Best Dx/Best Rx: Obesity

Obesity

Jonathan Q. Purnell, MD

Oregon Health and Science University, Portland, OR

Definition/Key Clinical Features
Differential Diagnosis
Best Tests
Best Therapy
Best References

Definition/Key Clinical Features

Obesity: abnormal accumulation of body fat in proportion to body size
Increased risk of comorbid disorders

Hypertension
Type 2 diabetes
Cardiovascular disease
Hyperlipidemia
Gallstones
High uric acid levels
Hepatic steatosis
Osteoarthritis
Obesity hypoventilation
Sleep apnea
Possibly, some types of cancer

Overweight persons have a body-fat proportion intermediate between normal and obese
Risk of comorbid conditions increases with body mass index (BMI) and waist circumference

Differential Diagnosis

Hypothyroidism
Hypercortisolemia
Deficiencies of growth hormone or gonadal steroids
Medications

Long-term glucocorticoid treatment of inflammatory conditions
Immunosuppression after transplantation
Cancer chemotherapy
Intensive glycemic control with insulin, a sulfonylurea, or a thiazolidinedione
Neuropsychotropic drugs, particularly newer antipsychotic and antiseizure medications

Best Tests

History

Obtain weight-gain history

Childhood versus adult
Gradual versus sudden
Associated with head trauma or medication use
Rapid weight gain should lower threshold for screening for conditions in the differential diagnosis

Current and past dietary and exercise habits
Evaluate for diseases for which obese patients are at higher risk

Hypertension
Impaired glucose tolerance or diabetes
Hyperlipidemia
Heart disease
Sleep apnea

Restless sleep at night
Snoring or observed apnea
Fatigue or headache upon awakening and during the daytime
Spontaneous daytime sleep when inactive or while driving

Physical Examination

BMI calculation; BMI = body weight (in kilograms) divided by height (in meters) squared

Underweight: BMI < 18.5
Normal: BMI = 18.5�24.9
Overweight: 25�29.9
Obese: BMI ≥ 30

Fat distribution

Increased relative risk of coronary artery disease, diabetes, and hypertension if waist circumference exceeds 40 in. (102 cm) for men and 35 in. (88 cm) for women

Acanthosis nigricans

Patches of feathery-pigmented skin (hyperkeratotic and hyperpigmented) on the extensor surfaces of the hands and elbows, in the axilla, or on the neck
Occurs in insulin resistance and type 2 diabetes

Presence of xanthomata

Eruptive xanthoma

Indicates elevated blood levels of chylomicrons

Palmar or tuberoeruptive xanthoma

Indicates type III hyperlipidemia

Tendon xanthoma

Indicates familial hypercholesterolemia

Cushing syndrome

Round facies
Facial plethora
Supraclavicular fat pad enlargement
Purplish striae
Thin (�cigarette paper�) skin
Muscle weakness

Hypothyroidism

Doughy skin
Loss of lateral eyebrows
Pretibial edema
Delayed relaxation phase of reflexes

Laboratory Tests

Increased risk for diabetes

Either a fasting plasma glucose level of 100�125 mg/dL, a 2-hr glucose level of 140�199 mg/dL after a 75 g oral glucose tolerance test, or a hemoglobin A_1c of 5.7�6.5%�

Type 2 diabetes

Two fasting blood glucose measurements of ≥ 126 mg/dL, a 2-hr glucose level of ≥ 200 mg/dL during an oral glucose tolerance test, or a random glucose level of ≥ 200 mg/dL and symptoms of diabetes or a hemoglobin A_1c ≥ 6.5%

Screening for thyroid disease, Cushing syndrome, and deficiencies of growth hormone and sex steroids when clinically indicated

Screening for Macrovascular Risk

Blood pressure, pulse rate, and rhythm measurements
Fasting lipid profile
Electrocardiography (ECG) when appropriate

Best Therapy*

Testing and treatment for any secondary causes of obesity and comorbid conditions
Manage with lifestyle measures for 3�6 mo; if weight loss is insufficient to lower long-term health risks, consider pharmacologic or surgical therapy
If BMI ≥ 30 or if BMI > 27 in patient with obesity-related risk factors (i.e., diabetes, hypertension, or hyperlipidemia), consider pharmacologic therapy
If BMI ≥ 40 or if BMI > 35 in patient with obesity-related risk factors, refer for surgery
Goal for pharmacologic or surgical treatment, together with lifestyle measures: sustained loss of ≥ 5% of initial body weight

Nonmedical (Lifestyle) Therapy

Diet Modification

Caloric restriction

Without additional interventions such as exercise or pharmacologic therapy, ≥ 95% of initially lost weight typically regained within 5 yr

Dietary-fat restriction
Restriction of dietary fat to 25%�30% of calories results in significant but modest weight loss
Dietary-carbohydrate changes

Increasing dietary carbohydrate intake while lowering total fat intake results in modest weight loss (~ 2�4 kg) in overweight and obese persons if the additional carbohydrates come from fruits, vegetables, and grain products
Can help sustain weight loss after a period of caloric restriction

Compared with a high-carbohydrate diet (low fat), severe carbohydrate restriction (< 25 g/day) followed by modest carbohydrate restriction leads to greater short-term (6 months to 1 year) weight loss followed by comparable long-term (1 to 2 years) weight loss
Dietary-protein changes

Protein intake should be limited to ~ 10%�15% of daily calories
Obese patients can have significantly greater weight loss on a high-protein diet (~ 30% total calories) than on a regular or a low-fat, high-carbohydrate diet, but potential adverse outcomes have not been adequately studied
High protein intake increases glomerular filtration rate, which may harm patients with existing renal disease or diabetes
Excessively high protein intake, especially from animal sources, may be associated with intestinal cancers, bone disease, and renal disease
Benefits on cardiovascular risk factors and insulin resistance proportional to weight loss
Total weight loss is highly variable

Exercise

Weight loss of 1�4 kg (2.2�8.8 lb) over 1 yr in randomized, controlled studies
Can help sustain weight loss after a period of caloric restriction
American College of Sports Medicine recommends a minimum exercise level of 1,000 kcal/wk for reducing body weight, but 2�3 times that level is more effective for significant, sustained weight loss
Should be encouraged because of health benefits attributable to fitness

Combined Diet and Exercise

Initial treatment of overweight and obese patients should include dietary-fat restriction and increased activity using individualized, sustainable behavioral and lifestyle changes
Dietary-fat restriction and exercise can improve lipid levels, increase insulin sensitivity, and reduce risk of progression of cardiovascular disease and of onset of type 2 diabetes
If lifestyle measures are not effective, medical and surgical treatments can be considered

Pharmacologic Therapy

Effective in achieving weight loss of up to 10% of initial body weight for at least 2 yr
In most studies, patients began a hypocaloric diet (daily caloric intake reduced by 500�1,000 kcal) before drug treatment
Weight loss with obesity agents varies considerably, usually < 10% of baseline weight
Weight loss is greatest during the first 3�6 mo, followed by a plateau at a new lower weight even with continued therapy
Rapid weight regain toward baseline follows discontinuance of medication
Treatment should be continued indefinitely unless the weight is regained or significant side effects develop

Agents Approved for Short-term Use

Phentermine

Inhibits appetite
Average weight loss, 8.7 kg (19.2 lb)
May cause anxiousness, insomnia, palpitations, dry mouth, vasospasm, psychosis, and ischemic events
May be used long term if weight loss sustained
Dose: 30 mg resin, or 15 or 37.5 mg tablets; doses > 37.5 mg not recommended

Agents Approved for Long-term Use

Orlistat

Reduces fat absorption
When combined with a calorie-restricted diet, results in an average weight loss of 7.24�13 kg (16 to 28.7 lb) and significant reduction in levels of total and low-density lipoprotein (LDL) cholesterol
Blood pressure and insulin levels decrease and glycemic control improves with weight loss
Side effects include abdominal discomfort, flatus, fecal urgency, oily spotting, and fecal incontinence
To minimize side effects related to fat malabsorption, candidates for orlistat treatment are first placed on a 30%-fat�restricted diet
Contraindicated in patients with existing malabsorptive states
Patients should take a daily multivitamin supplement during therapy
Dose: 250 mg with each meal

Non�FDA-Approved Medical Therapy for Obesity

Selective serotonin reuptake inhibitors

Weight loss is modest and short-lived

Bupropion plus modest daily caloric restriction

Can produce weight loss
Contraindicated in patients with seizures, anorexia nervosa, and bulimia
Dose: 300�400 mg/day

Topiramate plus modest daily caloric restriction

Weight loss between 5 and 7%
Side effects may include depression, memory difficulties, anxiety, and paresthesias
Begin with 25 mg b.i.d. and increase to 100 mg b.i.d. as tolerated

Growth hormone, sex steroids

No clear benefit for obesity unless there are clear hormonal deficiencies

Medications Associated with Weight Gain: Replace with Alternative Agents

Systemic steroids (glucocorticoids)

Alternatives

Asthma: inhalers
Cancer chemotherapy: non�glucocorticoid-based regimens
Rheumatoid arthritis: methotrexate and remitting agents

Antidiabetic drugs (insulin, sulfonylureas, thiazolidinediones)

Alternatives

Metformin
Acarbose
Sitagliptin (DPP IV inhibitor)
GLP-1 agonists

Exenatide
Liraglutide

Pramlintide

Antiepileptic drugs (gabapentin, valproic acid)

Alternatives

Lamotrigine
Topiramate

Antipsychotic agents (clozapine, olanzapine, risperidone, sertindole)

Alternatives

Haloperidol
Ziprasidone

Antidepressants (tricyclic antidepressants, monoamine oxidase inhibitors, mirtazapine)

Alternatives

Bupropion
Nefazodone
SSRIs
Venlafaxine

Bariatric Surgery

Can produce weight loss to up to 30% of initial weight for at least 5 yr
Best therapy to reverse or prevent type 2 diabetes and sleep apnea
Improvements in hypertension and lipid levels more closely related to amount of weight lost
Anatomically irreversible in most cases
Potentially high postoperative complication rate, including infections, wound complications, and pulmonary symptoms
Perioperative death rates, 0.2%�1.3%; complication rates, 13%�36%

Best References

Bray GA. J Clin Endocrinol Metab 2004;89:2583. [PMID 15181027]

Buchwald H, et al. JAMA 2004;292:1724. [PMID 15479938]

Morton GJ, et al. Nature 2006;443:289. [PMID 16988703]

Snow V, et al. Ann Intern Med 2005;142:525. [PMID 15809464]

The author has served as a consultant for Amylin Pharmaceuticals, Inc.

* To obtain additional drug information, click on the DrugInfo tab in the left column, or click on the following link: http://search.medscape.com/drug-reference-search?queryText=

February 2011