Obesity 

Updated: Mar 20, 2018
Author: Osama Hamdy, MD, PhD; Chief Editor: Romesh Khardori, MD, PhD, FACP 

Overview

Practice Essentials

Obesity is a substantial public health crisis in the United States, and internationally, with the prevalence increasing rapidly in numerous industrialized nations.[1] A report from the National Center for Health Statistics stated that in US individuals aged 20 years or older, the prevalence of obesity rose steadily from 19.4% in 1997 to 31.4% for the period January-September 2017.[179, 180]

The image below details the comorbidities of obesity.

Comorbidities of obesity. Comorbidities of obesity.

Signs and symptoms

Although several classifications and definitions for degrees of obesity are accepted, the most widely accepted classifications are those from the World Health Organization (WHO), based on body mass index (BMI). The WHO designations are as follows:

  • Grade 1 overweight (commonly and simply called overweight) - BMI of 25-29.9 kg/m2

  • Grade 2 overweight (commonly called obesity) - BMI of 30-39.9 kg/m2

  • Grade 3 overweight (commonly called severe or morbid obesity) - BMI ≥40 kg/m2

Some authorities advocate a definition of obesity based on percentage of body fat, as follows:

  • Men: Percentage of body fat greater than 25%, with 21-25% being borderline

  • Women: Percentage of body fat great than 33%, with 31-33% being borderline

The clinician should also determine whether the patient has had any of the comorbidities related to obesity, including the following[3] :

  • Respiratory: Obstructive sleep apnea,[4] greater predisposition to respiratory infections, increased incidence of bronchial asthma, and Pickwickian syndrome (obesity hypoventilation syndrome[176] )

  • Malignant: Reported association with endometrial (premenopausal), prostate, colon (in men), rectal (in men), breast (postmenopausal), gall bladder, gastric cardial, biliary tract system, pancreatic, ovarian, renal, and possibly lung cancer, as well as with esophageal adenocarcinoma and multiple myeloma[5, 6, 7]

  • Psychological: Social stigmatization and depression

  • Cardiovascular: Coronary artery disease,[8] essential hypertension, left ventricular hypertrophy, cor pulmonale, obesity-associated cardiomyopathy, accelerated atherosclerosis, and pulmonary hypertension of obesity

  • Central nervous system (CNS): Stroke, idiopathic intracranial hypertension, and meralgia paresthetica

  • Obstetric and perinatal: Pregnancy-related hypertension, fetal macrosomia, and pelvic dystocia[9]

  • Surgical: Increased surgical risk and postoperative complications, including wound infection, postoperative pneumonia, deep venous thrombosis, and pulmonary embolism

  • Pelvic: Stress incontinence

  • Gastrointestinal (GI): Gall bladder disease (cholecystitis, cholelithiasis), nonalcoholic steatohepatitis (NASH), fatty liver infiltration, and reflux esophagitis

  • Orthopedic: Osteoarthritis, coxa vera, slipped capital femoral epiphyses, Blount disease and Legg-Calvé-Perthes disease, and chronic lumbago

  • Metabolic: Type 2 diabetes mellitus, prediabetes, metabolic syndrome, and dyslipidemia

  • Reproductive (in women): Anovulation, early puberty, infertility, hyperandrogenism, and polycystic ovaries

  • Reproductive (in men): Hypogonadotropic hypogonadism

  • Cutaneous: Intertrigo (bacterial and/or fungal), acanthosis nigricans, hirsutism, and increased risk for cellulitis and carbuncles

  • Extremity: Venous varicosities, lower extremity venous and/or lymphatic edema

  • Miscellaneous: Reduced mobility and difficulty maintaining personal hygiene

See Clinical Presentation for more detail.

Diagnosis

Laboratory studies

  • Fasting lipid panel

  • Liver function studies

  • Thyroid function tests

  • Fasting glucose and hemoglobin A1c (HbA1c)

Evaluation of degree of body fat

BMI calculation, waist circumference, and waist/hip ratio are the common measures of the degree of body fat used in routine clinical practice. Other procedures that are used in few clinical centers include the following:

  • Caliper-derived measurements of skin-fold thickness

  • Dual-energy radiographic absorptiometry (DEXA)

  • Bioelectrical impedance analysis

  • Ultrasonography to determine fat thickness

  • Underwater weighing

See Workup for more detail.

Management

Treatment of obesity starts with comprehensive lifestyle management (ie, diet, physical activity, behavior modification).[10] The 3 major phases of any successful weight-loss program are as follows:

  • Preinclusion screening phase

  • Weight-loss phase

  • Maintenance phase - This can conceivably last for the rest of the patient's life but ideally lasts for at least 1 year after the weight-loss program has been completed

Medications

Currently, the 3 major groups of drugs used to manage obesity are as follows:

  • Centrally acting medications that impair dietary intake

  • Medications that act peripherally to impair dietary absorption

  • Medications that increase energy expenditure

Surgery

Among the standard bariatric procedures are the following:

  • Roux-en-Y gastric bypass

  • Adjustable gastric banding

  • Gastric sleeve surgery

  • Vertical sleeve gastrectomy

  • Horizontal gastroplasty

  • Vertical-banded gastroplasty

  • Duodenal-switch procedures

  • Biliopancreatic bypass

  • Biliopancreatic diversion

See Treatment and Medication for more detail.

Background

Obesity is a substantial public health crisis in the United States and in the rest of the industrialized world. The prevalence is increasing rapidly in numerous industrialized nations worldwide. This growing rate represents a pandemic that needs urgent attention if obesity’s potential toll on morbidity, mortality, and economics is to be avoided. Research into the complex physiology of obesity may aid in avoiding this impact. (See Pathophysiology and Etiology.)

The annual cost of managing obesity in the United States alone amounts to approximately $190.2 billion per year, or 20.6% of national health expenditures, according to a study.[11] Compared with a nonobese person, an obese person incurs $2741 more in medical costs (in 2005 dollars) annually. In addition, the annual cost of lost productivity due to obesity is approximately $73.1 billion,[12] and almost $121 billion is spent annually on weight-loss products and services.[13] (See Treatment and Medication.)

In a 2016 position statement, the American Association of Clinical Endocrinologists (AACE) and the American College of Endocrinology (ACE) proposed a new name for obesity, adiposity-based chronic disease (ABCD). The AACE/ACE did not introduce the name as an actual replacement for the term obesity but instead as a means of helping the medical community focus on the pathophysiologic impact of excess weight.[14]

For information on pediatric obesity, see Obesity in Children.

Measurements of obesity

Obesity represents a state of excess storage of body fat. Although similar, the term overweight is puristically defined as an excess of body weight for height. Normal, healthy men have a body fat percentage of 15-20%, while normal, healthy women have a percentage of approximately 25-30%.[15] However, because differences in weight among individuals are only partly the result of variations in body fat, body weight is a limited, although easily obtained, index of obesity.

The body mass index (BMI), also known as the Quetelet index, is used far more commonly than body fat percentage to define obesity. In general, BMI correlates closely with the degree of body fat in most settings; however, this correlation is weaker at low BMIs.

An individual’s BMI is calculated as weight/height2, with weight being in kilograms and height being in meters (otherwise, the equation is weight in pounds ´ 0.703/height in inches2). Online BMI calculators are available.

A person’s body fat percentage can be indirectly estimated by using the Deurenberg equation, as follows:

body fat percentage = 1.2(BMI) + 0.23(age) - 10.8(sex) - 5.4

with age being in years and sex being designated as 1 for males and 0 for females. This equation has a standard error of 4% and accounts for approximately 80% of the variation in body fat.

Although the BMI typically correlates closely with percentage body fat in a curvilinear fashion, some important caveats apply to its interpretation. In mesomorphic (muscular) persons, BMIs that usually indicate overweight or mild obesity may be spurious, whereas in some persons with sarcopenia (eg, elderly individuals and persons of Asian descent, particularly from South Asia), a typically normal BMI may conceal underlying excess adiposity characterized by an increased percentage of fat mass and reduced muscle mass.

In view of these limitations, some authorities advocate a definition of obesity based on percentage of body fat. For men, a percentage of body fat greater than 25% defines obesity, with 21-25% being borderline. For women, over 33% defines obesity, with 31-33% being borderline.

Other indices used to estimate the degree and distribution of obesity include the 4 standard skin thicknesses (ie, subscapular, triceps, biceps, suprailiac) and various anthropometric measures, of which waist and hip circumferences are the most important. Skinfold measurements are the least accurate means by which to assess obesity.

Dual-energy radiographic absorptiometry (DXA) scanning is used primarily by researchers to accurately measure body composition, particularly fat mass and fat-free mass. It has the additional advantage of measuring regional fat distribution. However, DXA scans cannot be used to distinguish between subcutaneous and visceral abdominal fat deposits.

The current standard techniques for measuring visceral fat volume are abdominal computed tomography (CT) scanning (at L4-L5) and magnetic resonance imaging (MRI) techniques. A simpler technique, using bioelectrical impedance, was recently introduced.[16] However, these methods are limited to clinical research.

Classification of obesity

Although several classifications and definitions for degrees of obesity are accepted, the most widely accepted classifications are those from the World Health Organization (WHO), based on BMI. The WHO designations include the following:

  • Grade 1 overweight (commonly and simply called overweight) - BMI of 25-29.9 kg/m2

  • Grade 2 overweight (commonly called obesity) - BMI of 30-39.9 kg/m2

  • Grade 3 overweight (commonly called severe or morbid obesity) - BMI greater than or equal to 40 kg/m2

The cut-off for each grade varies according to an individual’s ethnic background. For example, a BMI of 23 kg/m2 or higher may define grade 1 overweight and 27.5 kg/m2 or higher may define grade 2 overweight (obesity) in many Asian populations, in which the risk was shown to be high and extremely high for grade 1 and 2 overweight at these levels, respectively. Other BMI cutoffs identified as potential public health action points in these populations are 32.5 and 37.5 kg/m2.[17]

The surgical literature often uses a different classification to recognize particularly severe obesity. The categories are as follows:

  • Severe obesity - BMI greater than 40 kg/m2

  • Morbid obesity - BMI of 40-50 kg/m2

  • Super obese - BMI greater than 50 kg/m2

In children, a BMI above the 85th percentile (for age-matched and sex-matched control subjects) is commonly used to define overweight, and a BMI above the 95th percentile is commonly used to define obesity.

Comorbidities associated with obesity

Obesity is associated with a host of potential comorbidities that significantly increase the risk of morbidity and mortality in obese individuals. Although no cause-and-effect relationship has been clearly demonstrated for all of these comorbidities, amelioration of these conditions after substantial weight loss suggests that obesity probably plays an important role in their development. (See Presentation.)

Apart from total body fat mass, the following aspects of obesity have been associated with comorbidity:

  • Fat distribution

  • Waist circumference

  • Age of obesity onset

  • Intra-abdominal pressure

Fat distribution

Accumulating data suggest that regional fat distribution substantially affects the incidence of comorbidities associated with obesity.[3] Android obesity, in which adiposity is predominantly abdominal (including visceral and, to a lesser extent, subcutaneous), is strongly correlated with worsened metabolic and clinical consequences of obesity.

Waist circumference

The thresholds used in the National Cholesterol Education Program Adult Treatment Panel III definition of metabolic syndrome[18] state that significantly increased cardiovascular risk (metabolic central obesity) exists in men with waist circumferences of greater than 94 cm (37 in) and in women with waist circumferences of greater than 80 cm (31.5 in), as well as waist-to-hip ratios of greater than 0.95 in men and of greater than 0.8 in women. Circumferences of 102 cm (40 in) in men and 88 cm (35 in) in women indicate a markedly increased risk requiring urgent therapeutic intervention.

These thresholds are much lower in Asian populations. After analyzing survey results of Chinese, Malay, and Asian-Indian cohorts, Tan and colleagues concluded that a waist circumference of greater than 90 cm in men and of more than 80 cm in women were more appropriate criteria for metabolic central obesity in these ethnic groups.[19]

Age of obesity onset

An elevated BMI during adolescence (starting within the range currently considered normal) is strongly associated with the risk of developing obesity-related disorders later in life, independent of adult BMI.[20] Increases in BMI during early adulthood (age 25-40 y) are associated with a worse profile of biomarkers related to obesity than are BMI increases during later adulthood.[21] This is consistent with most emerging data regarding timing of changes in BMI and later health consequences.

Intra-abdominal pressure

Apart from the metabolic complications associated with obesity, a paradigm of increased intra-abdominal pressure has been recognized. This pressure effect is most apparent in the setting of marked obesity (BMI ≥ 50 kg/m2) and is espoused by bariatric surgeons.[22]

Findings from bariatric surgery and animal models suggest that this pressure elevation may play a role (potentially a major one) in the pathogenesis of comorbidities of obesity, such as the following[23] :

  • Pseudotumor cerebri

  • Lower-limb circulatory stasis

  • Ulcers

  • Dermatitis

  • Thrombophlebitis

  • Reflux esophagitis

  • Abdominal hernias

  • Possibly, hypertension and nephrotic syndrome

Osteoarthritis

A study by Losina et al found that obesity with knee osteoarthritis resulted in the loss of a substantial number of quality-adjusted life years. The association was most notable among black and Hispanic women.[27]

Focal glomerulosclerosis

Some reports, including those by Adelman and colleagues and by Kasiske and Jennette, suggest an association between severe obesity and focal glomerulosclerosis.[28, 29, 30] This complication, in particular, improves substantially or resolves soon after bariatric surgery, well before clinically significant weight loss is achieved.

Pickwickian syndrome

The so-called Pickwickian syndrome is a combined syndrome of obesity-related hypoventilation[176] and sleep apnea. It is named after Charles Dickens’s novel The Pickwick Papers, which contains an obese character who falls asleep constantly during the day.

The hypoventilation in Pickwickian syndrome results from severe mechanical respiratory limitations to chest excursion, caused by severe obesity. The sleep apnea may be from obstructive and/or central mechanisms. Obstructive sleep apnea is common among men with collar size greater than 17 in (43 cm) and women with collar size greater than 16 in (41 cm).

Increased and decreased sleep duration

Sleep duration of less than 5 hours or more than 8 hours was associated with increased visceral and subcutaneous body fat, in a study of young African Americans and Hispanic Americans.[31] This association relates mostly to decreased leptin hormone and increased ghrelin hormone levels.[32]

Additional comorbidities

Overweight and obese individuals are at increased risk for the following health conditions:

  • Metabolic syndrome

  • Type 2 diabetes

  • Hypertension

  • Dyslipidemia

  • Coronary heart disease

  • Osteoarthritis

  • Stroke

  • Depression

  • Non-alcoholic fatty liver disease (NAFLD)

  • Infertility (women) and erectile dysfunction (men)

  • Risk of stillbirth[24, 25]

  • Gall bladder disease

  • Obstructive sleep apnea

  • Gastroesophageal reflux disease (GERD)

  • Some cancers (eg, endometrial, breast, and colon)[5, 6, 7]

  • Asthma

A study by Abdullah et al indicated that not only the severity of a patient’s obesity but its duration as well is associated with the individual’s risk of developing type 2 diabetes mellitus. Based on a more than four decade follow-up of 5132 participants in the Framingham Offspring Study, the investigators found a significant rise in type 2 diabetes risk as obese-years increased.[26]

Research indicates that the likelihood of developing type 2 diabetes is not the same in all persons with overweight or obesity, with some of these individuals being genetically inclined toward an adiposity profile that lowers their chances for the disease. Fourteen genetic variants have been identified that investigators say lead to subcutaneous storage of excess fat rather than accumulation of the fat around organs such as the liver, thus reducing the diabetes risk.[181]

A Korean study, by Evangelista et al, found a higher prevalence of general and abdominal obesity in persons with some stages of chronic kidney disease (CKD) than in those without CKD. The greatest prevalence of these forms of obesity was found in patients with stage 2 CKD. The investigators also reported that general and abdominal obesity were not associated with stage 4 or 5 CKD.[177]

Pathophysiology

Hypertrophic versus hypercellular obesity

The adipocyte, which is the cellular basis for obesity, may be increased in size or number in obese persons. Hypertrophic obesity, characterized by enlarged fat cells, is typical of android abdominal obesity. Hypercellular obesity is more variable than hypertrophic obesity; it typically occurs in persons who develop obesity in childhood or adolescence, but it is also invariably found in subjects with severe obesity.

Hypertrophic obesity usually starts in adulthood, is associated with increased cardiovascular risk, and responds quickly to weight reduction measures. In contrast, patients with hypercellular obesity may find it difficult to lose weight through nonsurgical interventions.

Adipocytes

Products

The adipocyte is increasingly found to be a complex and metabolically active cell. At present, the adipocyte is perceived as an active endocrine gland producing several peptides and metabolites that may be relevant to the control of body weight; these are being studied intensively.[33]

Many of the adipocytokines secreted by adipocytes are proinflammatory or play a role in blood coagulation. Others are involved in insulin sensitivity and appetite regulation. However, the function of many of these identified cytokines remains unknown or unclear.

Proinflammatory products of the adipocyte include the following[34] :

  • Tumor necrosis factor–alpha

  • Interleukin 6

  • Monocyte chemoattractant protein–1 (MCP-1)

Other adipocyte products include the following[34] :

  • Lipotransin

  • Plasminogen activator inhibitor-1 (PAI-1) - Associated with cardiovascular risk

  • Adipocyte lipid-binding protein

  • Acyl-stimulation protein

  • Prostaglandins - Coagulation role

  • Adipsin

  • Perilipins

  • Lactate

  • Leptin - Appetite regulator

  • Adiponectin - Major role in insulin sensitivity

  • Monobutyrin

  • Phospholipid transfer protein

Metabolism and function

Critical enzymes involved in adipocyte metabolism and function include the following:

  • Endothelial-derived lipoprotein lipase - Lipid storage

  • Hormone-sensitive lipase - Lipid elaboration and release from adipocyte depots

  • Acyl-coenzyme A (acyl-CoA) synthetases - Fatty acid synthesis

In addition, a cascade of enzymes is involved in beta-oxidation and fatty acid metabolism. The ongoing flurry of investigation into the intricacies of adipocyte metabolism has not only improved our understanding of the pathogenesis of obesity but has also offered several potential targets for therapy.

Development

Another area of active research is investigation of the cues for the differentiation of preadipocytes to adipocytes. The recognition that this process occurs in white and brown adipose tissue, even in adults, has increased its potential importance in the development of obesity and the relapse to obesity after weight loss.

Among the identified elements in this process are the following transcription factors:

  • Peroxisome proliferator-activated receptor–gamma (PPAR-gamma)

  • Retinoid-X receptor ligands

  • Perilipin

  • Adipocyte differentiation–related protein (ADRP)

  • CCAAT/enhancer-binding proteins (C/EBP) alpha, beta, and delta

PPAR-gamma agonists increase the recruitment, proliferation, and differentiation of preadipocytes (healthy fat) and cause apoptosis of hypertrophic and dysfunctional adipocytes (including visceral fat). This results in improved fat function and improved metabolic parameters associated with excessive fat–related metabolic diseases (EFRMD), including type 2 diabetes mellitus, hypertension, and dyslipidemia.[35]

Hormonal influences on appetite

In addition to neurotransmitters and neurogenic signals, many hormones affect appetite and food intake. Endocannabinoids, through their effects on endocannabinoid receptors, increase appetite, enhance nutrient absorption, and stimulate lipogenesis. Melanocortin hormone, through its effects on various melanocortin receptors, modifies appetite.

Several gut hormones play significant roles in inducing satiety, including glucagonlike peptide-1 (GLP-1), neuropeptide YY (PYY), and cholecystokinin. Leptin and pancreatic amylin are other potent satiety hormones. On the other hand, ghrelin, which is secreted from the stomach fundus, is a major hunger hormone.

Odor detection threshold

Smell plays an important role in feeding behavior. Differences in the odor detection threshold (ie, the lowest concentration of a substance detectable by the human olfactory sense) were found in a study that measured thresholds in 8 lean, fasted individuals before and during a 2-hour hyperinsulinemic euglycemic insulin clamp.[36]

Increased insulin led to reduced smelling capacity, potentially reducing the pleasantness of eating. Therefore, insulin action in the olfactory bulb may be involved in the process of satiety and may be of clinical interest as a possible factor in the pathogenesis of obesity.[36]

Leptin

Friedman and colleagues discovered leptin (from the Greek word leptos, meaning thin) in 1994 and ushered in an explosion of research and a great increase in knowledge about regulation of the human feeding and satiation cycle. Leptin is a 16-kd protein produced predominantly in white subcutaneous adipose tissue and, to a lesser extent, in the placenta, skeletal muscle, and stomach fundus in rats. Leptin has myriad functions in carbohydrate, bone, and reproductive metabolism that are still being unraveled, but its role in body-weight regulation is the main reason it came to prominence.

Since this discovery, neuromodulation of satiety and hunger with feeding has been found to be far more complex than the old, simplistic model of the ventromedial hypothalamic nucleus and limbic centers of satiety and the feeding centers of the lateral hypothalamus. Potentially, leptin sensitizers may assist in changing feeding habits.

The major role of leptin in body-weight regulation is to signal satiety to the hypothalamus and thus reduce dietary intake and fat storage while modulating energy expenditure and carbohydrate metabolism, preventing further weight gain. Unlike the Ob/Ob mouse model in which this peptide was first characterized, most humans who are obese are not leptin deficient but are instead leptin resistant. Therefore, they have elevated levels of circulating leptin. Leptin levels are higher in women than in men and are strongly correlated with BMI.[37]

Patients with night-eating syndrome have attenuation of the nocturnal rise in plasma melatonin and leptin levels and higher circadian levels of plasma cortisol. These individuals have morning anorexia, evening hyperphagia, and insomnia. In one study, patients with night-eating syndrome averaged 3.6 awakenings per night; 52% of these awakenings were associated with food intake, with a mean intake per ingestion of 1134 kcal.[38]

Genetics

Mutations resulting in defects of the leptin receptor in the hypothalamus may occur. These mutations result in early onset obesity and hyperphagia despite normal or elevated leptin levels, along with hypogonadotropic hypogonadism, and defective thyrotropin secretion.

Murray et al first reported on a sequence variant within the leptin gene that enhances the intrinsic bioactivity of leptin, but which was associated with reduced weight rather than obesity.[39] This sequence variant within the leptin gene is also associated with delayed puberty.

Etiology

The etiology of obesity is far more complex than simply an imbalance between energy intake and energy output. Although this view allows easy conceptualization of the various mechanisms involved in the development of obesity, obesity is far more than simply the result of eating too much and/or exercising too little (see the energy-balance equation, below). Possible factors in the development of obesity include the following:

  • Metabolic factors

  • Genetic factors

  • Level of activity

  • Endocrine factors

  • Race, sex, and age factors

  • Ethnic and cultural factors

  • Socioeconomic status

  • Dietary habits

  • Smoking cessation

  • Pregnancy and menopause

  • Psychological factors

  • History of gestational diabetes

  • Lactation history in mothers

    Energy balance equation. Energy balance equation.

Nevertheless, the prevalence of inactivity in industrialized countries is considerable and relevant to the rise in obesity. In the United States, less than half of all adults meet the federal 2008 Physical Activity Guidelines, and fewer than 3 in 10 high school students get at least 60 minutes of physical activity every day.[40]

A study by Maripuu et al indicated that hypercortisolism associated with recurrent affective disorders increases the risk for metabolic disorders and cardiovascular risk factors such as obesity, overweight, large waist, high low-density lipoprotein (LDL) levels, and low high-density lipoprotein (HDL) levels. The study included 245 patients with recurrent depression or bipolar disorder and 258 controls.[41]

A study by Tester et al found that severely obese children (BMI at or above 120% of the 95th percentile) between ages 2 and 5 years were more likely to have the following characteristics[178] :

  • Be African American (odds ratio [OR]: 1.7) or Hispanic (OR: 2.3)
  • Engage in more than 4 hours of screen time (OR: 2.0)
  • Be from households characterized by a lower level of educational achievement (OR: 2.4)
  • Be from a single-parent household (OR: 2.0)
  • Be from a household living in poverty (OR: 2.1)

In addition, children in this age group who had never been breastfeed were at higher risk of severe obesity (OR: 1.9).[178]

Genetics

Two major groups of factors, genetic and environmental, have a balance that variably intertwines in the development of obesity. Genetic factors are presumed to explain 40-70% of the variance in obesity, within a limited range of BMI (18-30 kg/m2).

A study in which monozygotic twins were overfed by 1000 kcal per day, 6 days a week, over a 100-day period found that the amount of weight gain varied significantly between pairs (4.3 to 13.3 kg). However, the similarity within each pair was significant with respect to body weight, percentage of fat, fat mass, and estimated subcutaneous fat, with about 3 times more variance among pairs than within them.[42] This observation indicates that genetic factors are significantly involved and may govern the tendency to store energy.

Heritability

The strong heritability of obesity has been demonstrated in several twin and adoptee studies, in which obese individuals who were reared separately followed the same weight pattern as that of their biological parents and their identical twin. Metabolic rate, spontaneous physical activity, and thermic response to food seem to be heritable to a variable extent.

A study by Freeman et al found that having an overweight or obese father and healthy-weight mother significantly increased the odds of childhood obesity; however, having an obese mother and a healthy-weight father was not associated with an increased risk of obesity in childhood.[43] This discrepancy suggests a role for epigenetic factors in hereditary risk.

Genetic susceptibility loci

Rarely, obesity may be caused by a single gene, but much more commonly it is a complex interplay of susceptibility loci and environmental factors. Genome-wide association studies (GWAS) have found a robust number of genetic susceptibility loci associated with obesity. A single-nucleotide polymorphism (SNP) in the FTO (fat mass and obesity associated) gene and SNPs near the MC4R (melanocortin 4 receptor) gene have been highly associated with BMI.[44, 45, 46, 47]

Although many genetic susceptibility loci have been discovered, the effect sizes of the established loci are small, and combined they explain only a fraction of the variation in BMI between individuals. Their low predictive value means that they have limited value in clinical medicine.[48] Moreover, the fact that increases in the rate of obesity over the last few decades have coincided with changes in dietary habits and activity suggests an important role for environmental factors.

Monogenic models for obesity in humans and experimental animals

More than 90% of human cases of obesity are thought to be multifactorial. Nevertheless, the recognition of monogenic variants has greatly enhanced knowledge of the etiopathogenesis of obesity.[49] As previously mentioned, Friedman and colleagues discovered leptin (from the Greek word leptos, meaning thin) in 1994 and ushered in an explosion of research and a great increase in knowledge about regulation of the human feeding and satiation cycle.

POMC and MC4

Proopiomelanocortin (POMC) is converted into alpha–melanocyte-stimulating hormone (alpha-MSH), which acts centrally on the melanocortin receptor 4 (MC 4) to reduce dietary intake.[50] Genetic defects in POMC production and mutations in the MC4 gene are described as monogenic causes of obesity in humans.[51]

Of particular interest is the fact that patients with POMC mutations tend to have red hair because of the resultant deficiency in MSH production. Also, because of their diminished levels of adrenocorticotropic hormone (ACTH), they tend to have central adrenal insufficiency.

Data suggest that up to 5% of children who are morbidly obese have MC4 or POMC mutations.[52] If confirmed, these would be the most common identifiable genetic defects associated with obesity in humans (band 2p23 for POMC and band 18q21.3 for MC4).

Leptin deficiency

Rare cases of humans with congenital leptin deficiency caused by mutations in the leptin gene have been identified. (The involved band is at 7q31.) The disorder is autosomal recessive and manifested by severe obesity and hyperphagia accompanied by metabolic, neuroendocrine, and immune dysfunction.[53] It is exquisitely sensitive to leptin injection, with reduced dietary intake and profound weight loss.

Convertase mutation

Prohormone convertase, an enzyme that is critical in protein processing, appears to be involved in the conversion of POMC to alpha-MSH. Rare patients with alterations in this enzyme have had clinically significant obesity, hypogonadotropic hypogonadism, and central adrenal insufficiency. This is one of the few models of obesity not associated with insulin resistance.

PPAR-gamma

PPAR-gamma is a transcription factor that is involved in adipocyte differentiation. All humans with mutations of the receptor (at band 3p25) described so far have had severe obesity.

Inflammatory factors

Evolving data suggest that a notable inflammatory, and possibly infective, etiology may exist for obesity. Adipose tissue is known to be a repository of various cytokines, especially interleukin 6 and tumor necrosis factor alpha. One study showed an association between obesity and a high-normal level of plasma procalcitonin, a dependent variable that reflects a state of distress or inflammation.[54]

Data have shown that adenovirus-36 infection is associated with obesity in chickens and mice. In human studies, the prevalence of adenovirus-36 infection is 20-30% in people who are obese, versus 5% in people who are not obese. Despite these provocative findings, the roles of infection and inflammation in the pathogenesis of obesity remain unclear.

Epidemiology

United States statistics

Approximately 78 million adults above age 20 (37.5 million men and 40.6 million women) and 12.5 million children and adolescents (5.5 million boys and 7 million girls) in the United States are obese. A report from the National Center for Health Statistics stated that in US individuals aged 20 years or older, the prevalence of obesity rose steadily from 19.4% in 1997 to 31.4% for the period January-September 2017.[179, 180]

Approximately 20-25% of children are either overweight or obese, and the prevalence is even greater in some minority groups, including Pima Indians, Mexican Americans, and African Americans.[55]

Overweight and obesity were associated with nearly 1 in 5 deaths (18.2%) among adults in the United States from 1986 through 2006, according to a study published in the American Journal of Public Health.[57, 58] Previous research has likely underestimated obesity’s impact on US mortality.

Obesity appeared to have a particularly strong effect among black women, with 26.8% of deaths associated with a BMI of 25 kg/m2 or higher.[57, 58] In white women, 21.7% of deaths were associated with overweight or obesity. Among black men, 5.0% of deaths were associated with overweight or obesity, and among white men, 15.6% were. Data also show the more recent the birth year, the greater effect obesity has on mortality rates.[57, 58]

The researchers used data from 19 consecutive waves of the National Health Interview Survey covering 1986 through 2004 and linked those data with mortality information in the National Death Index through 2006.[57, 58] This study is the first to account for differences in age, birth cohort, sex, and race in analyzing Americans’ risk for death from obesity.

A randomized trial by Ludwig et al found that low-income persons who were assigned to live in higher-income neighborhoods gained less weight over time and had a lower risk of diabetes than did low-income persons who remained in predominantly low-income neighborhoods. The mechanisms behind this association are unclear, and further investigation is warranted.[59]

International statistics

The prevalence of obesity worldwide is increasing, particularly in the industrialized nations of the Northern hemisphere, such as the United States, Canada, and most countries of Europe. Available data from the Multinational Monitoring of Trends and Determinants in Cardiovascular Disease (MONICA) project suggest that at least 15% of men and 22% of women in Europe are obese.[60, 61]

Similar data are being reported in other parts of the world, including from many developing nations. Reports from countries such as Malaysia, Japan, Australia, New Zealand, and China have detailed an epidemic of obesity in the past 2-3 decades. Data from the Middle Eastern countries of Bahrain, Saudi Arabia, Egypt, Jordan, Tunisia, and Lebanon, among others, indicate this same disturbing trend, with levels of obesity often exceeding 40%.

Internationally, rates of obesity are higher in women than in men. A somewhat higher rate would be expected, given the biologically higher percentage of body fat in women.

Information from the Caribbean and from South America highlights similar trends. Although data from Africa are scant, a clear and distinct secular trend of profoundly increased BMIs is observed when people from Africa emigrate to the northwestern regions of the world. Comparisons of these indices among Nigerians and Ghanaians residing in their native countries with indices in recent immigrants to the United States show this trend poignantly.

In 2016, a study by the NCD Risk Factor Collaboration indicated, 124 million children and adolescents worldwide were obese, compared with 11 million in 1975. According to the study, 73% of this change resulted from an increased prevalence of obesity (as opposed to other factors, such as population growth). The study also reported that between 1975 and 2016, the number of obese adults worldwide rose from 100 million to 671 million. Figures for children/adolescents and adults who were overweight, but not obese, were 213 million and 1.3 billion, respectively, in 2016.[172, 173]

Although socioeconomic class and the prevalence of obesity are negatively correlated in most industrialized countries, including the United States, this correlation is distinctly reversed in many relatively undeveloped areas, including China, Malaysia, parts of South America, and sub-Saharan Africa.

Finucane et al conducted a comprehensive, constructive study that revealed growing global trends in BMI. This study may serve as wake-up call and initiate large-scale interventions in an effort to combat increasing body weight and associated adverse health consequences.[62]

Race-related demographics

Obesity is a cosmopolitan disease that affects all races worldwide. However, certain ethnic and racial groups appear to be particularly predisposed. The Pima Indians of Arizona and other ethnic groups native to North America have a particularly high prevalence of obesity. In addition, Pacific islanders (eg, Polynesians, Micronesians, Maoris), African Americans, and Hispanic populations (either Mexican or Puerto Rican in origin) in North America also have particularly high predispositions to the development of obesity.

Secular trends clearly emphasize the importance of environmental factors (particularly dietary issues) in the development of obesity. In many genetically similar cohorts of high-risk ethnic and racial groups, the prevalence of obesity in their countries of origin is low but rises considerably when members of these groups emigrate to the affluent countries of the Northern Hemisphere, where they alter their dietary habits and activities. These findings form the core concept of the thrifty gene hypothesis espoused by Neel and colleagues.[63]

The thrifty gene hypothesis posits that human evolution favored individuals who were more efficient at storing energy during times of food shortage and that this historic evolutionary advantage is now a disadvantage during a time of abundant food availability.

Age-related demographics

Children, particularly adolescents, who are obese have a high probability of becoming adults who are obese; hence, the bimodal distribution of obesity portends a large-scale obesity epidemic in the next few decades. Taller children generally tend to be more obese than shorter peers, are more insulin-resistant, and have increased leptin levels.[64]

Adolescent obesity poses a serious risk for severe obesity during early adulthood, particularly in non-Hispanic black women. This calls for a stronger emphasis on weight reduction during early adolescence, specifically targeting groups at greater risk.[65]

Prognosis

Data from insurance databases and large, prospective cohorts, such as findings from the Framingham and National Health and Nutrition Examination Survey (NHANES) studies, clearly indicate that obesity is associated with a substantial increase in morbidity and mortality rates.

The adverse consequences of obesity may be attributed in part to comorbidities, but results from several observational studies detailed by the Expert Panel on the Identification, Evaluation, and Treatment of Overweight Adults, as well as results from reports by Allison, Bray, and others, exhaustively show that obesity on its own is associated with increased cardiovascular morbidity and mortality and greater all-cause mortality.[66, 67, 68]

For a person with a BMI of 25-28.9 kg/m2, the relative risk for coronary heart disease is 1.72. The risk progressively increases with an increasing BMI; with BMIs greater than 33 kg/m2, the relative risk is 3.44. Similar trends have been demonstrated in the relationship between obesity and stroke or chronic heart failure.

Overall, obesity is estimated to increase the cardiovascular mortality rate 4-fold and the cancer-related mortality rate 2-fold.[5, 6, 7] As a group, people who are severely obese have a 6- to 12-fold increase in the all-cause mortality rate. Although the exact magnitude of the attributable excess in mortality associated with obesity (about 112,000-365,000 excess deaths annually) has been disputed, obesity is indisputably the greatest preventable health-related cause of mortality after cigarette smoking.[66]

For persons with severe obesity (BMI ≥40), life expectancy is reduced by as much as 20 years in men and by about 5 years in women. The greater reduction in life expectancy for men is consistent with the higher prevalence of android (ie, predominantly abdominal) obesity and the biologically higher percent body fat in women. The risk of premature mortality is even greater in obese persons who smoke.

Some evidence suggests that, if unchecked, trends in obesity in the United States may be associated with overall reduced longevity of the population in the near future. Data also show that obesity is associated with an increased risk and duration of lifetime disability. Furthermore, obesity in middle age is associated with poor indices of quality of life in old age.

The mortality data appear to have a U - or J -shaped conformation in relation to weight distribution.[69] Underweight was associated with substantially high risk of death in a study of Asian populations, and a high BMI is also associated with an increased risk of death, except in Indians and Bangladeshis.[70] A study in whites found that all-cause mortality is generally lowest with a BMI of 20-24.9 and reinforced that overweight and underweight lead to an increased risk of death.[71]

The degree of obesity (generally indicated by the BMI) at which mortality discernibly increases in African Americans and Hispanic Americans is greater than in white Americans; this observation suggests a notable racial spectrum and difference in this effect. The optimal BMI in terms of life expectancy is about 23-25 for whites and 23-30 for blacks. Emerging data suggest that the ideal BMI for Asians is substantially lower than that for whites.[17]

On the other hand, Boggs et al found that the risk of death from any cause among black women increased with a BMI of 25 or higher, which is similar to the pattern observed among whites. Waist circumference appeared to be associated with an increased risk of death only in nonobese women.[72]

Stated another way, individuals who have abdominal obesity (elevated waist circumference) are at risk for obesity-related health complications. Most individuals with a BMI of over 25 and essentially all persons with a BMI of more than 30 have abdominal obesity.

Factors that modulate the morbidity and mortality associated with obesity include the following:

  • Age of onset and duration of obesity

  • Severity of obesity

  • Amount of central adiposity

  • Comorbidities

  • Gender

  • level of cardiorespiratory fitness

  • Race

A study by Jung et al found a correlation between abdominal obesity and high-volume benign prostatic hyperplasia (BPH), ie, a prostate volume of 40 mL or greater. The report, which involved 571 participants, also found a positive association between serum leptin levels and high-volume BPH and a negative association between serum adiponectin and high-volume BPH.[73]

Morbidity in elderly persons

A longitudinal study by Stessman et al of more than 1000 individuals indicated that a normal BMI, rather than obesity, is associated with a higher mortality rate in elderly people.[74] The investigators determined that a unit increase in BMI in female members of the cohort could be linked to hazard ratios (HRs) of 0.94 at age 70 years, 0.95 at age 78 years, and 0.91 at age 85 years.

In men, a unit increase in BMI was associated with HRs of 0.99 at age 70 years, 0.94 at age 78 years, and 0.91 at age 85 years. According to a time-dependent analysis of 450 cohort members followed from age 70 to age 88 years, a unit increase in BMI produced an HR of 0.93 in women and in men.[74]

Similar results were found in a Japanese study of 26,747 older persons (aged 65-79 years at baseline). Tamakoshi et al found no elevation in all-cause mortality risk in overweight (BMI 25.0-29.9) or obese (BMI ≥30.0) men; slightly elevated hazard ratios were found in women in the obese group, but not in the overweight group, compared with women in the mid–normal-range group. In contrast, an association was found between a low BMI and an increased risk of all-cause mortality, even among persons in the lower-normal BMI range.[75]

Weight-loss programs

Most individuals are able to attain weight loss in the short term, but weight regain is unfortunately a common pattern. On average, participants in nonsurgical weight-management programs lose approximately 10% of their initial body weight over 12-24 weeks, but the majority regain two thirds of the weight lost within a year.

Old data indicated that 90-95% of the weight lost is regained in 5 years. Recent data show that more intensive and structured nonsurgical weight management may help a significant number of patients to maintain most of the weight lost for up to 4 years.

In the Look AHEAD study, 887 of 2570 participants (34.5%) in the intensive lifestyle group lost at least 10% of their weight at year 1. Of these, 374 (42.2%) maintained this loss at year 4 and another 17% maintained 7-10% weight loss at 4 years. More than 45% of all intensive lifestyle participants had achieved and maintained a clinically significant weight loss (≥ 5%) at 4 years.[76]

Patient Education

In studies among low-income families, adults and adolescents noted caloric information when reading labels.[77] However, this information did not affect food selection by adolescents or parental food selections for children.

NHANES found that patients who received a formal diagnosis of overweight/obese from a healthcare provider demonstrated a higher rate of dietary change and/or physical activity than did persons whose overweight/obese condition remained undiagnosed. These findings are important for any clinician caring for overweight/obese patients.[55]

A meta-analysis by Waters et al of 55 studies assessing educational, behavioral, and health promotion interventions in children aged 0-18 years found that these interventions reduced BMI (standardized mean difference in adiposity, 0.15 kg/m2).[78] The study concluded that child obesity prevention programs have beneficial effects.

For patient education information, see the Diabetes Health Center and Metabolic Syndrome Health Center, as well as Obesity, Weight Loss and Control, High Cholesterol, Cholesterol Charts (What the Numbers Mean), and Lifestyle Cholesterol Management.

 

Presentation

History

In most patients, the presentation of obesity is straightforward, with the patient indicating problems with weight or repeated failure in achieving sustained weight loss. In other cases, however, the patient may present with complications and/or associations of obesity.

A full history must include a dietary inventory and an analysis of the patient’s activity level. Screening questions to exclude severe or untreated depression are vital because depression may be a consequence or a cause of excessive dietary intake and reduced activity.

Because almost 30% of patients who are obese have eating disorders, screen for these in the history. The possibility of bingeing, purging, lack of satiety, food-seeking behavior, night-eating syndrome, and other abnormal feeding habits must be identified because management of these habits is crucial to the success of any weight-management program.

When taking the history, the clinician should investigate whether other members of the patient's family have weight problems, inquire about the patient's expectations, and estimate the patient's level of motivation. The clinician should also determine whether the patient has had any of the comorbidities related to obesity, including the following[3] :

  • Respiratory: Obstructive sleep apnea,[4] greater predisposition to respiratory infections, increased incidence of bronchial asthma, and Pickwickian syndrome (obesity hypoventilation syndrome[176] )

  • Malignant: Reported association with endometrial (premenopausal), prostate, colon (in men), rectal (in men), breast (postmenopausal), gall bladder, gastric cardial, biliary tract system, pancreatic, ovarian, renal, and possibly lung cancer, as well as with esophageal adenocarcinoma and multiple myeloma[5, 6, 7]

  • Psychological: Social stigmatization and depression

  • Cardiovascular: Coronary artery disease,[8] essential hypertension, left ventricular hypertrophy, cor pulmonale, obesity-associated cardiomyopathy, accelerated atherosclerosis, and pulmonary hypertension of obesity

  • Central nervous system (CNS): Stroke, idiopathic intracranial hypertension, and meralgia paresthetica

  • Obstetric and perinatal: Pregnancy-related hypertension, fetal macrosomia, and pelvic dystocia[9]

  • Surgical: Increased surgical risk and postoperative complications, including wound infection, postoperative pneumonia, deep venous thrombosis, and pulmonary embolism

  • Pelvic: Stress incontinence

  • Gastrointestinal (GI): Gall bladder disease (cholecystitis, cholelithiasis), nonalcoholic steatohepatitis (NASH), fatty liver infiltration, and reflux esophagitis

  • Orthopedic: Osteoarthritis, coxa vera, slipped capital femoral epiphyses, Blount disease and Legg-Calvé-Perthes disease, and chronic lumbago

  • Metabolic: Type 2 diabetes mellitus, prediabetes, metabolic syndrome, and dyslipidemia

  • Reproductive: In women: Anovulation, early puberty, infertility, hyperandrogenism, and polycystic ovaries; in men: hypogonadotropic hypogonadism

  • Cutaneous: Intertrigo (bacterial and/or fungal), acanthosis nigricans, hirsutism, and increased risk for cellulitis and carbuncles

  • Extremity: Venous varicosities, lower extremity venous and/or lymphatic edema

  • Miscellaneous: Reduced mobility and difficulty maintaining personal hygiene

Include questions to exclude secondary causes of obesity, some of which are rare. (See the chart below.)

Secondary causes of obesity. Secondary causes of obesity.

Physical Examination

In the clinical examination, measure anthropometric parameters and perform the standard, detailed examination required in evaluating patients with any chronic, multisystem disorder, such as obesity.

Waist and hip circumference are useful surrogates in estimating visceral fat; serial tracking of these measurements helps in estimating the clinical risk over time. Neck circumference is predictive of a risk of sleep apnea, and its serial measurement in the individual patient is clinically useful for risk stratification.[4]

Examination of organ systems should include the following:

  • Cutaneous - Search for intertriginous rashes from skin-on-skin friction; also search for hirsutism in women, acanthosis nigricans, and skin tags, which are common with insulin resistance secondary to obesity

  • Cardiac and respiratory - Exclude cardiomegaly and respiratory insufficiency

  • Abdominal - Attempt to exclude tender hepatomegaly, which may suggest hepatic fatty infiltration or NASH, and distinguish the striae distensae from the pink and broad striae that suggest cortisol excess

When examining the extremities, search for joint deformities (eg, coxa vara), evidence of osteoarthritis, and any pressure ulcerations. Localized and lipodystrophic fat distribution should also be identified, because of their common association with insulin resistance.

 

DDx

Diagnostic Considerations

Mesomorphic body states, as seen in body builders and people in related occupations (eg, professional wrestling), may be associated with elevated BMIs, but as a result of increased muscle mass rather than excess adiposity. In addition, anasarca may be mistaken for obesity if not carefully evaluated clinically. Other conditions to consider while examining for obesity include the following:

  • Depression

  • Type 2 diabetes mellitus

  • Fatty liver

  • Gastroesophageal reflux disease (GERD)

  • Hirsutism

  • Polygenic hypercholesterolemia

  • Hypothyroidism

  • Insulinoma

  • Kallmann syndrome and idiopathic hypogonadotropic hypogonadism

  • Generalized lipodystrophy

  • Polycystic ovarian disease (Stein-Leventhal syndrome)

  • Cushing syndrome

  • Adiposa dolorosa (Dercum disease)

  • Partial lipodystrophies associated with localized lipohypertrophy

Differential Diagnoses

 

Workup

Approach Considerations

Standard laboratory studies in the evaluation of obesity should include the following:

  • Fasting lipid panel

  • Liver function studies

  • Thyroid function tests

  • Fasting glucose and hemoglobin A1c (HbA1c)

Other tests are performed as indicated by clinical findings. For example, the 24-hour urinary free-cortisol test is needed only when Cushing syndrome or other hypercortisolemic states are clinically suspected. However, approximately 4% of patients with Cushing syndrome have normal urinary free-cortisol values.

Lipid panel

At minimum, test fasting cholesterol, triglycerides, and high-density lipoprotein cholesterol (HDL-C) levels. These levels may be normal, or the typical dyslipidemia associated with cardiometabolic syndrome may be found. This dyslipidemia is characterized by reduced HDL-C and elevated fasting triglyceride concentrations; however, increased low-density lipoprotein cholesterol (LDL-C) and normal to marginally increased total cholesterol are not uncommon among obese individuals.

Liver and thyroid function tests

Liver function tests yield normal results in most obese patients. However, elevated transaminase levels may indicate nonalcoholic steatohepatitis (NASH) or fatty infiltration of the liver).

Thyroid function test results are also typically normal, but checking them to detect primary hypothyroidism (characterized by increased serum thyrotropin and normal or reduced thyroxine and/or triiodothyronine levels) is worthwhile. Screening with a serum thyrotropin level is usually sufficient. Of importance, hypothyroidism itself rarely causes more than mild obesity.

Glucose and insulin studies

Obesity is associated with insulin resistance and increased serum levels of fasting insulin and C-peptide serum levels. However, insulin levels are normal in many persons who are obese.

All patients with obesity should be screened for diabetes. Additional information is gained by using glucose and HbA1c tests together if the patient is fasting. The American Diabetes Association currently recommends using the HbA1c test not only to screen for diabetes, but also to follow patients who already have the diagnosis.[19] In contrast, the American Association of Clinical Endocrinologists recommends that HbA1c be considered an additional, optional diagnostic criterion.[79]

Prediabetes is indicated by impaired fasting glucose (fasting plasma glucose levels of 100-125 mg/dL [5.6-6.9 mmol/L]) or impaired glucose tolerance (2-h oral glucose tolerance test values of 140-199 mg/dL [7.8-11.0 mmol/L]). Patients with these findings are at relatively high risk for the future development of diabetes. Type 2 diabetes is diagnosed when the fasting glucose is 126 mg/dL or greater or HbA1c is 6.5% or higher.[80]

Evaluation of Degree of Fat

Body mass index (BMI) calculation, waist circumference, and waist/hip ratio are the common measures of the degree of body fat used in routine clinical practice. Other procedures that are used in few clinical centers include the following:

  • Caliper-derived measurements of skin-fold thickness

  • Dual-energy radiographic absorptiometry (DEXA)

  • Bioelectrical impedance analysis

  • Ultrasonography to determine fat thickness

  • Underwater weighing

The standard techniques for measuring visceral fat are magnetic resonance imaging (MRI) and computed tomography (CT) scanning. Less expensive techniques for direct measurement of visceral fat include abdominal ultrasonography and abdominal bioelectrical impedance.

 

Treatment

Approach Considerations

Treatment of obesity starts with comprehensive lifestyle management (ie, diet, physical activity, behavior modification), which should include the following[10] :

  • Self-monitoring of caloric intake and physical activity

  • Goal setting

  • Stimulus control

  • Nonfood rewards

  • Relapse prevention

As with all chronic medical conditions, effective management of obesity must be based on a partnership between a highly motivated patient and a committed team of health professionals. This team may include the physician, a psychologist or psychiatrist, physical and exercise therapists, dietitians, and other subspecialists, depending on the comorbidities of the individual patient. Scientific evidence indicates that multidisciplinary programs reliably produce and sustain modest weight loss between 5% and 10% for the long-term.[81, 82]

In January, 2015, the Endocrine Society released new guidelines on the treatment of obesity to include the following:[83, 84]

  • Diet, exercise, and behavioral modification should be included in all obesity management approaches for body mass index (BMI) of 25 kg/m2 or higher. Other tools, such as pharmacotherapy for BMI of 27 kg/m2 or higher with comorbidity or BMI over 30 kg/m2 and bariatric surgery for BMI of 35 kg/m2 with comorbidity or BMI over 40 kg/m2, should be used as adjuncts to behavioral modification to reduce food intake and increase physical activity when this is possible.

  • Drugs may amplify adherence to behavior change and may improve physical functioning such that increased physical activity is easier in those who cannot exercise initially. Patients who have a history of being unable to successfully lose and maintain weight and who meet label indications are candidates for weight loss medications.

  • To promote long-term weight maintenance, the use of approved weight loss medication (over no pharmacological therapy) is suggested to ameliorate comorbidities and amplify adherence to behavior changes, which may improve physical functioning and allow for greater physical activity in individuals with a BMI of 30 kg/m2 or higher or in individuals with a BME of 27 kg/m2 and at least one associated comorbid medical condition (eg, hypertension, dyslipidemia, type 2 diabetes mellitus, and obstructive sleep apnea).

  • If a patient's response to a weight loss medication is deemed effective (weight loss of 5% or more of body weight at 3 mo) and safe, it is recommended that the medication be continued. If deemed ineffective (weight loss less than 5% at 3 mo) or if there are safety or tolerability issues at any time, it is recommended that the medication be discontinued and alternative medications or referral for alternative treatment approaches be considered.

  • In patients with type 2 diabetes mellitus who are overweight or obese, antidiabetic medications that have additional actions to promote weight loss (such as glucagon-like peptide-1 [GLP-1] analogs or sodium-glucose-linked transporter-2 [SGLT-2] inhibitors) are suggested, in addition to the first-line agent for type 2 diabetes mellitus and obesity, metformin.

  • In obese patients with type 2 diabetes mellitus who require insulin therapy, at least one of the following is suggested: metformin, pramlintide, or GLP-1 agonists to mitigate associated weight gain due to insulin. The first-line insulin for this type of patient should be basal insulin. This is preferable to using either insulin alone or insulin with sulfonylurea.

  • Angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and calcium channel blockers, rather than beta-adrenergic blockers, should be considered as first-line therapy for hypertension in patients with type 2 diabetes mellitus who are obese.

  • In women with a BMI of 27 kg/m2 or more with comorbidities or a BMI of 30 kg/m2 or more, seeking contraception, oral contraceptives are suggested over injectable medications because of weight gain with injectables, provided that women are well informed about the risks and benefits (ie, oral contraceptives are not contraindicated).

Weight-loss programs

The 3 major phases of any successful weight-loss program are as follows:

  • Preinclusion screening phase

  • Weight-loss phase

  • Maintenance phase - This can conceivably last for the rest of the patient's life but ideally lasts for at least 1 year after the weight-loss program has been completed

Evidence supports the use of commercial weight-loss programs. A 12-week randomized, controlled trial found that commercially available weight-loss programs are more successful and more affordable than primary care practice–based programs led by specially trained staff.[85]

Pharmacologic therapy

Few drugs are available for the treatment of obesity, and their effectiveness is limited to palliation (ie, production and maintenance of weight loss) rather than cure, with benefits fading when the drugs are stopped. Because all medications inherently have more risks than diet and exercise do, pharmacologic therapy should be used only in patients in whom the benefit justifies the risk.[86]

Surgery

In patients with morbid obesity associated with comorbidities, bariatric surgery is the only available therapeutic modality associated with clinically significant and relatively sustained weight loss. Well-performed bariatric surgery, in carefully selected patients and with a good multidisciplinary support team, substantially ameliorates the morbidities associated with severe obesity.

Comorbidities

The management of obesity is not complete without attention being paid to potential comorbidities. Addressing these issues can have profound effects on the patient's well-being and risk of morbidity and mortality.

According to guidelines released by the American College of Cardiology (ACC), the American Heart Association (AHA), and The Obesity Society (TOS) in 2013, weight loss should be encouraged at a BMI of 25 with just 1 comorbidity (instead of 2 as was the case in previous guidelines), and elevated waist circumference can be one of those comorbidities.[81, 82]

Weight-loss ̶ associated morbidity

Although obesity in itself is associated with increased morbidity and mortality, massive, poorly monitored weight loss and/or weight cycling can have equally dire consequences. Among the important potential complications to watch out for in the setting of weight loss are the following:

  • Cardiac arrhythmias

  • Electrolyte derangements - Hypokalemia is the most important of these

  • Hyperuricemia

  • Psychological sequelae - Including depression and the development of eating disorders (particularly binge-eating disorders)

  • Cholelithiasis

Patient Screening, Assessment, and Expectations

Before enrolling any patient in a weight-loss program, the clinician must have a clear idea of that individual’s expectations. A patient with unrealistic expectations should not be enrolled until these are changed to realistic and attainable goals. The clinician should guide the patient who seeks weight reduction to create goals that fit the mnemonic SMART: Specific, Measurable, Attainable, Realistic, and Timely.

A specific goal has a much greater chance of being accomplished than a general goal does. To set a specific goal, the patient must answer the following 6 W questions:

  • Who - Who is involved?

  • What - What do I want to accomplish?

  • Where - Identify a location

  • When - Establish a time frame

  • Which - Identify requirements and constraints

  • Why - Identify specific reasons for or purpose or benefits of the goal

Also crucial is a clear assessment of the patient's level of motivation regarding the changes in diet, exercise, and behavior required to maintain weight loss. This assessment should be completed before the patient is enrolled in a weight-loss program.

Comprehensive, written, informed consent must be obtained and should address details of the expected weight loss and the required changes. Clinical judgment may support a less stringent approach in some situations.

Psychiatric comorbidities

Because of the potential harm of attempting weight loss in an unsuitable candidate, all patients to be enrolled in any surgical, medical, or other weight-loss program should be screened for serious mental illness (eg, severe or untreated depression) and for eating disorders.

Many of the psychological and psychiatric problems commonly associated with obesity are not contraindications to enrollment in a weight-loss program; for example, mild to moderate depression typically improves with weight loss. Nevertheless, clinicians and patients must be aware of these problems before enrollment. In addition, the clinician must ensure that any such problems are relatively stable, quiescent, or well managed before the patient begins a weight-loss program.

Weight-Loss Goals

In general, body weight and body fat are tenaciously regulated. This underlies the challenge of weight loss and highlights the importance of setting realistic weight-loss goals. Recognition of this challenge, and of the value of modest weight loss, have led to a paradigm shift in the medical management of obesity from a goal of massive weight loss to one of maintaining the highest weight possible while still eliminating obesity-related comorbidities or reducing them to a minimum.

Available data suggest that a loss of approximately 10% of body weight in persons who are obese (body mass index [BMI] < 40 kg/m2) is associated with substantial health benefits regarding obesity-related comorbidities.[87] However, according to guidelines released by the American College of Cardiology (ACC), the American Heart Association (AHA), and The Obesity Society (TOS) in 2013, clinically meaningful health improvements can even be seen with weight loss in the range of 2%-5%.[81, 82]

A reasonable goal for weight loss in the setting of a medical treatment program is approximately 1-2 lb/wk. However, it is becoming increasingly apparent that the weight-loss goal for each patient must be individualized and cannot be unilaterally based on standard weight-for-height norms.

In addition to the patient’s weight, factors to consider when setting individualized weight loss goals are the weight of other family members, as well as the patient's cultural, ethnic, and racial background. A study of approximately 200 obese black women, the Obesity Reduction Black Intervention Trial (ORBIT), found evidence that greater weight loss can be achieved with a culturally adapted weight-loss program than with a more general health program.[88]

In ORBIT, the women randomized to a 6-month, culturally adapted program aimed at altering dietary and physical activity patterns (followed by 1 year of maintenance intervention) lost significantly more weight than did participants in a general program. Despite this success, however, the average weight loss in the culturally adapted program was still relatively modest, and the amount of weight loss varied greatly among the women in the program.

Weight-Loss Maintenance

Evidence from the National Weight Control Registry (NWCR), which tracks indices and predictors in individuals who have lost at least 30 pounds and have maintained that loss for at least 1 year, suggests that patterns associated with successful weight maintenance include the following:

  • Self-monitoring of weight

  • Consumption of a low-fat diet

  • Daily physical activity of approximately 60 minutes

  • Minimal sedentary “screen time”

  • Consumption of most meals at home

Although some data from randomized trials of diets of different macronutrient composition indicate that caloric restriction, self-monitoring, and program attendance are more important than any specific composition of dietary macronutrient, results from a large European study indicated that weight-loss maintenance is better achieved with a diet modestly high in protein with lower glycemic index comparison to other macronutrient compositions.[89]

According to a study by Blüher et al, patients regaining weight after initial weight loss on long-term dietary intervention nevertheless continued to show long-lasting improvements in high-sensitivity C-reactive protein, adiponectin, fetuin, high-density lipoprotein cholesterol, progranulin, and vaspin. This finding may indicate that there are delayed effects following initial weight loss and/or continuous beneficial effects from switching to a healthier diet.[90]

Diet-induced weight loss can result in elevated levels of hormones that increase appetite. After successful weight loss, circulating levels of these hormones do not decrease to levels recorded before diet-induced weight loss. Thus, long-term strategies are needed to prevent obesity relapse.[91]

Contrary to the original belief, however, weight loss after nonsurgical intervention can be maintained long-term. A study by Hamdy et al showed that patients with diabetes and obesity can maintain an average of 6.4% weight loss after 5 years of intensive lifestyle changes in real-world clinical practice. This study also found that patients who maintain 7% or greater weight loss after a year are more likely to maintain weight loss over the long-term.[92]

Treatment of Childhood Obesity

In cases of childhood obesity,[93, 94, 95] the goal is not to cause weight loss, but to reduce the rate of weight gain to fit normal growth curves. The basic principles of management include the following:

  • Modifying diet

  • Increasing appropriate physical activity and exercise

  • Reducing time spent in sedentary activities - Eg, watching television

  • Modifying behavior

Medication therapy may also be used in the management of pediatric obesity, but close monitoring and a combination of all the aforementioned modalities is required to achieve substantial and sustained weight loss. At the present, orlistat is the only medication approved by the US Food and Drug Administration (FDA) for use as an adjunct for weight loss in adolescents.

For full discussion of this topic, see the Medscape Reference article Obesity in Children.

Energy Expenditure and Weight Loss

Achieving a caloric deficit is still the most important component in achieving sustained weight loss. However, the considerable variance in individual energy expenditures and compliance with calorie-deficient plans make it difficult to reliably predict how much weight an individual will lose.

Among the caveats is the fact that energy expenditure is related to body weight; about 22 kcal/kg of energy is required for basal maintenance of 1 kg of weight in a typical adult. Therefore, weight loss tends to reduce energy expenditure, dampening the effect of caloric deficits.

Because of their lowered energy expenditure, older subjects have increased difficulty in achieving sustained weight loss. The estimated reduction in energy expenditure is 100 kcal per decade after the age of 30 years. Presumably because of their greater lean mass proportions, men tend to lose more weight than women do when caloric deficits are similar.[96]

In addition, some researchers have recommended using correction factors for estimating energy expenditure in obese patients.[97, 98] In a retrospective cross-sectional study of 1,331 patients with a body mass index (BMI) of at least 25 kg/m2, Wilms and colleagues found that calculating resting oxygen uptake with the widely used 1-MET (metabolic equivalent) value of 3.5 ml O2/kg/min overestimates actual values by 17% to 39% in overweight to severely obese individuals.[97, 98]

All subjects underwent resting energy expenditure (REE) testing with indirect calorimetry and 652 subjects also performed a symptom-limited bicycle cardiopulmonary exercise test to determine maximal achievable METs. Mean REE was 2.47 ml O2/kg/min in women and 2.62 ml O2/kg/min in men. MET-REE decreased significantly with increasing BMI, and the deviation of MET-REE values from the predicted 1-MET value of 3.5 ml O2/kg/min progressively increased.

The researchers developed sex-specific MET correction factors for distinct BMI groups. During the bicycle test, women performed 4.4 MET-peak and men performed 4.7 MET-peak. After the correction factors were applied, MET-peak increased to 6.2 in women and 6.1 in men.[97, 98]

Conventional Diets

Conventional diets can be broadly classified into 2 categories: balanced, low-calorie diets (or reduced portion sizes) and diets with different macronutrient compositions. The latter include the following:

  • Low-fat diets - Eg, the Ornish diet

  • Low-carbohydrate diets - Eg, the Atkins diet

  • Midlevel diets - Eg, the Zone diet, in which the 3 major macronutrients (fat, carbohydrate, protein) are eaten in similar proportions of 30-40%)

  • Joslin Why WAIT diet for diabetic patients - 40-45% carbohydrates, 20-30% protein, less than 35% fat

Reduced ̶ portion size diets and balanced, low-calorie diets

Balanced, low-calorie diets and reduced ̶ portion size diets are the types that dietitians and other weight-management professionals most commonly prescribe. Although these diets are useful for short-term weight loss, none of them alone is associated with reliable, sustained weight loss.

These diets underlie most of the popular, commercial weight-loss programs, such as those advocated by Jenny Craig, Weight Watchers, Take Off Pounds Sensibly (TOPS), and Overeaters Anonymous (OA). The basic premise for people on these diets involves obtaining their detailed dietary inventory and using it to estimate their mean daily caloric intake.

A reasonable goal for the caloric deficit is based on the new goal for total daily calories. Meal plans are then devised to provide this total, divided among 3 or more meals throughout the day.

Reduced ̶ portion size diets

The meals may be based on regular, everyday foods. In such cases, strategies for effective reduction of portion sizes become central.

Alternatively, portion control can be achieved by participation in structured weight loss programs (eg, Jenny Craig, Nutrisystem) or by the purchase of products such as meal-replacement shakes, bars, prepackaged meals, and frozen entrees (eg, Slim-Fast, Glucerna, Lean Cuisine, Healthy Choice, Smart Ones). These have adequate amounts of the major macronutrients based on the food pyramid from the US Department of Agriculture and recommended daily allowances (RDAs). These sources also have adequate micronutrients and trace elements.

Alcohol, sodas, most fruit juices, and highly concentrated sweets are generally calorie dense and nutrient deficient (so-called empty calories). Consequently, these are generally prohibited or reduced to a minimum.

Low-calorie diets

Low-calorie diets involve reducing daily caloric intake by 500-1000 kcal/day, to a level of 800-1800 kcal/day. These diets are associated with a mean weight loss of 0.4-0.5 kg per week (1-2 lb/wk). In ideal settings, total loss can be 5-10% of starting weight (10-20 lb for a 200-lb person) over 3-6 months, occasionally higher if the individual is very successful.

With any low-calorie diet, maintaining an intake of protein with a high biologic value of 1-1.5 g/kg of adjusted body weight (adjusted body weight = ideal body weight + one quarter of the excess weight) is vital to preserve lean body mass. Reducing intake to less than 1200 kcal/day while keeping the percentage protein at 15% may lead to protein malnutrition and significant muscle mass loss. For example, for a person following a 1200 calorie diet and aiming to consume 25% protein, the goal should be 300 kcal/day of protein (75 g).

Major potential complications to watch for include the following:

  • Vitamin deficiency

  • Starvation ketosis

  • Electrolyte derangements

  • Cholelithiasis

Diets with different macronutrient compositions

Diets with different macronutrient compositions involve a caloric intake of greater than 1200 kcal/day. This type of diet is designed to reduce the caloric intake by 500-1000 kcal/day from the patient's current dietary intake.

The suggested composition used by the best-validated dietary programs is as follows:

  • Protein intake of 0.8-1.5 g/kg of body weight (not to exceed 100 g/day)

  • 10-30% of total calories from fat (preferably ≥90% as polyunsaturated fat and < 10% as saturated fat)

  • Carbohydrate intake of 50 g/day or more

  • Water intake of 1 L or more

  • Adequate micronutrients and macronutrients based on the RDAs

Low-carbohydrate diets

Low-carbohydrate diets have become popular in the past few decades, with the Atkins diet being the most popular. The Atkins diet is a high-protein and/or high-fat, very-low-carbohydrate diet that induces ketosis. The very ̶ low-carbohydrate content is critical in inducing short-term weight loss in the first 2-4 weeks; this is largely the result of fluid mobilization.

Ketone bodies tend to be generated when an individual’s daily dietary carbohydrate intake is under 50 g, and sodium diuresis is forced, causing most of the short-term weight loss. No robust data about the safety or long-term effectiveness of this diet are available.

The premise of the diet is that caloric intake as protein is less prone to fat storage than is the equivalent caloric intake as carbohydrate; however, no physiologic data support this premise. Owing to the high fat content of such diets, low-density lipoprotein cholesterol (LDL-C) levels were found to be increased by at least 10% in 25% of patients who used this diet.

Data on the long-term effects of a high-protein diet in rodents cause concern. They indicate that these diets may be associated with a reduced life span and a predisposition to neoplasia.

In 2 randomized trials, weight loss with Atkins-type diets was compared with conventional low-fat or balanced calorie-deficit diets.[99, 100] Although the Atkins-type diet led to the greatest initial weight loss, weight loss became similar within 1 year. Adherence to this diet is poor; in those studies noted, the noncompliance rate in the Atkins-type group was close to 50%.

The South Beach diet is another low-carbohydrate diet. This program is more liberal in its carbohydrate allowance than the Atkins diet. In addition, the South Beach diet distinguishes between what are considered to be good and bad carbohydrates on the basis of their glycemic index.

Although the relevance and importance of the glycemic index is controversial, the diet encourages increased fiber intake, which is associated with lowered weight even when total caloric intake is relatively unchanged. Low glycemic index diets are better at helping to maintain weight loss than diets with a higher glycemic index; the same is true of diets with modestly increased protein intake, versus standard protein intake.[89]

Persons who decide to use a low-carbohydrate diet should choose heart-healthy sources of fat, including monounsaturated fats, polyunsaturated fats, and fats rich in omega 3 fatty acids, rather than saturated fat. Protein sources should be fish, nuts, legumes, and lean poultry rather than pork chops, steak, and mutton.

Comparison of diet programs

Dansinger and colleagues compared the Zone, Ornish, and Atkins diets to each other and to a typical balanced, calorie-restricted (Weight Watchers) diet and found them all to have a similar impact on weight.[101] The Ornish diet (a very ̶ low-fat diet) and the Atkins diet had the poorest compliance rates. At 1 year, the researchers observed no significant differences in weight loss among the 4 diets. Compliance and caloric deficits were more important predictors of weight loss and improvement in cardiovascular risk surrogates than was specific dietary composition.

A 2-year study found low-carbohydrate and low-fat diets to be equally efficacious in inducing weight loss. However, the study also found that a low-carbohydrate diet is associated with favorable changes in cardiovascular disease risk factors.[99] Nevertheless, better achievement of sustained weight loss is seen with low-fat diets than with low-carbohydrate diets, probably because of generally higher compliance.

Very-Low-Calorie Diets

Very–low-calorie diets (VLCDs) are best used in an established, comprehensive program. VLCDs involve reducing caloric intake to 800 kcal/day or less. When used in optimal settings, they can achieve a weight loss of 1.5-2.5 kg/wk (3.3-5.5 lb/wk), with a total loss of as much as 20 kg over 12 weeks. No good-quality evidence suggests that a daily calorie intake of less than 800 kcal/day achieves any additional weight loss in the long-term.[102]

VLCDs are associated with profound initial weight loss, much of which is from loss of lean mass in the first few weeks. However, this loss rapidly ceases, and weight-loss velocity then flattens. Such rapid weight loss is frequently followed with weight regain due to reduction in basal energy expenditure secondary to the loss of fat free mass.

Use special caution whenever VLCDs are prescribed to children, adolescents, or elderly patients. Use of VLCDs is contraindicated in the following settings:

  • Pregnancy

  • Protein-wasting states

  • Clinically significant cardiac, renal, hepatic, psychiatric, or cerebrovascular disease

  • Any other chronic disease

Although VLCDs are associated with notable short-term weight loss and improved blood pressure and glycemic control, they cannot be sustained for longer than 3-6 months. Compliance beyond a few weeks is poor, and close supervision is required to avoid mishaps.

Among the major complications to monitor are hair loss, skin thinning, hypothermia, cholelithiasis, and electrolyte derangement. VLCDs have little or no utility in long-term weight management and are probably best used as stopgap measures before bariatric surgery or a long-term, comprehensive weight-loss program in patients with very severe or morbid obesity and associated comorbidities (body mass index [BMI] ≥50).

Preoperative VLCDs have been postulated to decrease surgical risk by enhancing visualization during laparoscopic bariatric surgery. In a multicenter, randomized, controlled trial involving 298 morbidly obese patients who underwent gastric bypass surgery, van Nieuwenhove et al reported a significantly lower rate of intraoperative complications among those who had undergone a 14-day VLCD before the procedure.[103] In addition, the surgeons’ perceptions of the procedure’s difficulty was lower in the VLCD patients.

There were, however, no significant differences in operative time or intraoperative complications between the control and VLCD groups.[103]

Water Drinking

Dennis et al found that in overweight and obese middle-aged and older adults on a hypocaloric diet, drinking water before each main meal aided weight loss. In 48 adults aged 55-75 years with a BMI of 25-40 kg/m2, those who consumed 500 mL of water prior to each daily meal had a 44% greater decline in weight over 12 weeks than did individuals on a hypocaloric diet without premeal water consumption.[104]

Water drinking could assist weight loss in overweight children. Drinking 10 mL/kg of cold water could result in an additional weight loss of about 1.2 kg/y. This is achieved primarily through a water-induced increase in resting energy expenditure.[105]

Exercise Programs

Before prescribing an intensive exercise program, clinicians should screen patients for cardiovascular and respiratory adequacy. Any clinically significant anomalies found require full evaluation by appropriate specialist physicians, and only after these issues have been adequately managed and stabilized should the patient begin an active exercise program.[106] In contrast, patients starting a program of moderate exercise (eg, walking) do not require prescreening.

Aerobic isotonic exercise is of the greatest value for persons who are obese. The ultimate minimum goal should be to achieve 30-60 minutes of continuous aerobic exercise 5-7 times per week. Increased physical activity and exercise 300 min/week is associated with significant weight reduction and longer maintenance of the weight loss.[107]

Anaerobic isometric exercise, including resistance training, can be cautiously added as an adjunct after the aerobic goal described above is achieved. Resistance training is valuable in minimizing muscle mass loss and is particularly beneficial in patients with diabetes, as it increases glucose uptake by muscles.

Since approximately 27% of the diet-induced weight loss is from loss of muscle, the addition of exercise to caloric restriction is important. Studies have shown that muscle mass loss is reduced to approximately 13% of the total weight loss when diet and exercise are combined.[108]

Exercise also increases metabolic activity and reduces body fat. Although most patients may be unable to sustain enough regular exercise to achieve weight loss, consistent, moderate exercise is important in maintaining weight and in improving overall cardiorespiratory fitness.[109] Shorter bouts of exercise of around 10 minutes are associated with better adherence and more weight loss than are longer bouts of exercise.

A study by Goodpaster et al showed that patients with severe obesity who introduced exercise concurrently with or after dietary intervention had significant weight loss and modification of cardiometabolic risk factors.[110] Furthermore, a study by Hankinson et al indicated that benefits of exercise in young age may translate into benefits beyond, particularly in young women.[111] This information is useful for patients and physicians who may be discouraged by the patients’ initial inability to engage in exercise.

A study by Rejeski et al indicated that community weight-loss and physical activity programs can have a positive impact on mobility in elderly people who are overweight or obese and are in poor cardiovascular health.[112] In this study, participants with poorer mobility at baseline benefited the most from these interventions.

Behavioral Changes

Behavioral modification for weight loss addresses learned behaviors that contribute to excessive food intake, poor dietary choices or habits, and sedentary activity habits. Although this approach can yield improved results, it is inherently challenging and time-consuming.[113]

Effecting behavioral change starts with taking a detailed inventory of the patient’s daily activities, in order to identify activities, cues, circumstances, and practices that favor nonmeal eating and snacking. A trained professional must then have an in-depth discussion with the patient to develop an individualized plan to change these practices. The effectiveness of this modality depends on a highly motivated patient and a dedicated counselor who is willing to maintain long-term follow-up.[114, 115]

A sufficient amount of sleep favorably impacts the maintenance of fat-free mass during times of decreased energy intake. In contrast, insufficient sleep undermines the body's ability to limit expansion of fat mass. A healthy sleep pattern is therefore important to harness weight loss benefits from other interventions.[116] Seven to 8 hours of sleep are optimal. Shorter (< 6 h) or longer (>9 h) sleep duration is associated with increased total body weight. Treatment of obstructive sleep apnea, if present, also helps in weight reduction.

Antiobesity Medications

Few medications are available for the treatment of obesity. Examples of FDA-approved drugs that may be considered for the long-term treatment of obesity include orlistat (Xenical, Alli), lorcaserin (Belviq, Belviq XR), the combinations of phentermine and extended-release topiramate (Qsymia), and the fixed-dose combination of bupropion and naltrexone (Contrave). Generally, the medications approved by the US Food and Drug Administration (FDA) for obesity are intended for patients with a BMI of 30 kg/m2 or more or of 27 kg/m2 or more with a weight-related risk factor (eg, diabetes, hypertension). All are indicated as adjuncts to caloric restriction, increased physical activity, and behavior modification. Response to therapy should be evaluated by week 12. If a patient has not lost at least 5% of baseline body weight, stimulants should be discontinued, as it is unlikely that the patient will achieve and sustain clinically meaningful weight loss with continued treatment.

The FDA has issued a consumer alert about over-the-counter weight-loss pills that contain undeclared, active pharmaceutical ingredients. These products, which are promoted and sold on Web sites and in retail stores, may be marketed as “dietary supplements.” They have not been approved by the FDA, are illegal, and may be potentially harmful.[117] In April 2015, the FDA banned the use of the amphetaminelike stimulant (BMPEA) in supplements (sometimes labeled as acacia rigidula).[118]

Orlistat

Orlistat blocks the action of pancreatic lipase, reducing triglyceride digestion and, thus, absorption. Two major clinical trials showed sustained weight loss of 9-10% over 2 years.[119] Orlistat’s effectiveness in producing weight loss does not depend on systemic absorption. The drug may reduce absorption of some fat-soluble vitamins (A, D, E, K) and beta-carotene, as well as absorption of some medications. Adverse effects include flatulence, fatty/oily stool, increased defecation, and fecal incontinence.

Lorcaserin

Lorcaserin was approved by the FDA in June 2012 as an adjunct to a reduced-calorie diet and exercise for long-term weight management in individuals with an initial BMI of 30 kg/m2 or higher (obese) or 27 kg/m2 or higher (overweight) with at least 1 weight-related comorbid condition (eg, hypertension, dyslipidemia, type 2 diabetes mellitus).[120] Lorcaserin is a schedule IV substance, since it has potential for abuse.[121]

Lorcaserin is thought to decrease food consumption and promote satiety by selectively activating 5-HT2C receptors on anorexigenic pro-opiomelanocortin neurons in the hypothalamus. Approval of lorcaserin was based on 3 double-blind, randomized, placebo-controlled trials that found lorcaserin (along with diet and exercise) to be more effective than diet and exercise alone at helping patients lose 5% or more of their body weight after 1 year and managing the weight loss for up to 2 years.[122, 123, 124]

Required postmarketing studies of lorcaserin will include a long-term trial to assess the risk for major adverse cardiac events. Lorcaserin should be used with caution in patients with heart failure, and it has not been studied in patients with serious valvular heart disease.[120]

Liraglutide (Saxenda)

Liraglutide is a glucagonlike peptide-1 (GLP-1) analog. GLP-1 is a physiological regulator of appetite and calorie intake, and the GLP-1 receptor is present in several areas of the brain involved in appetite regulation.

Liraglutide is approved for chronic weight management as an adjunct to diet and exercise in adults with a BMI of 30 kg/m2 or higher (obese) or adults with a BMI of 27 kg/m2 or higher (overweight) who have at least 1 weight-related condition (eg, hypertension, type 2 diabetes, dyslipidemia). The dose for obesity differs from that of liraglutide (Victoza) that is used to treat diabetes. Saxenda is initiated at 0.6 mg SC once daily for 1 week, and is then increased by 0.6 mg/day in weekly intervals until a dose of 3 mg/day is achieved.

Approval was based on data from 3 clinical trials that included about 4800 obese and overweight patients with and without significant weight-related conditions. Results from a clinical trial that enrolled patients without diabetes or with diabetes showed that patients had an average weight loss of 4.5% and 3.7% from baseline respectively compared to treatment with a placebo at 1 year. Of those treated with liraglutide, 62% of persons without diabetes and 49% of persons with diabetes lost at least 5% of their body weight compared with 34% or 16% treated with placebo, respectively.[125]

Phentermine and topiramate

The combination of phentermine and extended-release topiramate (Qsymia) was approved by the FDA in July 2012 as an adjunct to a reduced-calorie diet and exercise for long-term weight management in individuals with an initial BMI of 30 kg/m2 or higher (obese) or 27 kg/m2 or higher (overweight) with at least one weight-related comorbid condition (eg, hypertension, dyslipidemia, type 2 diabetes mellitus).[126] Use during pregnancy is contraindicated.

Topiramate, which was first licensed as an adjunctive antiepileptic agent, has been associated with profound weight loss (an average of 5-7% of initial weight). The amount of weight loss appears to be greater with higher baseline weights. The exact mechanism of this effect is being actively investigated. Although the degree of efficacy is exciting, the propensity for adverse effects, especially CNS effects such as drowsiness, paresthesias, memory loss, and confusion, is cause for concern.

This combination drug contains an extended-release form of topiramate. In addition, the dose of topiramate in this product (46 mg, although a 92-mg dose form is available for select patients) is lower than those used for seizure management (usually 200 mg twice daily).

Bupropion and naltrexone

This combination is thought to cause a reduction in appetite and increase in energy expenditure by increasing the activity of pro-opiomelanocortin (POMC) neurons. Bupropion increases dopamine activity in the brain, which appears to lead to a reduction in appetite and increase in energy expenditure by increasing activity of POMC neurons. Naltrexone blocks opioid receptors on the POMC neurons, preventing feedback inhibition of these neurons and further increasing POMC activity.

The combination is taken once daily initially, and the dose is gradually increased each week until two tablets are taken twice daily by week 4.

Drugs for short-term treatment

Four agents are available in the United States for short-term (8-12 weeks) treatment of obesity: diethylpropion, phendimetrazine, benzphetamine, and phentermine. Any of these drugs may be used as an adjunct in a regimen of weight reduction based on caloric restriction in patients with an initial BMI of 30 kg/m2 or higher who have not responded to an appropriate weight-reducing regimen.

Medications used off-label

Several medications that are approved for other indications but that may also promote weight loss have been used off-label for obesity. These include several antidepressants, such as selective serotonin reuptake inhibitors (SSRIs). Medications used off-label for obesity include the following:

  • Methylphenidate - Not approved by the FDA for obesity management, but several anecdotal reports have described it as having variable success for this purpose[127]

  • Zonisamide - Gadde and colleagues reported that randomized use of the antiepileptic drug zonisamide in a cohort of 60 obese subjects was associated with a weight loss of about 6% of baseline weight, with few adverse effects[128]

  • Octreotide - Lustig and colleagues reported the potential utility of octreotide in ameliorating the distinct subclass of hypothalamic obesity[129]

Diabetes medications

Metformin does not have an indication for obesity, but it is useful in preventing diabetes and improving insulin resistance in conditions such as polycystic ovary syndrome. Its use was associated with weight neutrality or mild weight loss.[130]

The first glucagonlike peptide (GLP)-1 analogue, exenatide (Byetta), although not FDA approved for obesity management, has been associated with modest weight loss in subjects with type 2 diabetes. A similar effect was seen with liraglutide (Victoza) and long-acting exenatide (Bydureon), which also are not approved by the FDA for obesity management. Higher liraglutide doses of 2.4 mg and 3 mg/day were found to be significantly more effective than orlistat for the management of obesity in nondiabetic patients. The FDA approved liraglutide (Saxenda) for obesity in December 2014 (see above).

A systematic review and meta-analysis by Vilsbøll et al found that treatment with GLP-1 receptor agonists results in weight loss among overweight or obese patients with or without type 2 diabetes.[131] GLP-1 agonist regimens reviewed included exenatide twice daily, exenatide once weekly, and liraglutide once daily at clinically relevant doses for at least 20 weeks.

Antidepressants

Although not all are FDA approved for this purpose, several SSRIs may cause anorexia as one of their major adverse effects. Some of these medications have been used as adjuncts in the medical management of obesity, with variable success. A meta-analysis of antidepressants and body weight found that fluoxetine was associated with some weight loss, although this effect appeared to be limited to the acute phase of treatment.[126]

Bupropion is licensed for use as an antidepressant and for use in smoking cessation. It is associated with minimal to moderate weight loss in obese patients.[132] A combination of bupropion and naltrexone (Contrave) was approved on September 10, 2014 for use as adjunct to a reduced-calorie diet and increased physical activity for long-term weight management in adults with initial body mass index of 30 kg/m² (obese) or ≥27 kg/m² (overweight) in presence of at least one weight-related comorbidity (eg, hypertension, type 2 diabetes, or dyslipidemia).

Ephedrine and caffeine

Ephedrine and caffeine are second-line options in the medical management of obesity. They both act by increasing energy expenditure, but they are associated with the potential for tachycardia, hypertension, and palpitations. These medications are associated with greater weight loss when used in combination than when used alone. They cause 25-40% of their weight loss by inducing thermogenesis, but they also decrease food intake, which accounts for 60-75% of the weight-loss effect.

Currently, the evidence for the efficacy of these 2 drugs in promoting weight loss is inconclusive. Neither substance has an FDA-approved indication for the treatment of obesity.

Cannabinoid-receptor antagonists

The central cannabinoid system has an increasingly recognized role in appetite and feeding disorders.[133, 134, 135, 136] In particular, activation of the cannabinoid type 1 (CB1) receptor is associated with increased appetite and appears to be the basis for the effectiveness of dronabinol in enhancing diet in patients with acquired immunodeficiency syndrome (AIDS) and other wasting syndromes.

CB1-receptor antagonists showed great potential for weight management in several human trials. Rimonabant, the most-developed CB1-receptor antagonist, caused a mean weight loss of 3-6 kg over a 1-year follow-up at doses of 5-20 mg/day. Adverse effects, which were most prevalent at high doses, included dizziness, depression and suicidal ideation, headaches, nausea, vomiting, and diarrhea. The drug was rejected by the FDA because of side effects of depression and suicidal ideation; in Europe, it was approved but later recalled.

Catechin

A Japanese study found evidence that beverages containing high amounts of catechin, a flavonoid found in green tea, may aid in preventing obesity.[137] Patients in the investigation, all of whom had type 2 diabetes mellitus, ingested either 582.8 mg or 96.3 mg of catechins per day by drinking green tea. By the 12th week, participants receiving the higher catechin dose had undergone a significantly greater reduction in waist circumference than did patients receiving the lower dose.

Other potential antiobesity agents

The increasing knowledge that has come on the heels of the discovery of leptin by Friedman and colleagues in 1994 has spurred a whirlwind of research that has identified several potential pharmaceuticals. However, safety standards for obesity medications are necessarily high. Tolerance for adverse effects is limited; most persons who are obese are fairly healthy in the short term, but the risk for adverse drug effects is enhanced because patients must take antiobesity medications for extended periods (possibly for the rest of their lives).

Agents in early phases of investigation that may yet prove useful against obesity include the following:

  • Ghrelin antagonists,

  • Alpha–melanocyte-stimulating hormone analogs

  • Enterostatin

  • Neuropeptide YY antagonists

  • Beta3-adrenergic agonists

In addition, various nutraceuticals and herbal products have shown promise. For example, an extract from the African cactus Hoodia gordonii may cause clinically significant appetite suppression.

The diabetes drug pramlintide (Symlin), which is a synthetic analogue of the pancreatic hormone amylin, does not have an FDA indication for obesity management. However, this drug is clearly associated with variable weight loss in people with type 1 or 2 diabetes, while improving overall glycemic control. Higher doses (240 mcg before main meals) than those approved for the management of type 2 diabetes (60-120 mcg before main meals) have produced modest weight loss in obese or overweight patients with and without diabetes.[138]

Peptide YY (3-36) is being developed as a nasal inhaler. Ongoing, preliminary phase 1 and 2 trials yielded encouraging results.[139, 140, 141]

Leptin is still used in cases of the rare obesity subclass of leptin-deficient obesity and lipodystrophy, but a study of the leptin analogue metreleptin in obese patients with diabetes found that metreleptin did not alter body weight.[142] The combination of metreleptin with pramlintide, however, led to enhanced weight loss in one study,[143] but a more recent randomized clinical trial on the combination of these 2 drugs was stopped because of safety concerns.[144]

Preliminary reports suggest the potential utility of agents that impede dietary carbohydrate absorption. Tagatose is one of the compounds in this class that is undergoing trials.

Drugs no longer used or efficacy not proven

The history of obesity medications is replete with disasters that have taught caution in the use of this group of medicines. For example, among the initial medications used for obesity management were amphetamine, methamphetamine, and phenmetrazine. These were all withdrawn because of their high potential for abuse.

The combination of fenfluramine and phentermine (“fen-phen”) was used in some long-term trials with excellent results. However, fenfluramine was withdrawn in 1997 (along with D-fenfluramine) because of the potential for adverse cardiac, valvular, and pulmonary hypertensive effects in patients taking this drug.

Other former antiobesity medications, and the reasons for their abandonment, include the following:

  • Thyroid hormone - Hyperthyroidism, with its attendant sequelae

  • Dinitrophenol - Cataracts and neuropathy

  • Rainbow pills (a mixture of digitalis and diuretics) - Fatal arrhythmias and electrolyte derangements

  • Aminorex - Pulmonary hypertension

  • Phenylpropanolamine - Increased risk of myocardial infarction and stroke

Other drugs withdrawn from the US market include benzphetamine and mazindol.

Some agents that initially showed promise were later demonstrated to be poor prospects in rigorous randomized intervention trials. These include the following:

  • Guar gum

  • Chitosan

  • Axokine - Or ciliary neurotrophic factor, the use of which was associated with the development of autoantibodies and marked reduction in anorexiant potency in about 30% of subjects

  • St. John's wort

  • Psyllium

  • Conjugated linoleic acid

  • Chromium

  • Ginseng

Fat Substitutes

One strategy to prevent obesity that is being explored in the dietary industry involves the use of fat substitutes. Olestra (Olean) has been approved for use as a dietary supplement and additive in various foods, such as potato chips and crackers. Olestra has a calorie value of 0 kcal/g, whereas fat has a value of approximately 9.1 kcal/g. Olestra consists of a sucrose polyester backbone with 6-8 fatty-acid side chains; this structure makes the molecule too large for digestive enzymes of the gut to hydrolyze.

In many trials, olestra had fairly good tolerability, although foods containing it are apparently less tasty than foods cooked in regular fat. The major adverse effects reported were flatulence, bloating, diarrhea, and loose stools. Because of concerns regarding the possible malabsorption of fat-soluble vitamins, the FDA requires all olestra-prepared foods to be supplemented with these vitamins.

Two margarines, Benecol and Take Control, block cholesterol absorption in the intestine and can lower total and LDL-cholesterol levels 10% and 13-15%, respectively. Benecol contains stanols, predominantly sitostanol and campestan; Take Control is made up of sterols, primarily beta-sitosterol and campesterol. Weight-loss benefits have not been demonstrated.

Bariatric Surgery

Surgical therapy for obesity (bariatric surgery) is the only available therapeutic modality associated with clinically significant and relatively sustained weight loss in subjects with morbid obesity associated with comorbidities. Evidence shows that well-performed bariatric surgery, in carefully selected patients and with a good multidisciplinary support team, substantially ameliorates the morbidities associated with severe obesity.

Although bariatric surgery is the only therapeutic method associated with significant and rapid weight loss, it is expensive, highly procedure and surgeon specific, and certainly not the solution for the burgeoning obesity epidemic. Patient selection for bariatric procedures must be addressed along the same stringent lines as those discussed earlier for the selection of patients for medical weight-management programs.

At a minimum, patients should be considered candidates for these procedures only if they have a BMI of greater than 40 kg/m2 and/or a weight greater than 45 kg above the age- and sex-defined ideal weight. For subjects with BMIs of 35-40 kg/m2, at least 1 major comorbidity must be present to justify these procedures.[81, 82] The presence of comorbidities is not a contraindication to bariatric surgical procedures; however, the patient's condition must be stabilized and adequately treated before surgery.

Comorbidities that have been reported to be improved, ameliorated, or resolved through bariatric surgery include the following:

  • Obstructive sleep apnea

  • Type 2 diabetes mellitus

  • Hypertension

  • Heart failure

  • Peripheral edema

  • Respiratory insufficiency

  • Asthma

  • Dyslipidemia

  • Esophagitis

  • Pseudotumor cerebri

  • Operative risk

  • Osteoarthritis

  • Thromboembolism

  • Urinary incontinence

Other reports suggest improved quality of life and fertility after bariatric surgery. Although other outcomes are difficult to demonstrate and are awaiting clear documentation, these procedures may substantially reduce macrovascular complications (eg, myocardial infarction), stroke, amputations, obesity-related malignancies, and a predisposition to infection, hernias, and varicose veins.[145]

Although most bariatric procedures were initially developed in the setting of laparotomies, they now are increasingly performed laparoscopically, with reduced postoperative morbidity. The laparoscopic approach to bariatric surgery is particularly well developed in Europe.

Among the standard bariatric procedures are the following:

  • Roux-en-Y gastric bypass

  • Adjustable gastric banding

  • Gastric sleeve surgery

  • Vertical sleeve gastrectomy

  • Horizontal gastroplasty

  • Vertical banded gastroplasty

  • Duodenal-switch procedures

  • Biliopancreatic bypass

  • Biliopancreatic diversion

Available data on the effectiveness of many of these procedures are still relatively scant. However, reports and meta-analyses from large numbers of patients on the most commonly performed procedures (gastric restriction and gastric bypass) lend veracity to the long-term effectiveness of bariatric surgery.[60, 146, 147]

Guidelines from the American Association of Clinical Endocrinologists, The Obesity Society, and the American Society for Metabolic and Bariatric Surgery endorse sleeve gastrectomy as an effective alternative to gastric banding, gastric bypass, and other types of bariatric surgery, saying that the procedure has advanced beyond the investigational stage. However, the guidelines do not recommend any bariatric procedure as preferable over the others for patients with severe obesity.[148, 149, 150]

Vertical-banded gastroplasty

Ashley and colleagues, in an evaluation of 114 patients who underwent vertical-banded gastroplasty, found that about 60% of them lost more than 50% of their excess body weight over 1 year.[151] No patient lost less than 25%, and within a year of the surgery, mean BMI had decreased from 44.8 to 32.5 kg/m2.

Gastric bypass

Flickinger and associates, in an examination of 210 patients who received a Roux-en-Y gastric bypass, recorded a mean weight loss of 51 kg in 18 months, which was then maintained over 36 months of follow-up.[152] Only 4% of the patients required a repeat operation. Sugerman and colleagues reported that, among patients undergoing gastric bypass, two thirds of their excess body weight was lost over 2 years, 60% of the excess body-weight loss was maintained at 5 years, and more than 50% of excess body-weight loss was maintained at 8-9 years’ follow-up.[22]

Roux-en-Y and other gastric-bypass procedures generally result in more weight loss than do gastric-restriction procedures. When 329 patients receiving vertical gastroplasty procedures were compared with 623 persons undergoing Roux-en-Y gastric bypass, weight loss was maintained in 47% and 62% of patients, respectively, over 5-9 years of follow-up.[22]

According to a study by Plecka et al, in patients who are morbidly obese, gastric bypass (but not restrictive surgery) apparently reduces the risk levels for the development of type 2 diabetes and myocardial infarction to those for the general population. However, the mortality risk in these patients nonetheless remains higher than that in the general population.[153]

Mingrone et al reported regression of diabetes (defined as fasting glucose < 100 mg/dL and hemoglobin A1c [HbA1c] < 6.5% in the absence of pharmacologic therapy) at 2 years in 75% of Roux-en-Y gastric bypass patients and 95% of biliopancreatic-diversion patients.[154] This randomized, controlled trial included 60 patients with a BMI of more than 35, a history of at least 5 years of type 2 diabetes, and HbA1c of 7% or greater. Improvement in glucose control was unrelated to baseline BMI or overall weight loss.

A Norwegian study compared gastric bypass with duodenal switch and determined that duodenal switch surgery was associated with greater weight loss and greater reductions in total and LDL-C levels. However, duodenal switch surgery was also associated with reductions in concentrations of vitamin A and 25-hydroxyvitamin D, as well as with increased adverse effects.[155]

Similarly, a randomized trial from Sweden found greater postoperative weight loss in patients who had duodenal switch surgery than in those who had gastric bypass. Fasting glucose and HgA1c were also lower at 3 years in the duodenal switch group.[156]

A study by Schiavon et al indicated that bariatric surgery can lead to a reduction in the number of antihypertensive drugs required by persons with obesity taking multiple blood pressure agents and in some cases can eliminate the need for any such medications. The study involved 96 patients with a BMI of 30 to just under 40 kg/m2, including 49 who underwent laparoscopic Roux-en-Y gastric bypass and a control group of 47 treated only with medical and lifestyle therapy. The investigators found that 83.7% of the surgery group, but just 12.8% of the control patients, were able to reduce the total number of antihypertensive medications they were taking by at least 30%. Moreover, at 12 months, 51% of the surgery patients were able to maintain an office-measured blood pressure of under 140/90 mm Hg without any blood pressure drugs, a milestone that none of the control patients reached.[174, 175]

Gastric pacing

Emerging data suggest that gastric pacing achieved by using implantable electrodes may have significant weight-loss effects. This outcome was initially discovered with the use of gastric pacemaker devices for gastroparesis in patients with diabetes.

Cigaina reported that 10 patients in whom a pacing device was laparoscopically implanted showed a mean excess weight loss of about 25% at 3-year follow-up.[157] Similar findings were reported in several European studies with a total cohort of about 50 patients.

Other procedures

Other adjunctive procedures that may be performed but that have an unclear utility include visceral fat removal, omentectomy, subcutaneous fat panniculectomy, and large-volume subcutaneous fat liposuction. Klein and colleagues indicated that liposuction in itself has no utility in improving cardiac risk factors among patients with obesity.[158]

Some procedures, such as jaw wiring and insertion of a gastric balloon or a gastric wrap, are no longer popular because of their poor results compared with those of newer procedures and because of their high complication rates. Vagotomy has also declined in popularity, as the weight lost is typically regained within a few years. A few reports suggest that when vagotomy is performed with gastric bypass, it increases weight loss by as much as 20%, but this finding has not been consistently replicable.

Surgical complications

The mortality rate associated with standard bariatric surgical procedures in an experienced center should not exceed 1.5-2%. The surgical mortality rate is less than 0.5% at centers specializing in bariatric surgery. Mortality rates exceeding 2% suggest a risk-to-benefit ratio that probably is unacceptable.

Major procedure-specific postoperative complications include the following:

  • Wound dehiscence

  • Stomal strictures

  • Erosions or ulcers

  • Postprocedure diarrhea

  • Malabsorption

  • Nutritional and vitamin deficiency

  • Dumping syndrome

  • Anastomotic leaks with a potential for mediastinitis or peritonitis

In addition, gastric-specific operations can be associated with persistent vomiting and metabolic alkalosis. These operations are also more commonly associated with weight-loss failure and inadvertent splenectomy than are other surgical methods. Malabsorptive procedures (gastric bypass) can lead to deficiency of thiamine, iron, vitamin D, and vitamin B-12.

Gastric resection

Prevalences for adverse events with gastric resection procedures with or without bypass are approximately as follows[159] :

  • Dumping - 70%

  • Dairy intolerance - 50%

  • Constipation - 40%

  • Headaches – 40%

  • Depression - 15%

  • Hair loss - 33%

  • Vitamin B-12 deficiency - 25%

  • Incisional hernias, anemia, diarrhea, or abdominal pain - 15%

  • Arrhythmias – 10%

  • Single or multiple vitamin deficiencies not involving vitamin B-12 -10%

Malabsorptive procedures

Patients who receive bypass procedures are particularly prone to micronutrient deficiency states, especially of calcium, vitamin B-12, folate, and iron, as well as protein malnutrition.

Rare cases of postural hypotension and severe hypoglycemia from nesidioblastosis have been reported. Life-threatening hypoglycemia usually requires partial or total pancreatectomy, while severe postural hypotension that cannot be corrected with fludrocortisone and midodrine requires reversal of the surgery.

The following are among the major specific complications associated with malabsorptive operations:

  • Uncontrolled diarrhea

  • Steatorrhea

  • Malabsorption of fat-soluble vitamins

  • Potassium and/or magnesium deficiency

  • Blind-loop syndrome - Includes enteritis, arthropathy, and liver cirrhosis

  • Gallstone development

  • Urolithiasis

  • Metabolic encephalopathy

Failure rates

If failure is defined as an inability to ameliorate comorbidities or prevent their recurrence, gastric bypass appears to have a failure rate of approximately 20%. Failure rates based on weight loss are controversial.

The overall failure rates for malabsorptive procedures are relatively low, although the need for reversal of the surgery because of resulting adverse effects appears to be relatively high.

Follow-up studies

Despite the morbidity and mortality risk associated with bariatric surgery, the few reports involving follow-up on patients undergoing these procedures suggest overall improvement in quality of life. Even more convincing than this finding is that most subjects who undergo these procedures, despite their postoperative complications and difficulties, indicate that they would undergo the procedures again if necessary.

Inpatient Care

Inpatient evaluations of obese patients are important in the immediate postoperative period after antiobesity surgery. In addition, hospitalization may be required for the management of major complications, such as clinically significant respiratory or cardiac compromise.

Weight-management programs may be based in an outpatient or inpatient setting. No rigorous evidence suggests that inpatient programs are necessarily superior to outpatient programs of similar structure and content, however. Inpatient programs may offer the convenience of easy access to patients and ease of monitoring, but they are not only expensive to run and difficult to reimburse, they also generally cause considerable disruption to the patients' regular routine. In addition, they offer little guarantee of sustained effect.

Deterrence and Prevention

Because of the sheer prevalence of obesity and the anticipated worsening of the pandemic in the next few decades, prevention is by far the most desirable means to curb the medical and economic consequences of this condition. However, few trials have addressed this issue, and those performed thus far have had mixed results.[111]

Given the global proportions of obesity, a concerted approach is needed to address the problem and should involve the development of a massive public health education program aimed at adults and children as a means of changing their eating, activity, and behavioral habits. Cooperative efforts will also be needed among public health authorities, caterers, the fast food industry, and organizers of sports and outdoor games.

Results of some public health education initiatives in Singapore and parts of China that are only now being evaluated suggest, as hoped, that such programs have the potential for reducing the incidence and prevalence of obesity and may also have an impact on the major comorbidities of obesity, such as type 2 diabetes and hypertension. Until advances in gene therapy permit the alteration of genes that predispose to obesity, such programs are the only preventive options available.

Consultations

The following consultations are recommended in the treatment of obesity:

  • Dietitians

  • Exercise and physical therapists

  • Behavioral scientists and/or psychologists

  • Bariatric surgeon - In appropriate setting

In select cases, consultation with a psychiatrist may be indicated. Psychiatric consultation should be sought for patients with psychiatric disorders and personality disorders (eg, severe depression, mania, obsessive disorders) that may be worsened by attempts at weight loss if not adequately treated and controlled

Long-Term Monitoring

As with the management of other chronic medical conditions (eg, diabetes mellitus, hypertension, bronchial asthma), long-term success in the management of obesity is contingent on long-standing follow-up with the weight-loss program. Experience obtained from the lifestyle intervention group of patients in the Diabetes Prevention Program and information drawn from the ongoing Diabetes Prevention Program Observation study have borne out the importance of regular follow-up.

Patient visits may not need to occur as frequently during follow-up as during the initial weight-loss phase. Nevertheless, they are paramount if the lessons learned regarding diet, exercise habits, and behavioral patterns are to be maintained.

 

Guidelines

Guidelines Summary

In January, 2015, the Endocrine Society released new guidelines on the treatment of obesity to include the following:[83, 84]

  • Diet, exercise, and behavioral modification should be included in all obesity management approaches for body mass index (BMI) of 25 kg/m2 or higher. Other tools, such as pharmacotherapy for BMI of 27 kg/m2 or higher with comorbidity or BMI over 30 kg/m2 and bariatric surgery for BMI of 35 kg/m2 with comorbidity or BMI over 40 kg/m2, should be used as adjuncts to behavioral modification to reduce food intake and increase physical activity when this is possible.

  • Drugs may amplify adherence to behavior change and may improve physical functioning such that increased physical activity is easier in those who cannot exercise initially. Patients who have a history of being unable to successfully lose and maintain weight and who meet label indications are candidates for weight loss medications.

  • To promote long-term weight maintenance, the use of approved weight loss medication (over no pharmacological therapy) is suggested to ameliorate comorbidities and amplify adherence to behavior changes, which may improve physical functioning and allow for greater physical activity in individuals with a BMI of 30 kg/m2 or higher or in individuals with a BME of 27 kg/m2 and at least one associated comorbid medical condition (eg, hypertension, dyslipidemia, type 2 diabetes mellitus, and obstructive sleep apnea).

  • If a patient's response to a weight loss medication is deemed effective (weight loss of 5% or more of body weight at 3 mo) and safe, it is recommended that the medication be continued. If deemed ineffective (weight loss less than 5% at 3 mo) or if there are safety or tolerability issues at any time, it is recommended that the medication be discontinued and alternative medications or referral for alternative treatment approaches be considered.

  • In patients with type 2 diabetes mellitus who are overweight or obese, antidiabetic medications that have additional actions to promote weight loss (such as glucagon-like peptide-1 [GLP-1] analogs or sodium-glucose-linked transporter-2 [SGLT-2] inhibitors) are suggested, in addition to the first-line agent for type 2 diabetes mellitus and obesity, metformin.

  • In obese patients with type 2 diabetes mellitus who require insulin therapy, at least one of the following is suggested: metformin, pramlintide, or GLP-1 agonists to mitigate associated weight gain due to insulin. The first-line insulin for this type of patient should be basal insulin. This is preferable to using either insulin alone or insulin with sulfonylurea.

  • Angiotensin-converting enzyme (ACE) inhibitors, angiotensin receptor blockers (ARBs), and calcium channel blockers, rather than beta-adrenergic blockers, should be considered as first-line therapy for hypertension in patients with type 2 diabetes mellitus who are obese.

  • In women with BMI of more than 27 kg/m2 with comorbidities or BMI of more than 30 kg/m2 seeking contraception, oral contraceptives are suggested over injectable medications because of weight gain with injectables, provided that women are well informed about risks and benefits (ie, oral contraceptives are not contraindicated).

 

Medication

Medication Summary

Few medications are available for the management of obesity. Generally, the medications approved by the US Food and Drug Administration (FDA) for obesity are intended for patients with a BMI of 30 or above (obese) or of 27 or above (overweight) with a weight-related risk factor (eg, diabetes, hypertension). All are indicated as adjuncts to caloric restriction, increased physical activity, and behavior modification.

Some examples of obesity medications include orlistat (Xenical [Rx], Alli [OTC]), lorcaserin (Belviq, Belviq XR), a fixed-dose combination of immediate-release phentermine and extended-release topiramate (Qsymia), and a fixed-dose combination of bupropion and naltrexone (Contrave).

However, the list of potential antiobesity agents being investigated has increased considerably with the explosion in knowledge of the pathogenesis of obesity. Improved understanding of the neurocircuitry of the feeding-satiety cycle has provided many potential targets for designer therapeutic agents under development. (See the diagram below.)

Central nervous system neurocircuitry for satiety Central nervous system neurocircuitry for satiety and feeding cycles.

Currently, the 3 major groups of drugs used to manage obesity are as follows:

  • Centrally acting medications that impair dietary intake

  • Medications that act peripherally to impair dietary absorption

  • Medications that increase energy expenditure

Most medications for obesity are approved for short-term use only. Available literature indicates that their utility is severely limited when they are given in this fashion. Obesity is a chronic medical condition, and as with similar chronic conditions (eg, diabetes, hypertension), after therapeutic agents are stopped, the relapse rate is high. The need for any pharmaceutical regimen to be combined with a sustained exercise, dietary adjustment, and behavioral-change regimen to sustain weight loss further complicates the successful management of obesity.

Gastrointestinal Agents, Other

Class Summary

Lipase inhibitors may induce weight loss by inhibiting nutrient absorption.

Orlistat (Xenical, Alli)

Orlistat is a gastrointestinal and pancreatic lipase inhibitor that induces weight loss by inhibiting dietary fat absorption. Orlistat should be taken during or up to 1 hour after a meal containing fat. Its effectiveness in producing weight loss does not depend on systemic absorption. Orlistat is available over the counter (Alli) in a half-strength dose and as a prescription drug (Xenical) as a full-strength dose.

Orlistat may reduce absorption of some fat-soluble vitamins (A, D, E, K) and beta carotene. Administer a multivitamin supplement containing fat-soluble vitamins orally daily, 2 hours before or 1 hour after a meal. Orlistat may also affect the absorption of some medications. In particular, patients on warfarin need closer monitoring because of the potential for malabsorption of vitamin K.

At the full dose of 120 mg 3 times daily, Xenical is frequently associated with such adverse GI events as flatulence, oily stool, diarrhea, and stool incontinence. Frequently, these adverse events result from the common misconception that because orlistat blocks fat absorption, people can consume more fat. It is important to advise patients to reduce total fat intake while on orlistat to reduce the frequency and severity of adverse events.

Doses of the over-the-counter form of orlistat, Alli (60 mg), are associated with fewer adverse events. However, this dosage is less effective for weight loss.

CNS Stimulants, Anorexiants

Class Summary

Anorexiants are administered to manage obesity. Indications include weight loss and maintenance of weight loss, in conjunction with a reduced-calorie diet, specifically in patients who have an initial body mass index (BMI) of 30 or more (obese) or a BMI of 27 or more (overweight) and other risk factors (eg, diabetes mellitus, dyslipidemia, hypertension).

Adrenergic agonists that release tissue stores of epinephrine, causing subsequent alpha- and/or beta-adrenergic stimulation, have provided benefits to patients with obesity. Response to therapy should be evaluated by week 12. If a patient has not lost at least 5% of baseline body weight, stimulants should be discontinued, as it is unlikely that the patient will achieve and sustain clinically meaningful weight loss with continued treatment.

Lorcaserin (Belviq, Belviq XR)

Lorcaserin is indicated as an adjunct to a reduced-calorie diet and exercise for long-term weight management in patients with an initial BMI of ≥30 (obese) or in those with a BMI of ≥27 (overweight) who have at least 1 weight-related comorbid condition (eg, hypertension, dyslipidemia, type 2 diabetes mellitus).

The exact mechanism of action of lorcaserin is unknown, but this agent is thought to decrease food consumption and promote satiety by selectively activating 5-HT2C receptors on anorexigenic pro-opiomelanocortin neurons located in the hypothalamus.

Phentermine/topiramate (Qsymia)

This low-dose combination of phentermine, a sympathomimetic amine anorectic, and extended-release topiramate, an antiepileptic drug that possibly suppresses appetite and enhances satiety. The drug combination is indicated as an adjunct to a reduced-calorie diet and increased physical activity for long-term weight management in adults.

Phentermine (Adipex P, Lomaira)

Phentermine is a sympathomimetic amine that increases the release and reuptake of norepinephrine and dopamine. Its anorexiant effect occurs as a result of satiety-center stimulation in hypothalamic and limbic areas of the brain.

As a pharmacologic component of a comprehensive weight-reduction program (including behavioral modification, caloric restriction, and exercise), phentermine is intended for patients with an initial BMI of ≥30 (obese). It is also appropriate for patients with a BMI of ≥27 (overweight) who have other risk factors (eg, diabetes, hyperlipidemia, hypertension).

Phentermine is indicated for patients aged ≥16 y. It is available in capsules, tablets, and orally disintegrating tablets. This medication is contraindicated for use in pregnant women.

Diethylpropion

Diethylpropion is indicated for use as a short-term adjunct in the management of obesity. It is a sympathomimetic amine that reduces appetite, an effect that appears to be secondary to CNS effects. It is available in a 24-hour controlled-release formulation that should be taken at midmorning. It is indicated for patients aged ≥16 y.

Phendimetrazine (Bontril PDM)

Phendimetrazine is indicated for use as a short-term adjunct in the management of obesity in patients aged ≥17 y. It is a sympathomimetic amine that reduces appetite, an effect that appears to be secondary to CNS effects.

This agent is available in a 24-hour slow-release 105 mg capsule, which should be taken in the morning 30-60 minutes before breakfast. It is also available in 17.5-35 mg tablets, which should be taken 2 or 3 times daily and an hour before a meal. The maximum recommended dose is 70 mg TID. Phendimetrazine is contraindicated during pregnancy.

Benzphetamine (Regimex)

Benzphetamine is a sympathomimetic amine that reduces appetite, an effect that appears to be secondary to CNS effects. It is used as a short-term adjunct to caloric restriction in exogenous obesity. It is indicated for use in patients aged ≥12 y; the maximum dose is 50 mg TID. This medication is contraindicated during pregnancy.

Glucagon-like Peptide-1 Agonists

Class Summary

GLP-1 agonists have shown to promote weight loss in patient with or without type 2 diabetes mellitus.

Liraglutide (Saxenda)

Liraglutide is a glucagonlike peptide-1 (GLP-1) analog. GLP-1 is a physiological regulator of appetite and calorie intake, and the GLP-1 receptor is present in several areas of the brain involved in appetite regulation. It is indicated for chronic weight management as an adjunct to diet and exercise in adults with a BMI of ≥30 (obese) or adults with a BMI of ≥27 (overweight) who have at least 1 weight-related condition (eg, hypertension, type 2 diabetes, dyslipidemia).

Antidepressants, dopamine reuptake inhibitors; opioid antagonists

Class Summary

These agents may cause a reduction in appetite and increase in energy expenditure by increasing activity of pro-opiomelanocortin (POMC) neurons.

Bupropion and naltrexone (Contrave)

Bupropion: Increases dopamine activity in the brain, which appears to lead to a reduction in appetite and increase in energy expenditure by increasing activity of pro-opiomelanocortin (POMC) neurons

Naltrexone: Blocks opioid receptors on the POMC neurons, preventing feedback inhibition of these neurons and further increasing POMC activity

Combination may regulate activity in the dopamine reward system of the brain that helps control food cravings and overeating behaviors

 

Questions & Answers

Overview

What is the prevalence of obesity in the US?

How is obesity defined and classified?

What comorbidities are associated with obesity?

Which lab studies are useful in the diagnosis of obesity?

How is the degree of body fat measured in obese patients?

What are the phases of weight-loss programs for obesity?

What types of drugs are used to treat obesity?

Which bariatric procedures are used in the treatment of obesity?

How is body fat percentage estimated?

Is the prevalence of obesity increasing globally?

What is the economic impact of obesity and its treatment?

What is adiposity-based chronic disease (ABCD)?

Is body weight used as an index of obesity?

How is the body mass index (BMI) (Quetelet index) calculated?

What factors may lead to an incorrect interpretation of BMI?

What is the definition of obesity based on body fat percentage?

Other than body mass index (BMI) and body fat percentage, which indices are used to estimate obesity?

How is dual-energy radiographic absorptiometry (DXA) scanning used in obesity research?

What are the standard techniques for measuring visceral fat volume in obesity research?

What is the WHO obesity classification system?

How is severe obesity commonly classified in the surgical literature?

How is obesity defined in children?

What aspects of obesity are associated with comorbidity?

What comorbidities of obesity are associated with fat distribution?

What comorbidities of obesity are associated with waist circumference?

How does age of obesity onset affect risk of comorbidities?

Does elevated intra-abdominal pressure in obesity increase the risk of comorbidity?

What is the effect of obesity in osteoarthritis?

What is the effect of bariatric surgery on focal glomerulosclerosis in obesity?

How is Pickwickian syndrome related to obesity?

How does obesity affect sleep duration?

Obesity is a risk factor for which health conditions?

Which aspects of obesity increase the risk for type 2 diabetes?

How common is general and abdominal obesity in persons with chronic kidney disease (CKD)?

What is the difference between hypertrophic versus hypercellular obesity?

What is the role of adipocytes (fat cells) in body weight control and obesity?

What are the secretory products of adipocytes?

Which enzymes are involved in adipocyte metabolism and function?

What are the possible cues that induce differentiation of preadipocytes to adipocytes?

What is the role of hormones in the pathogenesis of obesity?

What is the role of smell in the pathogenesis of obesity?

What is the role of leptin in the pathogenesis of obesity?

What is night-eating syndrome?

What is the role of the leptin gene in obesity?

Which factors are involved in the etiology of obesity?

Does inactivity in industrialized countries increase the risk of obesity?

Does hypercortisolism increase the risk of obesity in patients with affective disorders (depression) (bipolar disorder)?

What are the risk factors for severe obesity among children?

Is obesity genetic or environmental?

Is obesity hereditary?

What is the role of genetic susceptibility loci in the development of obesity?

Are there monogenic variants of obesity?

What is the role of proopiomelanocortin (POMC) in the etiology of obesity?

What is the role of congenital leptin deficiency in the etiology of obesity?

What is the role of prohormone convertase in the etiology of obesity?

What is the role of PPAR-gamma in the etiology of obesity?

What is the role of infection and inflammation in the etiology of obesity?

What is the prevalence of obesity in the US?

How many deaths in the US are associated with obesity?

Does socioeconomic status affect the prevalence of obesity?

What is the global prevalence of obesity?

Is obesity more common in women or men?

Does emigration affect the prevalence of obesity?

How many people worldwide are obese?

What is the global trend in body mass index (BMI)?

Does obesity have a racial predilection?

Does obesity during childhood or adolescence increase the risk for severe obesity in adulthood?

Does obesity increase morbidity and mortality rates?

What is the mortality rate for individuals with obesity?

Does obesity reduce life expectancy?

Do obesity mortality rates differ among racial groups?

Does increased waist circumference affect risk of death?

Which factors modulate the morbidity and mortality associated with obesity?

Does obesity affect mortality in elderly people?

Are weight loss programs effective in reducing obesity?

Do caloric information labels affect food selection in low-income families?

Does a formal diagnosis of obesity motivate lifestyle changes?

Are educational, behavioral, and health promotion interventions effective in preventing obesity in children and adolescents?

Presentation

What is the typical presentation of obesity?

What should be the focus of the medical history for obesity?

Which comorbidities should be considered in patients with obesity?

What are the secondary causes of obesity?

Which measurements should be made during the physical exam in patients with obesity?

What should be included in exam of the organ systems in patients with obesity?

What should be included in exam of the extremities in patients with obesity?

DDX

What comorbidities should be considered in the diagnosis of obesity?

What are the differential diagnoses for Obesity?

Workup

What lab studies are involved in the evaluation of obesity?

What are the likely findings of a lipid panel in patients with obesity?

What do elevated transaminase levels indicate in obesity?

What are the likely findings of thyroid function tests in patents with obesity?

Why are glucose and insulin testing important in patients with obesity?

Which procedures and methods are used to measure degree of body fat in obesity?

Treatment

What should be included in lifestyle management for obesity?

Why is a multidisciplinary team beneficial in the management of obesity?

What are the Endocrine Society guidelines for the treatment of obesity?

What are the three phases of an effective weight-loss program for obesity?

What pharmacologic therapy is available for the treatment of obesity?

What surgical procedures are effective for the treatment of obesity?

What are the ACC, the AHA, and TOS treatment guidelines for obesity and one or more comorbidities?

Which complications can occur during weight loss?

What steps should be taken prior to enrolling a patient with obesity in a weight-loss program?

Screening for which psychiatric comorbidities should be completed prior to initiations of surgical, medical, or behavioral weight-loss interventions?

Why is it important to set realistic weight loss goals in patients with obesity?

How much weight loss is associated with clinically meaningful health benefits in patients with obesity?

What is a reasonable goal for weight loss in a medical treatment program for obesity?

What are the benefits of culturally adapted weight-loss programs for obesity?

What are the common factors associated with successful weight loss in patients with obesity?

What nutrients should a diet focus on for weight loss maintenance?

Are there positive health benefits after regaining weight after initial weight loss?

Why are long-term strategies needed to prevent obesity relapse?

How is childhood obesity managed?

What is the effect of weight loss on energy expenditure?

How are correction factors used in estimating energy expenditure in obese patients?

What are potential major complications of low-calorie diets for obesity?

What are very-low-calorie diets (VLCDs) for obesity?

How are conventional diets for obesity classified?

What are examples of balanced, low-calorie diets and reduced-portion size diets for obesity?

What are the strategies used for reducing portion size in diets for obesity?

What is the suggested nutrient composition of diets for obesity?

Are low-carbohydrate diets safe and effective?

How similar are the effects among differing diet programs for obesity?

How effective are very-low-calorie diets (VLCDs) for obesity?

When are very-low-calorie diets (VLCDs) contraindicated?

Are very-low-calorie diets (VLCDs) sustainable?

What are complications of very-low-calorie diets (VLCDs)?

Are preoperative very-low-calorie diets (VLCDs) effective in decreasing surgical risk in patients with obesity?

Does drinking more water aid in weight loss among patients with obesity?

What screening should be done prior to initiating an intensive exercise program in patients with obesity?

What exercise provides the greatest benefit in patients with obesity?

Why is exercise important in the treatment of obesity?

What are the benefits of exercise in patients with obesity?

What is the focus of behavioral modification in patients with obesity?

How is behavioral change initiated in patients with obesity?

What is the role of sleep in obesity?

What are the FDA-approved medications for weight-loss?

Is orlistat (Xenical, Alli) effective in the treatment of obesity?

Is lorcaserin (Belviq, Belviq XR) effective in the treatment of obesity?

Is liraglutide (Saxenda) effective in the treatment of obesity?

When are phentermine and topiramate (Qsymia) indicated in the treatment of obesity?

How do bupropion and naltrexone help with the management of obesity?

Which drugs are used for short-term treatment of obesity?

Which medications are used off-label to promote weight-loss in obesity?

Are diabetes medications effective in the management of obesity?

Are antidepressants effective in the management of obesity?

What are the roles of ephedrine and caffeine in the treatment of obesity?

What is the role of cannabinoid-receptor antagonists in the treatment of obesity?

Is catechin (green tea) effective in the treatment of obesity?

What agents are being investigated for the treatment of obesity?

Is pramlintide (Symlin) FDA approved for the management of obesity?

Are peptide YY (3-36), leptin, and tagatose approved for the treatment of obesity?

Which drugs are no longer used or are ineffective in the treatment of obesity?

How are fat substitutes such as olestra (Olean) used to prevent obesity?

What are the possible adverse effects of olestra (Olean)?

Does margarine lower total and LDL-cholesterol levels?

Is bariatric surgery an effective treatment for obesity?

When should patients with obesity be considered for bariatric surgery?

What comorbidities are resolved by bariatric surgery?

Can bariatric procedures be performed laparoscopically?

What are the standard bariatric procedures for the treatment of obesity?

Is sleeve gastrectomy effective in the treatment of obesity?

Is vertical-banded gastroplasty effective in the treatment of obesity?

Is Roux-en-Y gastric bypass effective in the treatment of obesity?

Is gastric pacing effective for the treatment of obesity?

Which bariatric procedures have unclear utility in the treatment of obesity?

What are surgical complications of bariatric surgery for the treatment of obesity?

What are the possible adverse events associated with gastric resection procedures?

What are the possible adverse events associated with malabsorptive procedures for obesity?

What are the failures rates for malabsorptive procedures for obesity?

Does bariatric surgery for obesity improve quality of life?

When is inpatient care indicated for obesity?

Are public health education programs effective for obesity prevention?

Which specialists should be consulted in the treatment of obesity?

Is regular follow-up needed for long-term management of obesity?

Guidelines

What are the Endocrine Society guidelines for the treatment of obesity?

Medications

When are medications indicated for the treatment of obesity?

What are the major drug groups used to manage obesity?

Are most medications for obesity approved for short-term or long-term use?

Which medications in the drug class Gastrointestinal Agents, Other are used in the treatment of Obesity?

Which medications in the drug class CNS Stimulants, Anorexiants are used in the treatment of Obesity?

Which medications in the drug class Glucagon-like Peptide-1 Agonists are used in the treatment of Obesity?

Which medications in the drug class Antidepressants, dopamine reuptake inhibitors; opioid antagonists are used in the treatment of Obesity?