Weight Loss Drugs: What Works?

[Guest guest]

Wanted: A Pill That Melts Fat

As Americans become more obese and the associated health problems reach

epidemic proportions, the need for a safe and effective weight loss drug has

become urgent. Over the years, this quest has been marked with short-lived

triumphs and many defeats, leaving patients and clinicians with less than

ideal weapons in the fight against obesity.

The few drugs that have actually reached the market in recent years promote

weight loss either by boosting the body's basal metabolic rate, blocking the

absorption of dietary fat, or suppressing appetite.People who take these

drugs typically lose weight for the first 6 months until they reach a

plateau that can't be surpassed without increasing exercise or caloric

restriction.The problems with many of these agents have been a lack of

proven long-term safety, and the fact that when such drugs are stopped, the

weight is usually regained.

Most clinicians are aware that pharmacotherapy is not indicated as a

first-line therapy for obesity, and should not be initiated until all

nonpharmacologic attempts at weight loss (diet, exercise) have failed.[1] It

is also important to evaluate other medications that the patient may already

be taking, as some may promote weight gain (eg, sulfonylureas,

thiazolidinediones, and insulin), thereby negating the effects of

anti-obesity drugs.[2]

The decision to prescribe a weight-loss drug involves a careful assessment

of the risks and benefits.[3] As a general rule, an effective regimen should

help patients lose at least 4 pounds in the first 4 weeks, or 5% of baseline

weight in the first 3 months on therapy.

As researchers continue searching for an ideal weight-loss agent, clinicians

must work with available therapies while awaiting newer drugs in the

pipeline.

Currently on the Market

Two classes of weight-loss agents are currently available by prescription:

noradrenergic agents for short-term weight loss and a lipase inhibitor for

long-term weight loss.

Phentermine

Phentermine is US Food and Drug Administration (FDA)-approved for short-term

(up to 12 weeks) treatment of obesity and is the most widely prescribed

weight-loss drug in the United States.[4] Phentermine is an adrenergic

reuptake inhibitor,[5] stimulating the sympathetic nervous system to release

norepinephrine, one of the neurotransmitters involved in modulating food

intake. Phentermine suppresses appetite and induces satiety much like

amphetamines, but has little effect on dopamine transmission, mitigating its

abuse potential.[1] Because its effects last about 12 hours, phentermine

should be taken in the morning. When used in combination with diet and

exercise, phentermine has produced an average 3.6 kg greater weight loss

than placebo.[6]

Phentermine is the relatively " safe half " of the formerly popular (but no

longer on the market) weight-loss drug phentermine-fenfluramine (phen-fen).

Fenfluramine (but not phentermine) was linked to pulmonary hypertension and

valvular heart disease. Phentermine alone was found to be an effective

anorectic, and it is still available as a prescription drug in 15 mg to 37.5

mg strengths[7] (although many manufacturers discontinued it).

Adverse effects include irritability, nervousness, restlessness, dry mouth,

insomnia, constipation, and headache, but it has also been associated with

hypertension, tachycardia, and palpitations, so it should not be taken by

patients with cardiovascular disease or significant hypertension. Blood

pressure should be monitored during therapy.

Diethylpropion

Like phentermine, diethylpropion is a noradrenergic agent with a similar

mechanism of action (releasing and inhibiting the uptake of

neurotransmitters norepinephrine and dopamine). Diethylpropion is available

in 25-mg standard or 75-mg extended-release formulations, and is approved

for short-term treatment of obesity.

In a recent study, 69 obese healthy adults were treated with diet and

diethylpropion or diet and placebo.[8] After 6 months, the diethylpropion

group lost an average of 9.8% of initial body weight vs 3.2% in the placebo

group (*P* < .0001). In 1 year, the mean weight loss in patients taking

diethylpropion was 10.6%. Dry mouth and insomnia were the most frequent

adverse events.[8]

Benzphetamine and Phendimetrazine

Two other sympathomimetic drugs benzphetamine and phendimetrazine are still

available by prescription for short-term weight loss. These drugs also act

centrally, releasing dopamine and norepinephrine, resulting in appetite

suppression, increased blood pressure, and increased heart rate. As schedule

III drugs, however, benzphetamine and phendimetrazine have more potential

for addiction and therefore are prescribed less often.[9]

All sympathomimetic drugs stimulate the central nervous system, and can

increase blood pressure and heart rate, while releasing glycerol and free

fatty acids.[9] Still, in a recent survey of obesity specialists in the

United States, these were among the most frequently prescribed drugs in the

clinical treatment of obesity. Most respondents (97%) reported prescribing

phentermine, 64% prescribed diethylpropion, and 60% prescribed

phendimetrazine.[4]

Orlistat

A gastrointestinal and pancreatic lipase inhibitor, orlistat was approved in

1999 as the first in a new class of anti-obesity agents. In the

gastrointestinal tract, orlistat binds to gastric and pancreatic lipases,

preventing these enzymes from hydrolyzing dietary fat into absorbable free

fatty acids.[1] When not absorbed, triglycerides are excreted in the feces,

along with cholesterol and fat-soluble vitamins. Taken with meals, orlistat

can block the absorption of 30% of ingested fat.[5] In this manner, orlistat

reduces caloric intake and may have additional benefits.

A Cochrane meta-analysis[10] of 11 randomized controlled trials of orlistat

found that overweight and obese individuals who took orlistat had a mean

weight loss of 2.9 kg (2.9%) more than those who took placebo. Compared with

placebo, orlistat also significantly reduced waist circumference, body mass

index (BMI), blood pressure, fasting glucose, and hemoglobin A1c

concentrations in patients with diabetes, as well as total cholesterol,

low-density lipoprotein cholesterol (LDL-C), and high-density lipoprotein

cholesterol (HDL-C) concentrations.[2]

Adverse effects of orlistat are fairly common, affecting 15%-30% of patients

and considered unpleasant and unacceptable by some patients.[2] These

include steatorrhea, bloating, fecal urgency, fecal incontinence, and oily

stools.[5] Orlistat might also interfere with the absorption of fat-soluble

vitamins, including vitamins A, D, E, and K, so it has been suggested that

patients taking orlistat should also take a multivitamin supplement

containing these micronutrients, at least 2 hours before or after the

administration of orlistat.

Concerns about a link between orlistat and colon cancer, as well as possible

liver damage, are currently being investigated.[11] Orlistat may also

interfere with the absorption, and therefore the effectiveness, of other

drugs the patient is taking, such as amiodarone and cyclosporine, and

through its effect on vitamin K, it can prolong bleeding in patients taking

warfarin.[11] This class of drug should probably be avoided in patients with

gastrointestinal disease or malabsorption syndromes.[2]

Orlistat is currently available as a prescription drug (Xenical® 120 mg) or

an over-the-counter weight loss supplement (Alli® 60 mg). Although it is

approved for long-term weight loss, orlistat's somewhat low tolerability and

high cost may limit its long-term use.

Withdrawn or Awaiting Approval

The fall of 2010 was a discouraging time for those who are desperate for a

new obesity treatment, including patients who say they would be willing to

accept some risk if they were able to lose weight. Hopes were raised and

then dashed as promising therapies slipped off the horizon in October, just

after an established drug was withdrawn from the market. But companies

touting the new therapies are continuing to collect safety information that

they hope will satisfy regulators and ultimately allow them to sell their

products.

Sibutramine

Abbott, maker of the sibutramine product Meridia®, issued a voluntary

product recall in October upon being asked by the FDA to stop marketing

Meridia in the United States; this followed reports of an increased risk for

heart attack and stroke in Meridia users. Meridia had already been recalled

earlier in Canada and Europe.

Sibutramine hydrochloride is a centrally acting monoamine reuptake

inhibitor, affecting primarily serotoninand norepinephrine, and to a lesser

extent, dopamine.[1] Originally used to treat depression, patients taking

sibutramine experienced weight loss as an unexpected effect. Although

diminished hunger and increased satiety are the most likely mechanisms of

weight loss, sibutramine may also increase thermogenesis, thus increasing

energy expenditure by increasing metabolism.[1]

The Sibutramine Cardiovascular OUTcomes (SCOUT) trial was a 6-year study of

10,000 patients, conducted to assess cardiovascular safety in high-risk

patients. It showed that, after 5 years (the end of the trial), the average

difference in body weight between patients taking Meridia and those taking a

placebo was about 2.5%. On long-term follow-up, a 16% increased risk for

nonfatal heart attacks and nonfatal strokes was seen in patients with

pre-existing cardiovascular risk factors.[12] This was considered by some to

be an unacceptable benefit to risk ratio. However, the manufacturer asserts

that the increased cardiovascular events occurred primarily in patients with

underlying cardiovascular disease, a patient population in whom Meridia is

contraindicated according to enhanced labeling initiated earlier this year.

[13]

Lorcaserin

Lorcaserin is an anti-obesity drug of the 5-HT2C agonist class. The

stimulation of specific central serotonin receptors suppresses appetite and

induces a feeling of satiety. Lorcaserin is highly selective for the

5-HT2C receptor,

which modulates fat and caloric intake.[14] Signaling through the 5-HT2A and

5-HT2B receptors (found on cardiac valves), however, is minimal.[2]

In a large trial (3182 patients), those who took lorcaserin lost an average

of 5.8% of their baseline body weight compared with 2.2% in those who took

placebo (*P* < .001).[15] Nearly half of the patients taking lorcaserin lost

5% or more of their baseline body weight, compared with 20% of those taking

placebo, and more of the lorcaserin patients maintained their weight loss

after the study had ended. Very few patients in the lorcaserin group failed

to lose weight.

Other improvements associated with lorcaserin were: reduced BMI and waist

circumference; lower fasting glucose, insulin, and A1c levels; and lower

total cholesterol, LDL cholesterol, and triglycerides. However, despite

beneficial effects on risk for cardiovascular disease (reduced C-reactive

protein, fibrinogen level, systolic and diastolic blood pressure, and heart

rate), the FDA voted against approval of lorcaserin in October, citing

concerns about lorcaserin-induced valvular heart disease (as well as brain

and breast tumors) in declining to recommend lorcaserin for the treatment of

obesity.[16]

The agency requested additional data about lorcaserin from drug maker Arena

Pharmaceuticals, and the company says it will meet with the FDA before the

end of the year, partly to discuss new, " encouraging " data regarding

lorcaserin's effects on obese patients with diabetes.

Phentermine/Topiramate

Qnexa® (made by Vivus, Inc.) combines low-dose phentermine with a

controlled-release form of topiramate, an antiepileptic drug often used for

the prevention of migraine headache. Topiramate inhibits excitatory

neurotransmissions by blocking voltage-gated sodium channels,[17] and is

sometimes prescribed as monotherapy for weight loss.[4] Topiramate reduces

hunger and promotes weight loss in a dose-dependent fashion, but the

peripheral and central nervous system effects (parasthesias, memory

impairment, taste disturbance) are significant and intolerable in some

patients.[18] Topiramate has the added advantage of having mood-stabilizing

properties.[5]

Harnessing the effects of the 2 different but complementary mechanisms of

phentermine and topiramate allows the use of lower doses of each agent,

which should increase safety.[19] This drug combination reportedly induces

substantial weight loss, an average of about 10% after 1 year, and

significantly reduces systolic blood pressure. Patients taking lower doses

of the drug combination lose less weight, but that is still more than those

taking placebo.

Despite evidence of effectiveness in phase 3 trials extending to 1 year, the

FDA voted against approval of Qnexa in October, expressing concerns about

adverse effects associated with its use, including cognitive disorders,

metabolic acidosis, increased heart rate, and birth defects, suggesting

possible teratogenicity.

Before Qnexa can be approved, the FDA has requested further evidence of its

safety.[19] If approved, it would be a schedule IV drug due to the

phentermine component.

Naltrexone/Bupropion

Contrave®, another new dual anti-obesity agent, is the combination of the

antidepressant bupropion and sustained-release (SR) naltrexone, a drug used

to treat alcoholism and other addictions. Bupropion, approved for both

depression and smoking cessation, also increases dopamine levels at specific

receptors in the brain, which is believed to be responsible for its

appetite-reducing effects.[20] These 2 drugs work on the brain reward system

and the hunger centers in the hypothalamus, and are believed to be

synergistic in reducing food intake.[21]

If approved, this combination therapy could be useful for patients who have

issues with food craving. When used with a mild hypocaloric diet and with

exercise instruction in overweight or obese patients, it is associated with

greater weight loss and greater improvement in several cardiometabolic risk

factors compared with placebo.[22] Combination treatment was generally well

tolerated; adverse effects included insomnia, nausea, headache, dry mouth,

and a small and transient increase in systolic and diastolic blood pressure.

[22]

Contrave has not yet been reviewed by the FDA, but phase 3 clinical trials

have been completed. The manufacturer, Orexigen, reports that Contrave met

all of its primary endpoints for weight loss in these trials, even in

patients with diabetes, it also was associated with improvements in

cardiometabolic risk markers such as waist circumference, HDL-C levels, and

triglyceride levels.[23] Contrave is up for review by the FDA's

Endocrinologic and Metabolic Drugs Advisory Committee in December 2010.[23]

The fate of this anti-obesity agent will not be known until sometime in

2011.

In the Pipeline Zonisamide/Bupropion

In clinical trials for the relatively new antiepileptic zonisamide, an

unanticipated effect was weight loss. It has, therefore, been studied for

its potential as a weight-loss agent, either in monotherapy or in

combination with other agents such as bupropion. Zonisamide has sodium and

calcium channel blocking activity, as well as dose-dependent biphasic

dopaminergic and serotonergic activity. Empatic™ (made by Orexigen) is a

fixed-dose combination of a proprietary formulation of zonisamide SR and

bupropion SR.

In trials at Duke University, zonisamide alone with a hypocaloric diet was

shown to be more effective in reducing weight than placebo.[24] The same

investigators have conducted a short-term, open-label trial of treatment

with zonisamide and bupropion, finding that the combination resulted in more

weight loss than zonisamide alone.[25] Fatigue, drowsiness, sedation,

nausea, and cognitive impairments (difficulty concentrating, memory

problems, speech and language difficulties) have all been reported with

zonisamide use.[25]

The manufacturer of Empatic recently reported that in phase 2b trials,

patients who took the drug for 24 weeks lost 9.9% of their baseline body

weight compared with 1.7% for patients taking placebo, without evidence of a

plateau. Improvements in waist circumference, triglycerides, fasting

insulin, and blood pressure were also reported.[23] Phase 3 trials are now

planned.

Tesofensine

Tesofensine (made by NeuroSearch) is a triple monoamine reuptake inhibitor

that blocks the presynaptic uptake of norepinephrine, dopamine, and

serotonin.[17] Originally being studied for neurodegenerative conditions

such as Parkinson and Alzheimer diseases, unintended weight loss was

observed in individuals treated with the drug.[26]

The mechanisms through which tesofensine leads to weight loss are a

pronounced effect on appetite suppression and increased energy expenditure.

[27] In phase 2 clinical trials with tesofensine in obese patients,

dose-related reductions in body weight, body fat, and waist circumference,

as well as improvements in other obesity-related measures, were observed.

Minor adverse events included elevations in heart rate and significant

increases in blood pressure only at the highest tested dose.[28] The drug is

soon to be tested in phase 3 clinical trials.[26]

Cetilistat

Cetilistat is a new lipase-inhibitor with a similar mode of action to

orlistat, inhibiting pancreatic lipase and blocking digestion and absorption

of dietary fat, so that it can be eliminated unchanged with the stool.

Cetilistat has completed a 12-week phase 2b trial in obese patients,

demonstrating weight loss consistent with other obesity medications and

significant improvements in other obesity-related parameters.[29] Unpleasant

adverse effects, including flatus with discharge and oily spotting, were

reported by fewer than 3% of patients using cetilistat.

It is probable that, like orlistat, cetilistat will also block the

absorption of fat-soluble vitamins, and this possibility was raised by the

FDA in 2009, cautioning that cetilistat could " lead to malabsorption of

nutrients and vitamin deficiency. " [30] Cetilistat has now been cleared to

conduct phase 3 trials in patients with obesity.

Pramlintide/Metreleptin

The combination of these 2 agents represents a novel integrated

neurohormonal approach to obesity.[31] Pramlintide is an analogue of amylin,

a hormone secreted by pancreatic beta cells along with insulin. Exogenous

amylin can increase the absorption of glucose, slow gastric emptying, and by

binding to hypothalamic receptors, promote satiety, reduce food intake and

elicit weight loss. Metreleptin is recombinant methionine human leptin.

Leptin is a neurohormone secreted by adipocytes that also binds to receptors

in the hypothalamus to promote satiety. When someone reduces dietary intake

to lose weight, leptin levels drop, and this triggers a host of

counter-regulatory responses aimed at maintaining body weight.

Administration of metreleptin restores leptin concentrations and attenuates

the effects of counter-regulation.[31]

Pramlintide is already an approved drug in the treatment of diabetes.

Metreleptin has been tested as monotherapy for obesity/weight loss, but

failed because of the development of leptin resistance. However, these 2

hormones are believed to act synergistically to reduce food intake and body

weight.

Mildly and moderately obese patients (without diabetes) who took this

combination lost about 13% of baseline body weight in 24 weeks with no

weight-loss plateau, significantly more than was seen with either drug

administered as a single agent. Patients who continued treatment with

pramlintide/metreleptin for a total of 52 weeks exhibited sustained weight

loss, whereas those who received placebo during the extension study regained

almost all of their lost weight. The combination therapy appeared to be

generally well tolerated. The most common adverse effect was nausea.[31]

Pramlintide/metreleptin combination is an injectable therapy, which may

limit its application in the general obese population.

Potential Future Therapies

ZGN-433, a methionine aminopeptidase inhibitor, targets the adipose tissue

rather than the central nervous system. This class of medication essentially

works by restoring control of adipose tissue lipolysis, ketogenesis, food

intake, and fat synthesis. ZGN-433 is believed to stimulate adipose tissue

to convert stored triglycerides into free fatty acids that can be used for

energy.[32]

ZGN-433 is still in the early stages of development but has shown promise in

rodent studies. A safety and tolerability study in humans is in progress.

Another novel therapy that may have a role in weight loss is ezlopitant, a

neurokinin receptor-1 (NK1R) antagonist. The NK1R system has been implicated

in both learned appetitive behaviors and addiction to alcohol and opioids;

recent evidence from rodent studies suggests that ezlopitant reduces the

appetite for sucrose as well, thus decreasing the consumption of sweetened

foods and drinks.[33] It has been suggested that sweet foods and drinks can

be addictive in the same way as alcohol, explaining the suppressant effects

of ezlopitant.

The antidiabetes drugs represent another possible drug class to mine for

potential weight-loss effects and for possible development as dual

diabetes/obesity agents. Metformin, a biguanide approved for the treatment

of type 2 diabetes, causes weight loss by reducing hepatic glucose

production and intestinal absorption from the gastrointestinal tract, and

enhancing insulin sensitivity.[34]

Liraglutide (Victoza®), another drug that is already approved for the

treatment of type 2 diabetes, induces moderate weight loss of approximately

2-3 kg.[35] The glucagon-like peptide-1 (GLP-1) receptor agonists exenatide

and liraglutide are newer medications for diabetes that have favorable

effects not only on glycemic control but also on weight loss.[3] Although

some of these agents might not induce enough weight loss to qualify as

anti-obesity agents, they could prove useful for overweight individuals who

have diabetes.[34]

Final Thoughts on Anti-Obesity Pharmacotherapy

Obesity is a chronic, relapsing, biologic condition that may well require

long-term pharmacotherapy, in the same manner as hypertension and diabetes.

To date, however, the average amount of weight lost with most pharmacologic

agents has been modest at best, and the typical patient will most likely

remain overweight or obese even with ongoing treatment.[12]

Weight-loss drugs are expensive; neither Medicare nor most insurance plans

cover them. In addition, most are associated with adverse effects.

Therefore, meeting efficacy criteria for weight loss is not good enough for

anti-obesity agents that will be taken by millions of people for many years.

The benefits of any weight-loss drug must outweigh the risks, and safety is

the overriding consideration.

It is too early to tell whether some of the novel weight loss drugs still in

development will offer greater efficacy and safety. What is certain is that

drug developers will continue to search for the Holy Grail of anti-obesity

drugs as the world's girth continues to expand.

www.medscape.com (free registration required)

--

Ortiz, MS, RD

*The FRUGAL Dietitian* <http://www.thefrugaldietitian.com>

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