Department of Medicine, Columbia University College of Physicians and Surgeons (J.K.), New York, New York 10032; and Weill Medical College of Cornell University, Comprehensive Weight Control Program (L.J.A.), New York, New York 10021
Address all correspondence and requests for reprints to: Dr. Judith Korner, Department of Medicine, Columbia University College of Physicians and Surgeons, 630 West 168th Street, Black Building, Room 905, New York, New York 10032. E-mail: jk181{at}columbia.edu.
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Introduction |
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Current pharmacotherapy for weight loss |
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Sibutramine inhibits norepinephrine and serotonin reuptake. Although ineffective as an antidepressant, for which purpose it was originally developed, sibutramine was found to reduce body weight and appetite and increase satiety. More than 10 prospective, randomized, controlled trials of sibutramine have supported its efficacy (3). An analysis of three trials of at least 1-yr duration shows that patients on sibutramine lost 4.3 kg or 4.6% more weight than those taking placebo; 34% more patients achieved at least 5% weight loss, and 15% more patients achieved at least 10% weight loss in the sibutramine arm compared with placebo (4). The most common adverse effects are dry mouth, constipation, and insomnia. On the average, systolic blood pressure increases by 4 mm Hg, and diastolic blood pressure by 24 mm Hg. Heart rate increases about 4 beats/min. Despite these changes, the safety and efficacy of sibutramine have been demonstrated in subjects with controlled hypertension; however, it is recommended that blood pressure and pulse rate be monitored regularly. The use of sibutramine is contraindicated in individuals with uncontrolled hypertension or cardiovascular disease or with concomitant use of monoamine oxidase inhibitors or other serotonin reuptake inhibitors. To date, there has been no association between the use of sibutramine and valvular heart disease, as became evident with the use of fenfluramine.
Orlistat, an inhibitor of pancreatic and gastrointestinal lipases, prevents the absorption of approximately 30% of dietary fat. Pooled results of 11 prospective randomized controlled trials demonstrate that subjects treated with orlistat displayed a 2.7-kg or 2.9% greater reduction in weight than placebo-treated patients after 1 yr of follow-up (4). Orlistat reduces low density lipoprotein and cholesterol levels independent of reductions in body weight, decreases the progression to a diabetic state, and leads to better glycemic control in patients with diabetes (3). Side effects due to the mode of action include oily spotting, liquid stools, fecal urgency or incontinence, flatulence, and abdominal cramping. As orlistat may impair the absorption of fat-soluble vitamins, a multivitamin supplement should be taken 2 h before or after the medication.
The noradrenergic agent, phentermine, is approved only for short-term treatment of obesity of up to 3 months duration due to the lack of long-term studies. Studies show a 2- to 10-kg greater weight loss in phentermine-treated patients than in those given placebo. Side effects include insomnia, dry mouth, constipation, restlessness, euphoria, nervousness, increased pulse rate, and blood pressure. The use of noradrenergic agents is contraindicated in patients with cardiovascular disease, hypertension, or history of drug abuse or in those taking monoamine oxidase inhibitors.
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Clinical trials |
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Ciliary neurotrophic factor (CNTF) was originally developed as a potential treatment for amyotrophic lateral sclerosis, but was found to produce anorexia and weight loss. CNTF reduces food intake through down-regulation of appetite-stimulating neuropeptides within the hypothalamus in both leptin-responsive and leptin-resistant rodents (11, 12). Prevention of binge-overeating and continued weight loss after the drug is stopped suggest that CNTF may reduce the hypothalamic body weight set-point in rodents, but raises some questions as to possible long-term central nervous system effects in humans. In a phase III trial, the efficacy of recombinant human CNTF (Axokine, Regeneron Pharmaceuticals, Tarrytown, NY) for obesity treatment was limited by the development of antibodies in two thirds of the subjects. Patients injected with Axokine lost 2.8 kg compared with a loss of 1.2 kg in patients receiving placebo after 1 yr; the 30% of participants who did not develop antibodies lost 5.7 kg.
Endocannabinoids stimulate food intake through CB1 cannabinoid receptors in the hypothalamus. An antagonist of the CB1 receptor, SR141716A or rimonabant, suppresses food intake in genetically obese and diet-induced obese animals (13). In phase II trials, rimonabant led to a dose-dependent weight loss of 4 kg over 16 wk with only minor gastrointestinal side effects. In a multicenter, double-blinded, phase III trial, 44% of subjects lost greater than 10% of body weight at 1 yr compared with 10% of subjects taking placebo. The results of other completed phase 3 trials for weight reduction and prevention of weight gain are pending.
Two antiepilepsy drugs, topiramate and zonisamide, and the antidepressant bupropion have also been studied for weight loss effects. In a randomized, double-blind, placebo-controlled trial, the mean percent weight loss was 2.6% in placebo-treated subjects vs. 6.3% in subjects treated with 192 mg/d topiramate for 24 wk (14). Topiramate has also been effective in the treatment of binge eating disorder (15). The frequency of adverse events, mostly related to the central and peripheral nervous system, such as paresthesias, somnolence, and difficulty with memory, has led to the termination of phase III trials while an extended release formulation is being developed by the manufacturer. As the use of topiramate may also cause a nonanion gap metabolic acidosis, it is recommended that serum bicarbonate levels be checked before initiating therapy and periodically thereafter. In a 16-wk, randomized, double-blind, placebo-controlled trial, zonisamide treatment resulted in a 6.0% loss of body weight compared with a 1.0% loss with placebo (16). A single-blind extension of the same treatment for a further 16 wk resulted in 9.4% and 1.8% weight losses in zonisamide and placebo groups, respectively. Adverse events that occurred more frequently in the treatment group were fatigue and a small, but significant, increase in serum creatinine. The efficacy of zonisamide on binge eating is currently under study. The mechanisms by which these antiepileptic drugs produce weight loss are unclear, but may be due to antagonism of the glutamate kainate receptor by topiramate and to the serotonergic and dopaminergic activities of zonisamide. In an 8-wk study of weight loss in overweight and obese women, bupropion, currently marketed for treatment of depression and as a smoking cessation aid, produced a 6.2% loss of body weight in those subjects who completed the study compared with 1.6% weight loss in the placebo group (17). The drug was well tolerated, but clinicians should be aware of the 0.4% risk of seizure when the drug dose is 400 mg/d. The mechanism of the drug responsible for weight loss may be due to inhibition of norepinephrine and dopamine uptake.
Metformin, approved for the treatment of type 2 diabetes, was studied in the Diabetes Prevention Program Research Trial as a means to prevent the development of diabetes in nondiabetic persons with elevated fasting and postload plasma glucose concentrations (18). Although less successful than a lifestyle modification program, treatment with metformin was associated with a 2.1-kg mean weight loss and a decrease in the incidence of diabetes by 31% compared with placebo treatment over the average follow-up period of 2.8 yr. Metformin may, therefore, be considered as adjunctive therapy in individuals at high risk for progression to diabetes.
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Future directions |
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Recognition of the importance of the hypothalamus in the regulation of energy homeostasis has led to the targeting of neuropeptides and their receptors in this region for weight loss therapies. NPY receptor antagonists are in early clinical trials for obesity treatment. Intranasal treatment with an MC4R agonist, MSH/ACTH410, reduced body weight by 0.79 kg when administered to normal weight humans for 6 wk (21); however, it did not change the body weight of two obese individuals with proopiomelanocortin deficiency due to loss of function mutations of the proopiomelanocortin gene (22). Of note, sc injection of melanotan II, a synthetic nonselective melanocortin agonist, was initially evaluated for initiation of erections in men with erectile dysfunction (23). Side effects included nausea and decreased appetite, but the trial was not designed to evaluate longer-term effects on body weight.
Although acting at different receptors within the arcuate nucleus, the actions of leptin and insulin appear to overlap, possibly due to convergence upon a single intracellular signal transduction pathway known as the insulin receptor substrate phosphatidylinositol 3-kinase pathway (24). Central administration of insulin or insulin mimetics reduces food intake and body weight (25), whereas impairment of hypothalamic insulin receptors causes hyperphagia and insulin resistance (26). Insulin and leptin have a cooperative anorectic effect, and intracerebroventricular infusions of phosphatidylinositol 3-kinase inhibitors impede the anorectic effects of both hormones. Inhibitors of protein tyrosine phosphatase 1B, a negative regulator of both leptin and insulin signal transduction, may provide opportunities for the treatment of obesity and insulin resistance (27).
Molecules within other regions of the hypothalamus influence energy balance. Melanin-concentrating hormone (MCH) is present in the lateral hypothalamus. Expression of MCH is increased with fasting and leptin deficiency. Disruption of the MCH gene or administration of an MCH1 receptor antagonist results in hypophagia and leanness in rodents. Such antagonists may be useful in the treatment of human obesity. Other molecules within the hypothalamus include corticotropin and TSH releasing hormones, and orexin A and B. As many of these hormones have pleiotropic effects, manipulation of their activity to produce weight loss without causing undesirable behavioral and metabolic responses will prove to be a challenge.
Our increased understanding of the neurohormones secreted by the gastrointestinal tract has provided us with other possible drug therapies for obesity. Peptide YY336 (PYY) is secreted postprandially in proportion to the calories ingested by endocrine L cells lining the distal small bowel and colon. Obese individuals exhibit a blunted postprandial PYY response compared with that in lean subjects. PYY decreases food intake through a gut-hypothalamic pathway that involves inhibition of NPY Y2 receptors in the arcuate nucleus and the dorsal motor nucleus of the vagus nerve (28). The release of PYY acts as an "ileal brake," suppressing gastric motility that probably induces a sense of satiety to promote meal termination. A single infusion of PYY in lean and obese subjects, compared with an infusion of saline, reduced appetite and food consumption by approximately 30% at a buffet lunch provided 2 h after the infusion (29, 30). Clinical trials of intranasal administration of PYY are being performed.
Premeal hunger and meal initiation are stimulated by interactions between gut hormones and the hypothalamus. Ghrelin is an acylated peptide secreted by oxyntic cells in the stomach fundus. Originally described as a GH secretagogue, the putative role of ghrelin in energy homeostasis has more recently been identified. Circulating ghrelin concentrations increase preprandially and decrease postprandially, and infusion of ghrelin in humans induces increased appetite and food intake (31, 32, 33). Diet-induced weight loss is associated with an increase in plasma ghrelin levels that may contribute to increased hunger and difficulty with the maintenance of weight loss. Discrepant results have been reported regarding the effect of Roux-en-Y gastric bypass surgery on ghrelin concentrations (34). Whether the decreases in meal frequency and size after surgery are due in part to inappropriately reduced ghrelin levels remains an open question. Although circulating ghrelin concentrations are decreased in obese humans and may not play an etiological role in their obesity, the effect of a ghrelin antagonist on food intake and body weight is an area of interest (35). Ghrelin antagonists may be particularly effective in the treatment of obesity in patients with Prader-Willi syndrome who have severalfold higher concentrations of ghrelin compared with equally obese controls; however, the effects on GH secretion will need to be elucidated.
Meal termination may also be regulated by the postprandial release of oxyntomodulin, a 37-amino acid peptide that arises from posttranslational processing of proglucagon in the same intestinal cells that secrete PYY and glucagon-like peptide-1 (GLP-1). A single infusion of oxyntomodulin suppresses appetite and reduces food intake in humans over a 12-h period and is associated with a reduction in fasting ghrelin concentrations (36). The effects of oxyntomodulin on food intake may be mediated by the receptor for GLP-1. Known as an incretin hormone that may be helpful in stimulating insulin secretion during hyperglycemia in type 2 diabetics, GLP-1 has also been shown to reduce gastric motility and short-term ad libitum energy intake and to increase satiety both in lean and overweight subjects (37). Treatment with the longer-acting GLP-1 agonist, exendin-4, decreases food intake and fat deposition and increases glucose tolerance in Zucker fatty rats (38). Phase III trials with GLP-1 derivatives and agonists that are resistant to inactivation by the enzyme dipeptidyl peptidase IV (DP-IV) are under way for use as potential treatments for type 2 diabetes. Of note, mice lacking DP-IV are protected against obesity and insulin resistance, suggesting that DP-IV inhibition may also be a therapeutic option for the treatment of diabetes and obesity (39).
Cholecystokinin (CCK), a peptide hormone released by the duodenum and jejunum in response to the presence of intraluminal digestive products, stimulates pancreatic secretion, gallbladder contraction, and intestinal motility and inhibits gastric emptying. There are two distinct CCK receptor subtypes: CCK-A, which is primarily expressed in alimentary tissues and specific brain sites, such as the nucleus of the solitary tract, area postrema, and dorsomedial nucleus of the hypothalamus; and CCK-B, which is found mainly within the brain (40). CCK acts as a satiety signal via CCK-A receptors on afferent vagal fibers to the brain causing termination of an individual meal (40). Phase II clinical trials with orally active CCK agonists are currently being conducted (41). Somatostatin is another gut peptide that inhibits gastrointestinal motility and endocrine and exocrine secretions, and may promote satiety (42). Treatment with octreotide, a long-acting somatostatin receptor agonist, attenuated the weight gain associated with pediatric hypothalamic obesity (43) and was associated with weight loss in obese hyperinsulinemic Caucasian adults in one small trial that lacked a placebo control arm (44).
Other therapeutic options for the treatment of obesity may involve drugs that affect substrate utilization and energy partitioning rather than appetite and food intake. The beneficial effects of GH therapy on fat distribution and lean muscle mass in patients with GH deficiency have not been reproducible in individuals with common obesity and, in fact, is usually associated with an increase in insulin resistance (45). However, the synthetic fragment of human GH, AOD9604, reduces body weight and body fat in obese mice, with no adverse effects on insulin sensitivity and is being studied in phase II clinical trials (46). The gut peptide, gastric inhibitory polypeptide (GIP), is released from duodenal endocrine K cells upon the absorption of fat or glucose. Wild-type mice fed a high fat diet exhibit hypersecretion of GIP and increased fat deposition with insulin resistance, whereas mice lacking the GIP receptor are protected from both obesity and insulin resistance (47). This resistance to obesity is presumably mediated through a peripheral, leptin-independent mechanism that invokes higher energy expenditure and increased fat oxidation rather than lower energy intake. Adiponectin (also known as Acrp30 or AdipoQ) is an adipocyte-derived hormone that increases fatty acid oxidation in muscle and decreases fat accumulation in mice without significantly affecting food intake (48). Circulating levels of adiponectin are decreased in both rodent and human models of obesity and insulin resistance. The phenotypes of adiponectin-deficient and transgenic adiponectin-overproducing animal models demonstrate the importance of adiponectin in the maintenance of glucose and lipid homeostasis (49).
Levels of intracellular metabolites reflect the availability of nutrients and modulate energy balance through nutrient-sensing hypothalamic neurons and peripheral tissues (50). Malonyl-coenzyme A (CoA) is an inhibitor of carnitine palmitoyltransferase 1 (CPT1), the enzyme that controls the entry of long-chain fatty acid-CoA into the mitochondria and is the rate-limiting step for the oxidation of fatty acids. Accumulation of malonyl-CoA inhibits CPT1 and reduces lipid oxidation, favoring lipid storage into triglycerides. Such accumulation in the brain is thought to generate a satiety signal. Indeed, an elevation of central levels of malonyl-CoA or fatty acids produced by either fatty acid synthase inhibitors such as cerulenin or C75 (51, 52) or inhibition of hypothalamic CPT1 (53) leads to anorexia and decreased body fat. Interestingly, genetic knockouts of acetyl-CoA carboxylase 2, the enzyme that catalyzes the synthesis of malonyl-CoA, have lower levels of malonyl-CoA in heart and muscle, yet accumulate less fat in their adipose tissue without producing anorexia (54).
Intracellular concentrations of glucocorticoids may also regulate fat metabolism. Although circulating levels of glucocorticoids are not elevated in the majority of obese subjects, local action on adipose tissue and skeletal muscle may be enhanced due to elevated enzyme activity of 11ß-hydroxysteroid dehydrogenase type 1 (11ßHSD1) (55). 11ßHSD1-knockout mice resist visceral fat accumulation and insulin resistance, whereas fat-specific 11ßHSD1 transgenic mice with increased enzyme activity similar to obese humans develop visceral obesity with insulin and leptin resistance, dyslipidemia, and hypertension. Thus, 11ßHSD1 is a potential target for the treatment of the metabolic syndrome associated with obesity.
Over 100 molecules are in various stages of preclinical and clinical development. A thorough review of all potential antiobesity treatments is beyond the scope of this article, but some have been included in the accompanying table (Table 1).
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Conclusions |
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Footnotes |
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Abbreviations: CCK, Cholecystokinin; CNTF, ciliary neurotrophic factor; CoA, coenzyme A; CPT1, carnitine palmitoyltransferase 1; DP-IV, dipeptidyl peptidase IV; GIP, gastric inhibitory polypeptide; GLP-1, glucagon-like peptide-1; 3ßHSD1, 11ß-hydroxysteroid dehydrogenase type 1; MCH, melanin-concentrating hormone; MC3R, melanocortin 3 receptor; MC4R, melanocortin 4 receptor; NPY, neuropeptide Y; PYY, peptide YY336.
Received February 20, 2004.
Accepted March 18, 2004.
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References |
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