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Endocrinology - Obesity - Fast Facts | NEJM Resident 360

Obesity has emerged as a leading public health concern in the last century. Obesity-related conditions are leading causes of preventable death in the United States. The health effects of obesity are far-reaching and include hypertension, obstructive sleep apnea, osteoarthritis, and cancer. In this section, we review management options for obesity. The following graph shows the age-standardized prevalence trends at the global level and according to sociodemographic index (SDI) quintile from 1980 through 2015 among adults.

Prevalence of Obesity at the Global Level in Adults, According to Sociodemographic Index (SDI)

Shown is the prevalence of obesity at the global level among adults.
(Source: Health Effects of Overweight and Obesity in 195 Countries over 25 Years. N Engl J Med 2017.)

Classification of Obesity

Although body mass index (BMI) is not a perfect marker of obesity, some organizations use BMI to classify obesity according to the following categories:

Classification of Overweight and Obesity by BMI

Weight	BMI (kg/m2)	BMI (kg/m2) for Asians
Normal weight	18.5–24.9	18.5–22.9
Overweight	25.0–29.9	23–26.9
Obesity class I	30.0–34.9	27–32.4
Obesity class II	35.0–39.9	32.5–37.4
Obesity class III	>40	>37.5

Body mass index (BMI) = weight in kilograms divided by the square of height in meters

Pathophysiology

The prevalence of obesity has been rising worldwide. This is likely a multifactorial problem, and the postulated factors that have influenced its rise in the last few decades include an increasingly sedentary lifestyle, processed and caloric-dense foods, large portion sizes, and obesogenic environments such as food “deserts” and fast food “islands.”

On a microscopic level, adipose tissue deposition occurs over time in the subcutaneous and visceral tissue and has several effects including increasing mechanical stress, releasing proinflammatory cytokines, and increasing sympathetic activity. The following figure illustrates the pathophysiology of obesity and its health-related complications.

Some Pathways through Which Excess Adiposity Leads to Major Risk Factors and Common Chronic Diseases

Common chronic diseases are shown in red boxes. The dashed arrow denotes an indirect association.
(Source: Mechanisms, Pathophysiology, and Management of Obesity. N Engl J Med 2017.)

Some of the health-related effects of obesity are reversible with weight loss. For instance, studies have shown that a 5% weight loss is associated with improvement in pancreatic beta-cell function and insulin sensitivity in liver and the skeletal muscle. A 5%–10% weight loss has been associated with clinically meaningful improvements in obesity-related complications, including hypertension and hyperlipidemia.

After the initial period of weight loss, patients tend to regain weight because of factors that include:

• decreased adherence to diet

• decreased activity

• increased endogenous compensatory mechanisms

Treatment

Treatment of obesity is a complex process that depends on the patient’s weight, associated medical conditions, and functional capacity. The main treatment options are lifestyle intervention, pharmacotherapy, and bariatric surgery.

Lifestyle interventions: As the first-line option in weight management, lifestyle interventions involve reduced food intake, increased physical activity, and behavioral motivational training. Studies that provide data to support the efficacy of lifestyle interventions include the Finnish Diabetes Prevention Study, Diabetes Prevention Program, and the Look AHEAD study. The table below summarizes guidelines for both weight loss and subsequent maintenance of weight loss from the 2013 AHA/ACC/TOS Guideline for the Management of Overweight and Obesity in Adults.

(Source: Mechanisms, Pathophysiology, and Management of Obesity. N Engl J Med 2017.)

Counselling patients on weight loss is challenging. The “ABCDEF” approach is one method to consider to guide weight counseling with patients.

Although dietary modification is key to weight loss and maintaining weight loss, no single dietary strategy has been shown to be clearly superior. Current AHA/ACC guidelines recommend a diet high in vegetables, fruits, whole grains, fish, and legumes, with low intake of sugar, sweetened beverages, and red meats.

Medical management: Pharmacotherapy is recommended as an adjunct to dietary modification in patients with a BMI ≥30 or a BMI ≥27 and a weight-related coexisting condition. There are currently 9 medications that have been approved by the U.S. Food and Drug Administration for chronic weight management. The primary effect of these medications is to decrease appetite and improve dietary adherence. Once started on therapy, patients should be assessed for response to treatment. A target weight loss of 3%–5% should be achieved within 3 months, otherwise the medication should be discontinued. The following table reviews these medications and their study findings.

Medications Approved by the Food and Drug Administration for Long-Term Weight Management

| Drug | Main Mechanism
of Action | Dose | Study Duration
(weeks) | Mean Weight Loss
kg (%) | Common Adverse Effects | Contraindications | | --- | --- | --- | --- | --- | --- | --- | | Orlistat | Pancreatic and gastric lipase inhibitor; resulting fat malabsorption reduces net energy intake | 120 mg before meals (three times a day) | 52 | Drug, 8.8 (8.8);
placebo, 5.8 (5.8);
PSWL, 2.6 | Oily spotting, flatus with discharge, fecal urgency, oily evacuation, increased defecation, fecal incontinence | Pregnancy, chronic malabsorption syndrome, cholestasis | | Liraglutide | GLP-1 agonist; delays gastric emptying to reduce food intake | Starting dose, 0.6 mg given subcutaneously once daily;
dose increased weekly by 0.6 mg as tolerated to reach 3.0 mg | 56 | Drug, 8.4 (8.0);
placebo, 2.8 (2.6);
PSWL, 5.3 | Nausea, vomiting, constipation, hypoglycemia, diarrhea, headache, fatigue, dizziness, abdominal pain, increased lipase levels | Pregnancy, personal or family history of medullary thyroid cancer or multiple endocrine neoplasia type 2 | | Semaglutide | GLP-1 agonist; delays gastric emptying to reduce food intake | Starting dose, 0.25 mg given subcutaneously once weekly for first 4 weeks, with the dose increased every 4 weeks to reach the maintenance dose of 2.4 mg | 68 | Drug, 15.3 (14.9);
placebo, 2.6 (2.4);
PSWL, 12.7 | Nausea, vomiting, constipation, hypoglycemia, diarrhea, headache, fatigue, dizziness, abdominal pain, increased lipase levels | Pregnancy, personal or family history of medullary thyroid cancer or multiple endocrine neoplasia type 2 | | Phentermine– topiramate | Norepinephrine-releasing agent (phentermine), GABA receptor modulation (topiramate); decreases appetite to reduce food intake | Starting dose, 3.75 mg/ 23 mg for 2 wk; recommended
dose, 7.5 mg/
46 mg;
maximum dose, 15 mg/92 mg | 56 | Drug, 8.1 (7.8)
at recom-
mended dose,
10.2 (9.8) at
maximum dose;
placebo, 1.4 (1.2);
PSWL, 8.8 | Insomnia,
dry mouth, constipation, paresthesias, dizziness, dysgeusia | Pregnancy, hyperthyroidism, glaucoma, MAOIs, hypersensitivity
to sympatho-
mimetic amines | | Naltrexone– bupropion | Opioid antagonist (naltrexone), dopamine and norepinephrine reuptake inhibitor (bupropion);
acts on CNS pathways to reduce food intake | 1 tablet (8 mg of naltrexone and 90 mg of bupropion) daily for 1 wk; dose subsequently increased each wk by 1 tablet per day until maintenance dose of
2 tablets twice
a day at wk 4 | 56 | Drug, 6.2 (6.4);
placebo, 1.3 (1.2);
PSWL, 5.0 | Nausea, constipation, headache, vomiting, dizziness, insomnia,
dry mouth,
diarrhea | Uncontrolled hypertension, seizure disorders, anorexia nervosa or bulimia,
drug or alcohol
withdrawal,
use of MAOIs,
long-term
opioid use,
pregnancy |

Abbreviations: PSWL, placebo-subtracted weight loss; CNS, central nervous system; GABA, gamma-aminobutyric acid; GLP-1, glucagon-like peptide 1; 5HT2C, 5-hydroxytryptamine 2C; MAOI, monoamine oxidase inhibitors

(Adapted from: Mechanisms, Pathophysiology, and Management of Obesity. N Engl J Med 2017.)

Surgical management: Weight loss through surgery should be considered in patients with BMI ≥40 or a BMI ≥35 and a coexisting condition (e.g., type 2 diabetes, sleep apnea, osteoarthritis). Currently, the following four types of weight-loss surgery are performed most often in the United States:

• gastric banding

• sleeve gastrectomy

• Roux-en-Y gastric bypass

• biliopancreatic diversion with duodenal switch

Read about the advantages and disadvantages of these surgical options here.

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