Clinical Feature: New Pharmacologic Approaches to Obesity

Changed lifestyles and diet have been associated with the current obesity epidemic. Pharmacologic interventions date back to the Greco-Roman era when laxatives coupled with exercise and other modalities to facilitate weight loss were prescribed or used. Many still remember the use of the following medications: thyroid hormone, amphetamines, digitalis, diuretics and dinitrophenol. These were early 20^th century options. Phentermine was approved in 1959 by the U.S. Food and Drug Administration (FDA) as an adjunct to diet. Its mechanism of action appears to be related to stimulation of the hypothalamus to release norepinephrine resulting in reduced appetite while increasing at-rest energy expenditure. While phentermine was still on the market and although riddled with side effects such as insomnia and irritability, new players emerged. Fenfluramine (3-trifluoromethyl-Nethylamphetamine) is a drug that was part of the fen-phen anti-obesity regimen, the other component was phentermine.

Fenfluramine was introduced on the U.S. market in 1973. Dexfenfluramine was introduced 20 years later as a "reduced side effects" fenfluramine. Fenfluramine and dexfenfluramine likely upregulated 5HT_2B receptors as their weight-loss mechanism.

Patients were only to be on the "fenphen" combination for 12 weeks. Late in 1997 there were reports of significant valvulopathy in patients who had been on the medications for more than six months. These led to the withdrawal of fenfluramine and dexfenfluramine but not phentermine.

Orlistat entered the market in 1999 as the prescription medication Xenical®. The action mechanism is to inhibit gastric and pancreatic lipases and when taken with a meal containing fat. This concept renders the medication less effective for patients on a low-fat, low-carbohydrate diet. While the weight loss was modest, the orlistat in the Prevention of Diabetes in Obese Subjects (XENDOS) study showed patients taking orlistat lost an average of 2.7 kg more in 1 year compared to placebo.² Common adverse reactions with orlistat include oily spotting, flatus with discharge, fecal urgency, fatty/oily stool, oily evacuation, increased defecation and fecal incontinence. Monitoring of renal function because of increases in oxalate levels also is recommended.³

In 2007, the FDA approved over-thecounter orlistat under the brand name Alli. It is available as a 60mg capsule - the prescription dose is 120mg - and is administered the same way as the prescription version. Because of its interference with absorption of fat from the gastrointestinal tract, the absorption of fat-soluble vitamins (A, D, E and K) may be impaired. Consequently patients should take a daily multivitamin supplement containing these vitamins when using this agent.

While it would appear that a non-absorbed agent would be totally safe, the FDA in 2010 added information about reported cases of liver injury tied to orlistat.^4,5 The package insert notes some success when tested with adolescent patients ages 12-16. Additional studies show that weight regain remains less with orlistat compared to a placebo.⁶

As previously noted, phentermine remains on the market in various generic formulations. It appears to reduce appetite through augmentation of adrenergic nerve transmission, both peripherally and centrally. Similar to amphetamines, it is classified as a Schedule IV drug with very low abuse potential. The FDA’s labeled indications say it should be used for a few weeks (no>3mos) along with diet, exercise and behavioral modification for the management of obesity.⁷ To avoid insomnia, the medication should be taken in the morning. While not FDA approved, some continue treatment beyond 12 weeks.

Two new obesity medications recently were approved by the FDA. Lorcaserin (Belviq®) and phentermine-topiramate (Qsymia®). These were approved for use in patients as an adjunct to diet and exercise for chronic weight management in adult patients with an initial body mass index (BMI) of 30 kg/m² or more (obese) or 27 kg/m² or more (overweight) in the presence of at least one weight-related comorbid condition (e.g., hypertension, dyslipidemia, type 2 diabetes).^8,9 With new action mechanisms, these modalities are the first recent additions to obesity therapy in many years.

Lorcaserin is a selective agonist of 5-HT2C receptors that are mainly in the brain – in areas of the cortex, choroid plexus, hippocampus, cerebellum, amygdala, thalamus and hypothalamus. The activated proopiomelanocortin (POMC) cell region of the hypothalamus is believed to trigger proopiomelanocortin production and promote satiety.¹⁰ Lorcaserin’s selectivity for the 5-HT2C receptor is significantly less than for the 5-HT2A and 5-HT2B receptors. Lorcaserin's exact action mechanism to decrease food consumption and promote satiety is not fully known.¹¹

The approved dose is 10mg twice daily with no regard to administration with meals. The medication is administered in mild to moderate renal impairment (CrCl 30-50ml/min) without altering dose. There is limited data in patients with Child-Pugh Class C hepatic impairment or in patients with CrCl <30ml/min, so caution is advised. Side effects including headache, sinusitis and upper respiratory tract infection are mild and well tolerated. Lorcaserin is in pregnancy Category X.^8,11

Three pivotal trials demonstrated lorcaserin efficacy, the first being a 52-week trial of the 10mg-twice-daily and 10mg-once-daily doses versus placebo. The criterion for success was 5% weight loss from baseline. More weight loss (47.2%) was noted with the twice-daily group versus the oncedaily (40.2%) or placebo (25%) groups. Dropout rates approximated half of the study population. Side effects were mild, as previously noted.¹²

Similarly, in another trial, 47.5% of those in the lorcaserin-twice-daily group achieved targeted results as compared to 20.3% of those in the placebo group.¹³ In the BLOOM-DM diabetes trial more patients lost ≥5% body weight with lorcaserin daily (44.7%) compared to twice daily (37.5%) or placebo (16.1%).¹⁴ Vavlulopathies at one year occurred in 2.4% of patients assigned to lorcaserin and 2% of those in the placebo group. In the Behavioral Modification and Lorcaserin Second Study for Obesity Management (BLOSSOM) study, 12% developed valvular regurgitation in the twice-daily group and 11% in the once-daily cohort. There were minimal improvements in serum lipids with lorcaserin. After two years of exposure to lorcaserin, the rate of valvulopathy was 2.6%; it was 2.7% in the placebo arm.^12,13,14 The FDA originally delayed approval in 2010 because of concerns about tumors in rats receiving high doses of lorcaserin. With subsequent studies, the FDA approved the medication in 2012.^15,16

The combination of phenterminetopiramate also was recently approved by the FDA. Unlike lorcaserin, this product is governed by a Risk Evaluation and Mitigation Strategy (REMS) program. The mechanism of phentermine was previously discussed and, while the exact mechanism is unclear, topiramate increases satiety and suppresses appetite. Possible mechanisms include increasing the activity of the neurotransmitter gamma-aminobutyrate, modulation of voltage-gated ion channels, inhibition of alpha-amino-3-hydroxyl-4- isoxazole-propionic acid/kainite excitatory glutamate receptors, or inhibition of carbonic anhydrase.

Doses start at 3.75mg/23mg (phentermine/ topiramate) for 14 days then increase to the 7.5mg/46mg dose. If a 3% loss in total body weight is not reached by Week 12, then the medication is discontinued. Doses can be increased to the maximum 15mg/92mg dose, but the drug should be discontinued if a 5% weight loss is not achieved after 12 weeks on the maximum dose. To avoid seizure, the drug should be slowly discontinued (taken every other day) for a week.

Adverse events such as tachycardia, paresthesia, dizziness, dysgeusia, insomnia, constipation and dry mouth are infrequent. Phetermine/topiramate is in pregnancy Category X. In the EQUIP study, a significant difference in weight loss was noted with the 3.75mg/23mg and 15mg/92/mg doses compared to the placebo. Patients receiving the maximal dose showed significant improvements in fasting glucose, triglycerides, high-density lipoprotein (HDL) cholesterol and lowdensity lipoprotein (LDL) cholesterol. In the large CONQUER study, between 60% and 70% (low dose versus high dose) of patients achieved the target of at least 5% weight loss from baseline.^12,13,14 While attractive as moderate weight loss drugs, costs and lack of insurance coverage for these agents (Table 1) may limit their use.

Other medications that are currently under investigation include a fixed combination of naltrexone, bupropion and liraglutide. Table 1 provides a summary of the common current weight-loss medications. Full drug information on each of these available medications is available from the manufacturers.

Popular OTC medications for weight loss include green tea, green coffee, conjugated linoleic acid, guarcia, guarana chromium and bitter orange, among others. While interactions are possible, they usually concentrate around those items with stimulant activities and other stimulant medications, including monoamine oxidase (MAO) antidepressants. Items such as green coffee extract, green tea extract and bitter orange may have moderate interactions with stimulant drugs.

OTC diet supplements containing ephedra were removed from the market by the FDA in 2004. Ephedra was a non-selective alpha and beta receptor stimulant. Adverse reaction reports linked ephedra to serious side effects, including hypertension, myocardial infarction (MI), seizure, stroke, psychosis and other illness.²⁰

There has been a long time desire for pharmacotherapy options to enhance weight loss not achieved by diet and exercise alone. The currently available medications offer a variety of choices for the clinicians – whether pediatric, adult or geriatric – to offer their patients. The agent of choice should be closely monitored for effects and adverse reactions.

Disclosure statement: Dr. Kellick has no disclosures to report.