Weight Loss Drugs: What Works?

Laura A. Stokowski, RN, MS

December 13, 2010

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]

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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]

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Weight Loss Drugs: What Works?

Potential Future Therapies

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Laura A. Stokowski, RN, MS

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The Weight-Loss Imperative

Clinical Interventions for Obesity

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