Bariatric Times

APR 2018

A peer-reviewed, evidence-based journal that promotes clinical development and metabolic insights in total bariatric patient care for the healthcare professional

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The Medical Student Notebook 9 Bariatric Times • April 2018 which is why the FDA approved this medicine. Lomaira itself, however, has not been specifically tested in clinical trials, making these claims debatable. 4 Phentermine is one of the more affordable weight-loss medications on the market, with an average retail price of $34.78 for 30 tablets (cost per dose: $1.16). With coupon, this medicine is available for $10.26. 13 Orlistat (Alli). Orlistat (marketed as Alli or Xenical) is a lipase inhibitor approved by the FDA first in 1999 as a prescription drug for obesity management and again in 2007 as an over-the-counter medication for weight loss. Orlistat achieves its effect by interrupting the absorption of fat in the gastrointestinal system. A double-blind, randomized, controlled trial in 1999 demonstrated that a third of patients who received the drug lost greater than five percent of their body weight and saw a significant drop in their serum lipid levels. 14 The interference of fat absorption led to some predictable side effects, including fatty stools, flatulence, oily spotting, and fat-soluble vitamin deficiencies, among others. 15 Orlistat is the most affordable weight-loss drug with an average retail price of $39.94 for 60 pills (cost per dose: $0.67). 16 Lorcaserin (Belviq). Approved in June 2012, lorcaserin (trade name Belviq) works by centrally suppressing appetite. Specifically, lorcaserin selectively activates the 5-HT2 C receptors in the pro- opiomelanocortin neurons of the hypothalamus to promote satiety. In a 2010 trial, nearly 50 percent of lorcaserin-treated patients lost five percent or more of their body weight compared to only 20 percent of placebo-treated patients. 17 Adverse effects of the drug were minimal, with most patients citing headache, dizziness, and nausea as their primary complaints. Few patients experienced the adverse cardiovascular events that less selective drugs of the serotonin class like fenfluramine caused. 4 Belviq has an average retail price of $322.27 for 60 tablets (cost per dose: $5.37). Patients can use a free coupon to receive 13 percent off the medication, bringing the price down to $279.39. 18 Phentermine/topiramate (Qsymia). In July of 2012, phentermine was approved for weight loss yet again. This time, it achieved an improved therapeutic effect in combination with topiramate, an antiepileptic drug known to induce anorexia. While the exact mechanism of action is not clearly understood, the drug combination led to a significantly higher proportion of patients achieving greater than five percent weight loss compared to placebo (67% vs 17%, respectively). 19 Drug-treated patients also saw significant reductions in hypertension and hyperlipidemia. Major adverse effects included insomnia, dry mouth, and constipation. 4 Just as phentermine can be independently taken for weight loss, so too can topiramate. Topiramate alone can achieve the appetite suppression that Qsymia produces. This strategy should be employed when patients cannot use phentermine due to side effects or contraindications. 11 Importantly, though, the efficacy of this drug combination reported above is specific to the Qsymia combined formulation. The effect is not as significant when phentermine and topiramate are separately prescribed but simultaneously taken. The average retail price of Qsymia is $235.94 (cost per dose: $7.86), although discounts bring the price down to $193.25. Some patients may be prescribed the components of the combination individually for a cheaper overall price, despite decreased weight-loss effectiveness. 20 Naltrexone/buproprion (Contrave). The naltrexone/ buproprion combination drug was approved in September 2014 under the trade name Contrave. It achieved its therapeutic effect by targeting the same pro-opiomelanocortin neurons that lorcaserin acted on. Uniquely, though, the naltrexone component of Contrave antagonized opioid receptors to augment buproprion's activation of those neurons. The effect led to significantly reduced food craving and appetite suppression in patients. Approximately 56 percent of patients treated with Contrave lost greater than five percent of their weight compared to only 18 percent on placebo. 21 The most common side effect patients reported was nausea, with minimal other adverse effects. The average retail price is $310.30 for 120 tablets (cost per dose: $2.59), but free rebates can bring the price down to $234.69. 22 Liraglutide (Saxenda). Liraglutide, a GLP-1 agonist originally approved for Type 2 diabetes management, is an injectable therapy that both promotes satiety and affects glucose homeostasis. Liraglutide is produced by Novo Nordisk (Bagsværd, Denmark) in two formulations: Victoza and Saxenda. Victoza is used for glucose homeostasis in diabetes management. Saxenda is specifically indicated for weight loss. Saxenda's 3.0mg dose versus Victoza's maximum 1.8mg dose make Saxenda more effective at promoting weight loss. In 2014, the results of a double-blind, placebo-controlled trial demonstrated that 76 percent of patients on Saxenda lost greater than five percent of their weight compared to only 30 percent on placebo. 23 Moreover, Saxenda reduced both hypertension and hyperglycemia in treated patients. Nausea and vomiting were the most common adverse effects, with the therapy being otherwise well tolerated. Saxenda for weight loss is by far the most expensive prescription weight loss medication on the market. Its average retail price is $1,405.38 for 30 injections (cost per dose: $46.85), but coupons can bring the cost down to $1,233.57 and additional rebates are also available. 24 RISKS In addition to the side effects of prescription weight loss drugs mentioned above, ranging from nausea to stimulant-like effects of phentermine to even the fatty stools and vitamin deficiencies caused by orlistat, there are other considerable risks of these medicines that should be kept in mind. Accordingly, patients with particular conditions that could be worsened by these side effects are contraindicated from taking those medications. Patients with cardiovascular disease, hyperthyroidism, history of drug abuse, or who are currently on monoamine oxidase inhibitors (MAOIs) or tricyclic antidepressants are recommended against using phentermine, phentermine/topiramate, or naltrexone/bupropion. 4 Those with cholestasis or malabsorption problems should not use orlistat. Pregnant patients should avoid using all weight-loss drugs. 10 Liraglutide is contraindicated in individuals with a family or personal history of thyroid malignancy or multiple endocrine neoplasia Type 2 (MEN2) because of its association with medullary thyroid cancer. 4 Most of the medicines with the worst reported adverse effects have been withdrawn from the market, including sibutramine for increasing risk of cardiovascular disease, rimonabant for increasing risk of depression, and fenfluramine for increasing risk of cardiac valvulopathies and primary pulmonary hypertension. 25,26 CONCLUSION Weight-loss therapeutics are important tools in obesity management. They offer auxiliary support for patients struggling to achieve their weight loss goals through diet, exercise, and behavior changes alone. Most of them help patients lose 3 to 7 percent of their excess body weight in the long term. Importantly, though, these medications are only successful when coupled with intensive lifestyle intervention. Additionally, their risks are not insignificant. Patients with certain comorbidities must be careful to avoid anti-obesity medicines that will have adverse effects on them. Given the history of hazardous drugs for weight loss, physicians are likely to be more reluctant prescribing these therapies for their patients. And although most of these medicines are reasonably priced, the more recently approved ones are less affordable. While rebates and discounts can make these drugs more affordable, patients without adequate insurance coverage might struggle to purchase them for an extended period of time. Of the options for weight loss available to patients with obesity, lifestyle interventions remain the most safe and accessible and bariatric surgery remains the most efficacious. The reviewed medicines, while helpful as adjuncts, are not effective enough to be considered first-line. These drugs are, however, helpful for patients who do not meet the more stringent BMI criteria of 40 or 35 with comorbidities for bariatric surgery. They can also be considered for patients who need assistance with maintaining weight loss after receiving bariatric surgery, although no specific trials have been conducted to measure TABLE 1. Summary of therapeutic options for weight loss (WL) approved by the United States Food and Drug Administration (FDA) NAME (TRADE) MECHANISM OF ACTION EFFICACY* SIDE EFFECTS** COST*** Phentermine Sympathomimetic—suppresses appetite (a) 46% (b) 4.5kg Anxiety, dizziness, hypertension, constipation (a) $34.78 (b) $1.16 Orlistat (Alli) Lipase inhibitor—reduces fat absorption (a) 33% (b) 2.0kg Vitamin deficiencies, fatty stools, flatulence (a) $39.94 (b) $0.67 Lorcaserin (Belviq) Selective 5-HT2C receptor agonist — promotes satiety (a) 50% (b) 3.6kg Headache, dizziness, nausea (a) $322.27 (b) $7.86 Phentermine/ Topiramate (Osymia) Sympathomimetic + antiepileptic— suppresses (a) 67% (b) 7.5kg Topiramate: numbness/tingling of hands or paresthesias; Phentermine: see above (a) $235.94 (b) $7.86 Naltrexone/buproprion (Contrave) Norepinephrine reuptake inhibitor + pure opioid antagonist—suppresses appetite (a) 56% (b) 4.6kg Nausea (a) $310.30 (b) $2.59 Liraglutide (Saxenda) GLP-1 agonist —suppresses appetite + glucose homeostasis (a) 76% (b) 4.4kg Nausea, vomiting (a) $1,405.38 (b) $46.85 * (a) Percentage of patients on intervention that lost >5 percent weight in randomized, controlled trial; (b) Absolute intervention weight loss minus placebo weight loss in randomized, controlled trial ** See text section on risks for contraindications *** (a) Average retail cost; (b) Cost per dose

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