6. Nissen SE, Nicholls SJ, Wolski K, et al; STRADIVARIUS Investigators. Effect of rimonabant on progression of atherosclerosis in patients with abdominal obesity and coronary artery disease: the STRADIVARIUS randomized controlled trial. JAMA 2008; 299:1547–1560.
  7. Hendricks EJ, Greenway FL, Westman EC, Gupta AK. Blood pressure and heart rate effects, weight loss and maintenance during long-term phentermine pharmacotherapy for obesity. Obesity (Silver Spring) 2011; 19:2351–2360.
  8. Hauptman J, Lucas C, Boldrin MN, Collins H, Segal KR. Orlistat in the long-term treatment of obesity in primary care settings. Arch Fam Med 2000; 9:160–167.
  9. Rossner S, Sjostrom L, Noack R, Meinders AE, Noseda G. Weight loss, weight maintenance, and improved cardiovascular risk factors after 2 years treatment with orlistat for obesity. European Orlistat Obesity Study Group. Obes Res 2000; 8:49–61.
  10. Smith SM, Meyer M, Trinkley KE. Phentermine-topiramate for the treatment of obesity. Ann Pharmacother 2013; 47:340–349.
  11. Gadde KM, Allison DB, Ryan DH, et al. Effects of low-dose, controlledrelease, phentermine plus topiramate combination on weight and associated comorbidities in overweight and obese adults (CONQUER): a randomised, placebo-controlled, phase 3 trial. Lancet 2011; 377:1341– 1352.
  12. Garvey WT, Ryan DH, Look M, et al. Two-year sustained weight loss and metabolic benefits with controlled-release phentermine-topiramate in obese and overweight adults (SEQUEL): a randomized, placebo-controlled, phase 3 extension study. Am J Clin Nutr 2012; 95:297–308.
  13. Richa S, Yazbek JC. Ocular adverse effects of common psychotropic agents: a review. CNS Drugs 2010; 24:501–526.
  14. Weissman NJ, Sanchez M, Koch GG, Smith SR, Shanahan WR, Anderson CM. Echocardiographic assessment of cardiac valvular regurgitation with lorcaserin from analysis of 3 phase 3 clinical trials. Circ Cardiovasc Imaging 2013; 6:560–567.
  15. US Department of Justice Drug Enforcement Administration. Schedules of controlled substances: placement of lorcaserin into Schedule IV. Federal Register 2013; 78:26701–26705.
  16. Contrave (naltrexone HC1 and bupropion HC1) extended release tablets [package insert]. Orexigen Therapeutics, 2017.
  17. Sweeting AN, Hocking SL, Markovic TP. Pharmacotherapy for the treatment of obesity. Molecular and Cellular Endocrinology. 418(2015); 173-183.
  18. Pharmacology and Pharmacotherapeutics. Page no- 592-596.