Weight Loss Drugs: What Works?

Laura A. Stokowski, RN, MS

December 13, 2010

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.

1 2 3 4 5 6

Next Section

Cite this: Laura A. Stokowski. Weight Loss Drugs: What Works? - Medscape - Dec 13, 2010.

The Weight-Loss Imperative

The classifications of "overweight" and "obese" are defined by BMI, calculated from a patient's weight and height. A person with a BMI ≥ 25 kg/m² is considered "overweight" and someone with a BMI ≥ 30 k/m²is considered^, "obese." Using these definitions, 68% of the adults in the United States are overweight, and 34% are obese.^[36]

The days when obesity was considered primarily a cosmetic problem are long gone. We now know that obesity is a complex disease that develops from a combination of genetic and environmental factors, and that the health implications of obesity are vast (see Table). In addition to elevated rates of type 2 diabetes, cardiovascular disease, and cancer, obesity can make surgical management more difficult and result in more postoperative complications.^[37,38]

Evidence of a survival benefit for obesity in select clinical situations is not enough to compensate for the overwhelming health risks, including death, associated with excessive body weight.^[4]

Table. Diseases Associated With Obesity^[39]

Organ System	Conditions
Cardiovascular	Hypertension, peripheral vascular disease, myocardial infarction, cerebral vascular accidents, peripheral venous insufficiency, thrombophlebitis, pulmonary embolism
Respiratory	Asthma, obstructive sleep apnea, obesity-hypoventilation syndrome
Metabolic	Type 2 diabetes mellitus, impaired glucose tolerance, hyperlipidemia
Musculoskeletal	Back strain/disc disease, osteoarthritis
Gastrointestinal	Cholelithiasis, gastrointestinal reflux disease, nonalcoholic fatty liver disease, hepatic cirrhosis, hepatic carcinoma, colorectal carcinoma
Urologic	Stress incontinence
Endocrine/Reproductive	Polycystic ovary syndrome, pregnancy/fetal abnormalities, male hypogonadism, endometrial, breast, ovary, prostate cancer, pancreatic cancer
Dermatologic	Intertriginous dermatitis
Neurologic	Pseudotumor cerebri, carpal tunnel syndrome
Psychologic	Depression, eating disorders, body image disturbance

Clinical Interventions for Obesity

The chief clinical intervention for obesity is lifestyle change, which usually involves counseling and behavioral therapy for reducing caloric intake and increasing physical activity. For patients who fail to lose weight with lifestyle intervention, pharmacotherapy and surgical approaches may be indicated.

The benefits of weight reduction, even on a fairly modest scale (5%-10% of body weight) are well documented. Among other benefits, weight loss is associated with a lower incidence of diabetes, hypertension, and dyslipidemia,^[40]improved urinary incontinence,^[41]and reduced inflammation in osteoarthritis.^[42]Patients with diabetes who lose even small amounts of weight have better metabolic control, fewer cardiovascular risk factors, and lower mortality rates.^[43,44] Continually losing and regaining weight (weight cycling), however, might be worse than maintaining a stable excessive weight. The evidence on weight cycling and threats to health is inconsistent, but raises the question of its safety.^[45]

Unfortunately, the degree of weight loss that is usually achieved with lifestyle intervention alone is insufficient. Efforts to lose weight are often thwarted by a compensatory slowing of the metabolism and high rates of recidivism.^[2]

Comments

Commenting is limited to medical professionals. To comment please Log-in.

Comments on Medscape are moderated and should be professional in tone and on topic. You must declare any conflicts of interest related to your comments and responses. Please see our Commenting Guide for further information. We reserve the right to remove posts at our sole discretion.

Weight Loss Drugs: What Works?

In the Pipeline

Zonisamide/Bupropion

Tesofensine

Cetilistat

Pramlintide/Metreleptin

Tables

References

Authors and Disclosures

Authors and Disclosures

Author(s)

Laura A. Stokowski, RN, MS

Sidebar

The Weight-Loss Imperative

Clinical Interventions for Obesity

Comments

Email This

Feedback