Obesity is defined as an excess of body fat. Body weight can vary nearly tenfold, with small changes in lean body mass making fat the main accretion tissue during weight gain. The body mass index (BMI = weight/height², in which weight is measured in kg and height in meters) is useful as a measure of fatness independent of height and has been widely used as a simple and accurate method to measure adiposity (Table 1)¹ and to stratify persons at risk for morbidity and mortality.² There is a close relationship between BMI and obesity-related morbidity, including type 2 diabetes mellitus, hypertension, cardiovascular disease, and obstructive sleep apnea among others.¹ The distribution of the fat mass is also important, with intra-abdominal adiposity being associated with the metabolic syndrome (insulin resistance, hypertension and hyperlipidemia) and with a higher prevalence of type 2 diabetes mellitus and cardiovascular disease.^{3, 4} A convenient marker for abdominal obesity is the waist circumference, which correlates well with visceral obesity. In clinical practice, cut-off points for waist circumference have been adopted (Table 2), identifying patients at risk.¹

Table 1. Calculation of body mass index (BMI)

  BMI = weight (kg) / height² (meters) or
  BMI = weight (pounds) × 703/ height² (inches)

Table 2. High risk: waist circumference

Adapted from the National Heart, Lung, and Blood Institute: The practical guide to identification, evaluation and treatment of overweight and obesity in adults. NIH publication # 00–4084, 2000.

Overweight is defined as a BMI between 25 and 29.9 kg/m²; obesity is defined as a BMI of 30 kg/m² or above (Table 3). The prevalence of both conditions has increased dramatically during the past 30 years.⁵ The association between BMI and death in healthy people who have never smoked forms a J-shaped curve with a nadir at a BMI between 23.5 and 24.9 for men or between 22.0 and 23.4 for women.⁶ These data are concordant with epidemiologic studies obtained from life insurance data showing decreasing longevity with increasing BMI⁷ and from the Framingham Heart Study, which showed that the risk of death within 26 years increased by 1% for each pound (0.45 kg) increase in weight between the ages of 30 and 42 years and by 2% between the ages of 50 and 62 years.^{4, 8} Data from the National Health and Nutrition Examination Survey 1999–2002 show that 65.1% of US adults are either overweight or obese, as evidenced by a BMI higher than 25 kg/m².⁹ The prevalence of overweight and obesity is even higher in specific ethnic subgroups, such as Mexican Americans and African-American women in the United States.⁸ The epidemic of obesity is not confined to North America, with increases in BMI being reported in Europe,¹⁰ Asia,¹¹ and other parts of the world.

Table 3. Classifications for body mass index (BMI)

Adapted from the National Heart, Lung and Blood Institute. The practical guide: identification, evaluation and treatment of Overweight and Obesity in Adults. NIH publication # 00-4084, 2000.

Body weight is determined by the interaction among genetic, environmental, and psychosocial factors. The genetic basis for obesity most probably operates through susceptibility genes, increasing the risk for developing obesity in favorable environmental circumstances.¹² Genetic syndromes causing obesity are rare (e.g., Prader-Willi syndrome), and generally the etiology is clear because of the other clinical components of the syndrome.⁵

There has been a rapidly increasing expansion of knowledge regarding the hosts of obesity since adipose cells have been found to be an active endocrine organ and not inert as once thought (Fig. 1).¹³ Leptin was the first adipokine found in 1994.¹⁴ Leptin is a hormone produced by adipocytes whose main function is to indicate the state of the fat reserve, centrally affecting food intake and energy expenditure.¹² Leptin deficiency or leptin receptor mutations have been shown to be the cause of obesity in just a few human cases,⁶ whereas the great majority of obese persons have high circulating leptin levels in proportion to fat mass, suggesting leptin resistance.⁷ Serum leptin concentrations change more during weight loss than during weight gain, suggesting that the main function of leptin is to preserve body fat rather than prevent obesity. Weight reduction of 10–15% results in a decrease in fat mass and leptin levels, triggering through different mechanisms an increase in appetite and a decrease in metabolic rate, preventing further weight loss or even promoting weight gain.⁴

Several other candidate genes may contribute to human obesity, among them the beta-3-adrenergic receptor and the family of uncoupling proteins, which are important in the mechanism of thermogenesis.⁸

The endocannabinoid system regulates feeding behavior and body weight. There are two cannabinoid receptors, the CB1 and CB2 receptor. The CB1 receptor is the one mediating its metabolic effect, whereas the CB2 receptor has immune effects. The CB1 receptors are widely distributed in the brain, hypothalamus, liver, adipose tissue, thyroid, and pancreas. CB1 receptor antagonists promote weight loss and improve dyslipidemia and insulin sensitivity beyond the weight loss effect, possibly due to direct CB1 antagonistic effect at the adipose tissue and liver.¹⁰ A CB1 antagonist (Rimonabant) was approved for weight loss but due to an increased risk of suicide it was withdrawn from the market.

Gut hormones have an important role in the regulation of hunger and satiety and are presently widely investigated as pharmacologic targets for weight loss. Cholecystokinin (CCK) was the first gut hormone to influence food intake, promoting satiety. It is secreted from the I cells of the intestine in response to food containing fat or protein. Its secretion affects gut and gallbladder contractility, gastric emptying and CCK has also a paracrine effect on vagal branches.¹⁵ Ghrelin, a gut hormone secreted from the stomach and duodenum, plays an important role in feeding initiation and cessation, with its levels rising before meals and rapidly decreasing at the end of the meal.¹⁶ Peptide tyrosine-tyrosine (PYY) is a peptide secreted postprandially by the L cells lining the distal small bowel and colon. Food intake promotes its secretion, particularly lipid and it promotes satiety.¹⁷ PYY secretion was found to be reduced in obese subjects and PYY infusion reduced hunger in both obese and lean subjects . Another gut derived hormone, glucagon-like peptide 1 (GLP-1), a product of the glucagon gene expressed in endocrine cells of the intestinal mucosa, has an insulinotropic effect and promotes satiety through peripheral and central mechanisms, therefore decreasing food intake. Presently, GLP-1 agonists are approved for the treatment of type 2 diabetes.¹⁸

The increased prevalence of obesity in the population is best explained by changes in environmental factors interacting with susceptibility genes. Decreased physical activity or overconsumption of palatable high-caloric foods accounts for most of the weight gain reported worldwide.¹¹ Supporting this theory are migration studies showing a marked increase in weight when a specific population changes environmental conditions,¹⁹ and studies showing a negative correlation between BMI and physical activity.²⁰

Adiposity is a risk factor for several conditions that contribute to the increased morbidity and mortality in persons who are overweight or obese.

Type 2 diabetes mellitus

Type 2 diabetes mellitus is strongly associated with obesity. The relative risk for type 2 diabetes is significant even at normal BMI levels. In the Nurses' Health Study, an increase in BMI from 23 to 25 was associated with a fourfold risk of developing type 2 diabetes compared with women whose BMI was less than 22. In subjects with severe obesity (BMI more than 35), the risk was 93 times higher than in women whose BMI was less than 22.²¹ Moderate weight loss in this population (5 kg) was associated with a 50% reduction in the risk of developing type 2 diabetes. In a study of 522 middle-aged subjects with impaired glucose tolerance investigating the impact of lifestyle changes (weight reduction, increase in fiber, decrease in total and saturated fat consumption, and physical activity), the mean reduction of weight in a period of 3.2 years was 4.2 ± 5.1 kg in the intervention group and 0.8 ± 3.7 in the control group. The risk of progression to diabetes was reduced by 58% in the intervention group. In another similar study, the Diabetes Prevention Program randomized 3234 patients to lifestyle changes (a weight loss of 7% and 150 min/week of physical activity), metformin therapy, or control group. In the lifestyle group there was a 58% reduction in the incidence of diabetes compared to the control group, and in the metformin group, there was a 31% decrease in the incidence of diabetes. Both studies show that type 2 diabetes can be prevented by lifestyle changes in high-risk individuals.^{22, 23}

Moderate weight reduction (5–10% of actual weight) has been associated with marked improvement in insulin resistance and glucose control and a decreased need for subsequent medical therapy.^{24, 25}

Hypertension

The mechanism by which obesity leads to hypertension has yet to be elucidated. In obesity-mediated hypertension there is increased sympathetic nervous activation and increased renal sodium resorption, possibly mediated or exaggerated by insulin resistance and/or hyperleptinemia.²⁶ Despite the lack of knowledge of the precise mechanism causing hypertension, the link between obesity and hypertension is well known: hypertension is three times more common in obese than in normal-weight individuals.²⁷ Most studies show that a moderate weight loss of as little as 4.5 kg has a beneficial effect in lowering blood pressure.^{28, 29} In the Dietary Approaches To Stop Hypertension (DASH) trial, a diet rich in fruits, vegetables, low-fat dairy products, and reduced saturated and total fat was shown to reduce systolic blood pressure by 5.5 mmHg and diastolic pressure by 3.0 mmHg more than the control diet (typical American diet).³⁰ Blood pressure was substantially decreased in hypertensive and normotensive subjects, showing that a healthy diet can have beneficial effects beyond weight loss.³¹

Cardiovascular disease

Cardiovascular disease is the number one cause of death in women in the United States.³² Excess weight is independently associated with an increase in coronary artery disease in women and men.³³ In a Finnish cohort of more than 16,000 persons followed for 15 years, the risk of death from all causes, including cardiovascular disease, increased with increasing BMI in both men and women.³⁴ In the Nurses' Health Study, during a follow-up of 14 years, the incidence of coronary heart disease declined by 31%, partially explained by a 41% decline in smoking, an increase of 175% in hormonal replacement therapy, and improvement in diet. However, during this period, the proportion of women who were overweight (BMI more than 24.9) increased by 38%, probably slowing the decline in the incidence of coronary heart disease.³⁵

The pattern of fat distribution is an important predictor of the risk of coronary artery disease, with central obesity being associated with an increased risk for coronary artery disease and an increased waist circumference is one of the diagnostic criteria for the diagnosis of the metabolic syndrome according to the National Cholesterol Education Program (NCEP).^{36, 37} In the Nurses' Health Study, a higher waist-to-hip ratio and a larger waist circumference were independently associated with a greater risk for coronary artery disease in women between 40 and 65 years of age.³⁸

Gallstones

The risk of developing gallstones increases with BMI. The risk of either gallstones or cholecystectomy is as high as 20 per 1000 women per year for women with a BMI of more than 40, compared with 3 per 1000 among women with a BMI less than 24.³⁹

The risk of gallstone formation in the obese is also increased with weight loss, particularly rapid weight loss,⁴⁰ and is also associated with weight cycling among women.⁴¹ The risk for gallstone formation should be assessed in any weight management program on the basis of current BMI and rate of weight loss, especially during the first few weeks of dieting. It has been shown that ursodeoxycholic acid (600 mg/day), a bile acid salt that reduces cholesterol solubility, is highly effective in preventing gallstone formation in patients experiencing dietary-induced weight reduction.⁴²

Cancer

There is epidemiologic evidence of an increased risk of breast cancer in postmenopausal women with increasing BMI, waist-to-hip ratio, and waist circumference. Weight loss appears to decrease the risk, especially when occurring later in life. Possible causative factors linking BMI with breast cancer include increased levels of endogenous sex hormones, insulin resistance, and insulin-like growth factors. Interestingly, the risk for breast cancer in premenopausal women decreases with higher BMI.⁴³ Obesity also appears to increase the risk of endometrial cancer, gallbladder cancer, and kidney cancer in women.^{44, 45}

Impact of obesity on reproductive life

The level of adiposity has a major impact on a woman's reproductive life. There is a secular trend toward earlier menarche, correlated with increasing obesity in all ethnic groups, which is most pronounced in African-American girls.⁴⁶ The impact of early menarche on a girl's life extends far beyond the psychological effect of a shortened childhood. Obese children and adolescents have lower self-esteem, and as young adults they may experience an adverse socioeconomic outcome, with a decreased income and lower educational levels compared with young adults of the same age who are not obese.^{47, 48} Later in adult life, early menarche and increased body fatness confer a higher risk of cardiovascular disease and breast cancer.^{49, 50}

The polycystic ovarian syndrome (PCOS) occurs in 4–7% of women of reproductive age,^{51, 52} causing infertility and abnormal bleeding and increasing the risk for endometrial carcinoma and cardiovascular disease.^{53, 54} Hyperandrogenism and insulin resistance are the hallmarks of the syndrome. Of women with PCOS 40–50% are obese,⁵⁵ exacerbating the insulin resistance. There is a strong association between PCOS and glucose intolerance and eventually diabetes,^{56, 57} reinforcing the role of insulin resistance in this syndrome. Diet and exercise have been shown to be effective in improving insulin sensitivity and restoring fertility in this group,^{55, 58, 59} and should always be part of the arsenal of therapy for obese women with PCOS. Current evidence shows that the use of insulin-sensitizing agents (metformin and thiazolidinediones) in women with PCOS improves biochemical manifestations of hyperandrogenism and increases ovulatory rates.^{60, 61, 62}

Obese women who become pregnant are at higher risk for maternal and fetal complications.⁶³ The rates of preeclampsia and eclampsia increase with increasing maternal weight,⁶⁴ as does the risk of late fetal death,⁶⁵ fetal macrosomia, and congenital malformations.^{66, 67} Gestational diabetes mellitus has been reported in 10% of pregnancies in obese women, and the prevalence of hypertension is increased tenfold.⁶⁸ Because of difficulties in labor and delivery, obese pregnant women are more likely to have a cesarean section than are normal-weight pregnant women.⁶⁹

Recently the Institutes of Medicine (IOM) revised the previous guideline on weight gain during pregnancy that was published in 1990. The present guidelines advise assessment of pre-pregnancy BMI according to the categories adopted by the National Heart, Lung, and Blood Institute (NHLBI) (Table 3). The IOM recognized four weight groups: underweight (BMI <18.5 kg/m²), normal weight (BMI 18.5–24.9 kg/m²), overweight (BMI 25–29.9 kg/m²), and obese (BMI ≥30 kg/m²) with this group including all classes of obesity. Underweight women are advised to gain 28–40 lb during pregnancy, normal weight women between 25 and 35lb, overweight women between 15 and 25 lb, and obese women should gain between 11 and 20 lb. The IOM’s lack of specific recommendations for the different classes of obese women has been criticized.⁷⁰ It is possible that an even lower weight gain may be safe and reduce complications as shown by Cedergren et al. in a retrospective series of  298,648 singleton pregnancies in Sweden in which a weight gain of less than 11 lb was related to better maternal and fetal outcome.⁷¹ These guidelines are appropriate for singleton pregnancies, whereas no specific recommendations have been issued for multiple pregnancies, different ethnic groups, adolescents, and short women. 

Many women attribute retained weight from pregnancy as a cause for their subsequent obesity.⁷² In some women weight gain may indeed be explained by retention of gestational weight gain as well as negative postpartum lifestyle changes.^{73, 74} In large cohorts of pregnant women, the effect of pregnancy on average body weight after 18 months postpartum was an increase of less than 0.5 kg; a subgroup of 15–20% of the women gained a more significant amount of weight after pregnancy.⁷⁵ In a study of 1300 healthy women aged 18–41 years, 6.4% became overweight after the index pregnancy with high gestational weight gain, young age at menarche, younger age, and time from menarche to first pregnancy were all associated with an increased risk of becoming overweight after pregnancy.⁷⁶

Weight loss during lactation differs markedly among women, with some women even gaining weight during lactation.⁷⁷ An average weight loss of 0.5 kg/week for 10 weeks in lactating overweight and obese women who were exclusively breastfeeding did not affect the growth of their infants,⁷⁸ suggesting that lifestyle modifications and moderate weight loss are safe in lactating women and their infants.

Adding to the beneficial effects of lactation in the neonate, it has been shown that the risk of becoming overweight during older childhood and adolescence is lower among children who were breastfed for 7 months or more compared with those who were breastfed for 3 months or less,⁷⁹ suggesting a role for breastfeeding as an important tool in the prevention of obesity during childhood.

Treatment of the overweight or obese patient must be preceded by an evaluation of the degree of obesity and an estimation of disease risk. This increases the likelihood of identifying the most appropriate treatment plan for the patient. The BMI is the most frequently used index for adiposity and, along with waist circumference, can be used to determine health risk.⁸⁰

The treatment for overweight and obese patients, regardless of BMI, includes diet modification, increased physical activity, and behavior therapy. Pharmacotherapy is indicated for patients with a BMI of 30 or above, or a BMI of 27 or above for patients with at least one comorbidity related to obesity (Table 4). Surgery for obesity may be indicated for patients with a BMI of 40 or above or a BMI of 35 or above with the presence of obesity-related comorbidities.

Table 4. Obesity-associated comorbidities

Type 2 diabetes mellitus
Hypertension
Coronary heart disease
Dyslipidemia
Stroke
Osteoarthritis
Cholelithiasis
Infertility
Cancer
   Postmenopausal breast cancer
   Endometrial carcinoma
   Colon cancer
   Gallbladder cancer
   Prostate cancer
Obstructive sleep apnea

After the initial assessment of the health risk and the degree to which the patient is overweight, a plan that includes treatment strategies and goals should be developed between the health care provider and the patient. A weight loss goal of 10% of initial body weight over 6 months has been recommended to reduce risks to health risk.³⁶ This recommendation was based on evidence from trials showing that moderate weight loss (5–10% of initial weight) can produce significant decreases in blood pressure,⁸¹ serum lipid levels,⁸² and blood glucose levels.²⁴ The goal of the medical treatment of obesity is to achieve weight loss through a twofold mechanism: a decrease in caloric intake and an increase in energy expenditure. Maintenance of weight loss can be achieved and sustained only with a modification in lifestyle.⁸³

The cornerstone of dietary management is the low-calorie diet (LCD), which provides 800–1500 kcal/day.⁸² The very-low-calorie diet provides 250–800 kcal/day, but there are very few circumstances in which this diet is indicated, because it requires intensive medical monitoring.⁸³ Furthermore, weight loss at 1 year after treatment with very-low-calorie diets is not significantly different from that of LCDs after 1 year.⁸⁴ LCDs have been shown to produce a reduction in body weight of 8–10% over a period of 6 months. A reasonable estimate of 1000–1200 kcal/day for women and 1200–1500 for men will produce an approximate deficit of 500–1000 kcal/day, resulting in a weight loss of 1–2 pounds per week on average.⁸² The composition of the diet does not seem to play a role in promoting weight loss as long as the total caloric intake is decreased from usual intake.^{85, 86} Caloric balance (calories ingested vs. calories burned) rather than macronutrient composition is the major determinant of weight loss. Comparison of low carbohydrate diet to low fat diets showed that the weight loss at 6 months was 4–5 kg greater in the low carbohydrate diet, but by the end of 1 year the weight loss was similar between groups.^{87, 88, 89} It is possible, however, that the composition of macronutrients may have some effect on weight maintenance and adherence to diet.⁹⁰ It is important to provide the patient with the recommended dietary allowances; if these are not met, supplementation with vitamins and minerals should be given. A balanced diet with 30% or less total fat (less than 10% saturated fat, 15% monounsaturated fatty acids, less than 300 mg cholesterol, and up to 10% polyunsaturated fatty acid), with carbohydrates supplying 55% of calories and protein supplying 15% of calories, is appropriate when weight loss is warranted.⁸²

An increase in physical activity is recommended in any weight loss program because it increases the energy deficit, improves comorbid conditions, alleviates depressive symptoms, and facilitates maintenance of weight loss.^{83, 91} In a study comparing women who had regained their lost weight with those who were successful at maintaining their weight loss, 90% of the maintainers reported engaging in vigorous exercise at least three times per week for at least 30 minutes, whereas only 34% of the regainers reported this level of activity.⁹² In 1995, The Center for Disease Control and Prevention (CDC) and American College of Sports Medicine recommended 30 minutes of moderate intensity physical activity at least 5 times/week.⁹³ In 2002, the Institute of Medicine (IOM), recommended at least 60 minutes of moderate intensity physical activity every day. Patients who did not meet either of the recommendations were found to have higher BMIs.⁹⁴

Behavior modification techniques are used in the treatment of obesity to induce weight loss and ensure long-term weight maintenance by changing eating and exercise behaviors.⁹⁵ Behavioral therapy is best provided by weekly sessions to small groups of individuals. During these sessions, patients are introduced to nutrition education, problem solving, stimulus control techniques, and self-reinforcement. Other modalities such as telephone and internet sessions have also proven to be effective.⁹¹ Food and exercise diaries are simple but markedly successful strategies and should always be part of the behavioral treatment,⁹⁶ especially because it has been reported that obese subjects tend to underestimate their actual caloric intake.⁹⁷

Pharmacologic therapy for weight loss may be considered in patients with a BMI of 30 or more, or 27 or more when a comorbidity associated with obesity is present. Medical therapy should be considered only as an adjunct to diet and exercise. It has been shown that a combined approach will increase weight loss, and satisfaction with weight change and self-esteem is higher in the group receiving combined therapy compared with monotherapy with anorexigenic medicine.⁹⁸

Two drugs, sibutramine and orlistat, have been approved by the Food and Drug Administration (FDA) for induction and long-term maintenance of weight loss. Phentermine, an amphetamine derivative, is FDA-approved for short-term use (up to 3 months) as an anorectic drug (Table 5). Another drug, Rimonabant, an antagonist to the cannabinoid receptor 1 (CB1), has been approved in Europe and other countries for weight loss, but is not FDA approved, and the drug was recently withdrawn from the market in Europe due to a more than expected rate of depression. The future of this drug and other similar compounds is not clear.⁹⁹

Table 5. Pharmacotherapy of obesity

Sibutramine is a selective inhibitor of the reuptake of serotonin and norepinephrine. Sibutramine promotes a dose-dependent weight loss correlated with decreased food intake secondary to decreased appetite and early satiety.¹⁰⁰ The usual dosage is 10 mg/day once daily in the morning, but the dosage can be increased to 15 mg/day or decreased to 5 mg/day. Patients taking sibutramine for 1 year maintained a 15% weight loss, while the placebo group regained part of the lost weight during this period.¹⁰¹ This benefit was still shown in patients treated for 2 years, with the treatment group exhibiting superior weight loss maintenance compared with placebo-treated patients.¹⁰² In this study, 43% of sibutramine-treated patients maintained 80% of the original weight loss versus 16% of the control group.

The most common side effects reported with sibutramine therapy are constipation, insomnia, and dry mouth. Nevertheless, increases in blood pressure and pulse may occur,¹⁰¹ requiring regular monitoring of those two parameters and deferring therapy in patients with uncontrolled blood pressure. If blood pressure is substantially elevated while receiving therapy, reducing the dose or discontinuing the medication will decrease blood pressure or restore it to pretreatment values.

Recently, sibutramine was withdrawn from the European Union because of new data from the Sibutramine Cardiovascular Outcome trial (SCOUT).¹⁰³ The SCOUT study was designed to investigate whether patients with a high cardiovascular risk would benefit from weight loss with sibutramine therapy. Patients were assigned to sibutramine or placebo in addition to lifestyle changes. The sibutramine group had an increased risk of heart attacks and stroke compared to the placebo group. The FDA did not withdraw sibutramine from the market, but demanded that contraindications for some patients be emphasized, such as cardiovascular disease, arrhythmias, and uncontrolled hypertension.

Orlistat is an inhibitor of pancreatic lipase that decreases fat absorption in the intestine and blocks the digestion of approximately 30% of dietary fat. The recommended dosage is 120 mg three times a day before meals. Because the drug is minimally absorbed, no systemic side effects have been reported. The major side effect of orlistat is steatorrhea, especially if the diet consists of more than 30% of calories as fat.¹⁰⁴ Because orlistat impairs absorption of fat-soluble vitamins, a multivitamin should be taken several hours apart from orlistat. In several studies, orlistat has been shown to significantly increase weight loss and maintenance compared with diet and exercise alone.^{104, 105} A study on the prevention of diabetes in obese subjects (XENDOS) was designed to evaluate weight loss and development to type 2 diabetes. In this study, orlistat produced greater weight loss compared to placebo (−5.8 kg vs. −3 kg; P<0.001) and a 38% risk reduction for the development of type 2 diabetes, mostly pronounced in the group with impaired glucose tolerance.¹⁰⁶

Phentermine is prescribed at dosages of 8–37.5 mg/day, given as a single dose in the morning. Increases in pulse and blood pressure are the major significant side effects of this drug.⁸²

Rimonabant is a CB1 receptor antagonist. The drug blocks the overactive cannabinoid system in the brain and adipocytes. Through its inhibition there is a central inhibition for food seeking and its effect on adipocytes promotes fat oxidation and insulin sensitivity.¹⁰⁷ The recommended dose of rimonabant is 20 mg/day. The weight loss promoted is similar to the other medications, but it seems that the improvements in cardiovascular risk factors (increase in adiponectin, increase in HDL and decrease in waist circumference) are beyond the expected effect of weight loss and are partially mediated through the inhibition of CB1 receptors in adipocytes. Reported side effects include gastrointestinal, neurological, and psychiatric effects. Rimonabant is contraindicated in patients treated, or with a history of depression.¹⁰⁸ As mentioned above the drug has been withdrawn from the market in Europe and its clinical use remains uncertain.

Glucagon-like peptide 1 (GLP-1) analog (exenatide) is  presently approved to treat diabetes. Unlike other antidiabetic agents, exenatide improves glucose control while promoting a modest but continuous weight loss. GLP-1 agonists are presently being evaluated for weight loss and as adjunctive therapy in women with polycystic ovary syndrome (PCOS).¹⁰⁹

Sibutramine, orlistat, phentermine, and rimonabant are contraindicated during pregnancy and lactation because of lack of studies in this population.

Over-the-counter medications or herbal extracts (such as ma huang) may contain unknown amounts and combinations of active substances and therefore should not be included in the pharmacologic arsenal to promote weight loss.¹¹⁰

It is important to realize that obesity is a chronic disease and that pharmacotherapy may be needed for long periods, based on the high recidivism rate of even moderate weight loss.¹¹⁰

There is extensive research in the field of pharmacotherapy for the treatment of obesity. Included among the many substances under investigation are those that block food intake centrally and peripherally, those that activate thermogenesis and lipolysis, and those that block fat absorption or affect fat metabolism.^{111, 112}

Surgical procedures for weight reduction involve intestinal malabsorption, gastric restriction, or both. Malabsorptive procedures involve bypassing a small portion of small intestine to decrease the functional length of the intestinal mucosa and achieve a decrease in nutrient absorption. Restrictive procedures involve the creation of a small neogastric pouch and gastric outlet, allowing the ingestion of only small portions and delaying gastric emptying.¹¹³ To date, surgical therapy is the most effective modality for the treatment of severe obesity. The successful outcome of weight reduction surgery depends on patient compliance as well as the work of a multidisciplinary team including surgeons, internists, dietitians, nurses, and psychologists.¹¹⁴

The two procedures most commonly performed are the Roux-en-Y gastric bypass procedure and the vertical banded gastroplasty, but a new procedure, sleeve gastrectomy, is gaining popoularity. The Roux-en-Y procedure is the gold standard and results in weight loss of approximately one third of body weight. In skilled hands, the mortality and reoperation rates are less than 1%, and the incidence of complications is 10%. The most common complications reported are stomal stenosis, ulceration, and nausea and vomiting in the postoperative period. Long-term complications include formation of gallstones, malabsorption of micronutrients such as folate, vitamin B₁₂, and iron and dumping syndrome.¹¹⁵ Most of the weight lost after the Roux-en-Y procedure and the vertical banded gastroplasty occurs during the first 2 years after surgery.¹¹⁶

In women of reproductive age, because of concerns about nutritional status of the mother and fetal growth retardation,¹¹⁷ it seems prudent to delay pregnancy until the benefits of surgery are achieved and weight loss has stabilized.¹¹⁸ Overall, in women who have had gastric bypass surgery for morbid obesity and have subsequently become pregnant, there have been fewer pregnancy-related complications compared with pregnancies in that group before surgery.^{119, 120}

Despite successful weight loss, many individuals regain weight, with weight cycling being reported by many obese persons. The National Weight Control Registry seeks to identify persons who have lost at least 30 lb (13.6 kg) and have succeeded in maintaining the weight loss for at least 1 year. Maintainers in the National Weight Control Registry reported common behavioral strategies such as eating a diet low in fat, frequent self-monitoring of body weight and food intake, and high levels of regular physical activity. On average, individuals in the Registry expend approximately 2778 kcal per week in physical activity.^{121, 122, 123} Portion-controlled servings and meal replacements were shown to enhance weight loss and weight maintenance.⁹¹ It is important to enrol the patient in a weight maintenance program.¹²⁴

The best therapy for obesity is prevention, as is true for most diet-related disease states. Despite the many comorbidities associated with obesity, the prevalence of the disease has been increasing markedly during the past three decades.^125,126 Action should be taken when even small increases in weight are observed in the adult population, instituting lifestyle changes immediately. Especially alarming is the increased prevalence of obesity in children and adolescents, because they will be at increased risk for obesity during adulthood.¹²⁷

Obesity is a chronic disease requiring permanent lifestyle changes to combat it successfully. Failure to adhere to those changes is responsible for the high recidivism rate of obesity. It is possible that in the future, patients will be treated with multiple pharmacologic agents affecting different mechanisms responsible for appetite and thermogenesis. These agents, used as adjuncts to lifestyle changes, might increase the success rate for permanent weight loss or preferably would be used as preventive treatments for obesity in high-risk groups.