3.1 ASSESSING RISK

The medical history, physical examination and laboratory evaluation should be focused on assessing obesity co-morbid diseases. There is no single laboratory test or diagnostic evaluation that is indicated for all patients with obesity. The specific evaluation performed should be based on presentation of symptoms, risk factors and index of suspicion. However, based on several other screening guideline recommendations, all patients should have a fasting lipid panel (total, LDL and HDL cholesterol and triglyceride levels) and blood glucose measured at presentation along with blood pressure determination. Symptoms and diseases that are directly or indirectly related to obesity are listed in Table 8.3. Although individuals will vary, the number and severity of organ specific co-morbid conditions usually rise with increasing levels of obesity.

Table 8.3 Obesity-related organ systems review

An increased waist circumference has been found to be predictive of a constellation of metabolic risk factors termed the metabolic syndrome that includes elevated blood pressure, impaired fasting glucose or glucose intolerance, hypertriglyceridemia, and low HDL cholesterol.⁶ Although the components and cutoff values selected to define the metabolic syndrome are useful for clinical practice, the constellation of abnormalities associated with insulin resistance is much broader. These ‘non-traditional risk factors’ include increased biomarkers of chronic inflammation (C-reactive protein, tumor necrosis factor-a, interleukin-6), a prothrombotic state (increased plasma plasminogen activator inhibitor (PAI)-1 and fibrinogen), endothelial dysfunction (decreased endothelium-dependent vasodilatation), hemodynamic changes (increased sympathetic nervous activity and renal sodium retention), hyper-uricemia, and non-alcoholic fatty liver disease (NAFLD). OSA often co-exists with these traditional and non-traditional cardiovascular risk factors, leading one author to coin the term ‘Syndrome Z’.¹³

Measurement of waist circumference is a surrogate marker for visceral adipose tissue (VAT) which refers to adipose tissue located within the abdominal cavity, below abdominal muscles, and comprising omental and mesenteric adipose tissue, as well as adipose tissue of the retroperitoneal and perinephric regions (Fig. 8.1). Visceral fat accumulation has also been shown to have a significant negative impact on glycemic control in patients with type 2 diabetes. Recent studies have linked the metabolic and inflammatory abnormalities seen in abdominal obesity to the secretion of adipocyte and adipose connective tissue products called adipokines. Secreted factors include leptin, IL-6, TNF-α, angiotensinogen, PAI-1, transforming growth factor (TGF)-β, and adiponectin among many others.¹⁴ Secretion of these products results in altered endocrine, paracrine and autocrine functions. The metabolic dysregulation and systemic inflammation seen in OSA is likely related, in part, to VAT- derived secretory products.^15–17

Fig. 8.1 Waist circumference is an independent prediction of metabolic risk and is a surrogate marker for intra-abdominal or visceral adipose tissue (VAT). VAT is considered an active endocrine organ that is associated with metabolic and inflammatory abnormalities and secretion of adipocyte and adipose connective tissue adipokines. To measure waist, place a measuring tape in a horizontal plane around the abdomen at the level of the iliac crest.

4.1 LIFESTYLE MANAGEMENT

Lifestyle management incorporates three essential components of obesity care: dietary therapy, physical activity and behavior therapy. Since obesity is fundamentally a disease of energy imbalance, all patients must learn how and when energy is consumed (diet), how and when energy is expended (physical activity) and how to incorporate this information into their daily life (behavior therapy). Lifestyle management has been shown to result in a modest (typically 3–5 kg) weight loss compared to no treatment or usual care.

The primary focus of diet therapy is on reducing overall consumption of calories. The NHLBI guidelines recommend initiating treatment with a diet producing a calorie deficit of 500–1000 kcal/day from the patient’s habitual diet with the goal of losing approximately 1–2 lb per week.^21,22 This can be accomplished by suggesting substitutions or alternatives to the diet to achieve the desired calorie deficit. Examples include choosing smaller portion sizes, eating more fruits and vegetables, consuming more whole grain cereals, selecting leaner cuts of meat and skimmed dairy products, reducing fried foods and other added fats and oils, and drinking water instead of caloric beverages. Since portion control is one of the most difficult strategies for patients to manage, use of pre-prepared products, called meal replacements, is a simple and convenient suggestion. Examples include frozen entrees, canned beverages and bars. Use of meal replacements in the diet has been shown to result in a 7–8% weight loss. It is important that the dietary counseling remains patient centered and consistent with his or her cultural preferences.

Although exercise alone is only moderately effective for weight loss, the combination of dietary modification and exercise is the most effective behavioral approach for treatment of obesity. Focusing on simple ways to add physical activity into the normal daily routine through leisure activities, travel and domestic work should be suggested. Examples include walking, using the stairs, doing home and garden work, and engaging in sport activities. Asking the patient to wear a pedometer to monitor total accumulation of steps as part of the activities of daily living, or ADLs, is a useful strategy. Step counts are highly correlated with inactivity (low number of steps) as well as with activity (high number of steps). Studies have demonstrated that lifestyle activities are as effective as structured exercise programs in improving cardiorespiratory fitness and weight loss. The American College of Sports Medicine (ACSM) recommends that overweight and obese individuals progressively increase to a minimum of 150 minutes of moderate-intensity physical activity per week as a first goal.²³ However, for long-term weight loss, higher amounts of exercise (200–300 minutes per week or ≥2000 kcal/week) are needed. The Dietary Guidelines for Americans 2005 found compelling evidence that at least 60–90 minutes of daily moderate-intensity physical activity (420–630 minutes per week) are needed to sustain weight loss.²⁴ The ACSM also recommends that resistance exercise supplement the endurance exercise program. These recommendations will feel daunting to most patients and need to be implemented gradually. Many patients would benefit from consultation with an exercise physiologist or personal trainer.

When recommending any behavioral lifestyle change, have the patient identify what, when, where and how the behavioral change will be performed, have the patient and yourself keep a record of the anticipated behavioral change, and follow up progress at the next office visit.

4.2 PHARMACOTHERAPY

Adjuvant pharmacological treatments should be considered for patients with a BMI of 30 kg/m² or with a BMI of 27 kg/m² who also have concomitant obesity-related risk factors or diseases and for whom dietary and physical activity therapy has not been successful. When prescribing an anti-obesity medication, patients should be actively engaged in a lifestyle program that provides the strategies and skills needed to effectively use the drug since this support increases total weight loss. There are several potential targets of pharmacological therapy for obesity, all based on the concept of producing a sustained negative energy (calorie) balance.^25,26

4.3 CENTRALLY ACTING ANOREXIANT MEDICATIONS

Appetite-suppressing drugs, or anorexiants, affect satiation – the processes involved in the termination of a meal, satiety –the absence of hunger after eating, and hunger – a biological sensation that initiates eating. By increasing satiation and satiety and decreasing hunger, these agents help patients reduce caloric intake while providing a greater sense of control without deprivation. Their biological effect on appetite regulation is produced by variably augmenting the neurotransmission of three monoamines: norepinephrine, serotonin (5-hydroxytryptamine, 5-HT), and, to a lesser degree, dopamine. The classic sympathomimetic adrenergic agents such as phentermine function by either stimulating norepinephrine release or blocking its reuptake. In contrast, sibutramine (Meridia) functions as a serotonin and norepinephrine reuptake inhibitor (SNRI). Sibutramine is not pharmacologically related to amphetamine and has no addictive potential. Sibutramine is the only drug in this class that is approved for long-term use. It produces a dose-dependent weight loss with an average loss of about 5–9% of initial body weight at 12 months. The medication has been demonstrated to be useful in maintenance of weight loss for up to 2 years.

The most commonly reported adverse events of sibutramine are headache, dry mouth, insomnia and constipation. These are generally mild and well tolerated. The principal concern is a dose-related increase in blood pressure and heart rate that may require discontinuation of the medication. A dose of 10–15 mg/day causes an average increase in systolic and diastolic blood pressure of 2–4 mm Hg and an increase in heart rate of 4–6 beats/min. For this reason, all patients should be monitored closely and seen back in the office within 1 month after initiating therapy. The risk of adverse effects on blood pressure is no greater in patients with controlled hypertension than in those who do not have hypertension and the drug does not appear to cause cardiac valve dysfunction. Contraindications to sibutramine use include uncontrolled hypertension, congestive heart failure, symptomatic coronary heart disease, arrhythmias, or history of stroke. Similar to other anti-obesity medications, weight reduction is enhanced when the drug is used along with behavioral therapy.

4.4 PERIPHERALLY ACTING MEDICATION

Orlistat (Xenical) is a synthetic hydrogenated derivative of a naturally occurring lipase inhibitor, lipostatin. Orlistat is a potent slowly reversible inhibitor of pancreatic and gastric lipases which are required for the hydrolysis of dietary fat in the gastrointestinal tract. The drug’s activity takes place in the lumen of the stomach and small intestine by forming a covalent bond with the active serine residue site of these lipases. Taken at a therapeutic dose of 120 mg tid, orlistat blocks the digestion and absorption of about 30% of dietary fat. On discontinuation of the drug, fecal fat usually returns to normal concentrations within 48–72 hours.

Multiple randomized, 1- to 2-year double-blind, placebo-controlled studies have shown that after 1 year, orlistat produces a weight loss of about 9–10% compared with a 4–6% weight loss in the placebo-treated groups. Since orlistat is minimally (<1%) absorbed from the gastrointestinal tract, it has no systemic side effects. Tolerability to the drug is related to the malabsorption of dietary fat and subsequent passage of fat in the feces. Six gastrointestinal tract adverse effects have been reported to occur in at least 10% of orlistat-treated patients; oily spotting, flatus with discharge, fecal urgency, fatty/oily stool, oily evacuation, and increased defecation. The events are generally experienced early, diminish as patients control their dietary fat intake, and infrequently cause patients to withdraw from clinical trials. Psyllium mucilloid is helpful in controlling the orlistat-induced GI side effects when taken concomitantly with the medication. The manufacturer’s package insert for orlistat recommends that patients take a vitamin supplement along with the drug to prevent potential deficiencies. Orlistat was approved for over-the-counter (OTC) use in 2007.

4.5 THE ENDOCANNABINOID SYSTEM

Cannabinoid receptors and their endogenous ligands have been implicated in a variety of physiological functions, including feeding, modulation of pain, emotional behavior, and peripheral lipid metabolism.²⁷ The cannabinoid receptors, the endocannabinoids and the enzymes catalyzing their biosynthesis and degradation constitute the endocannabinoid system or ECS. Cannabis and its main ingredient, Δ⁹-tetrahydrocannabinol (THC), is an exogenous cannabinoid compound. Two endocannabinoids have been identified: anandamide and 2-arachidonyl glyceride (2-AG). Two cannabinoid receptors have been cloned termed CB₁ (abundant in the brain) and CB₂ (present in immune cells). The brain ECS is thought to control food intake through reinforcing motivation to find and consume foods with high incentive value and regulate actions of other mediators of appetite. The first selective cannabinoid CB₁ receptor antagonist, called rimonabant, was discovered in 1994. The medication is effective in antagonizing the appetite-stimulating effect of THC and suppressing appetite when given alone in animal models.

Thus far, several large prospective, randomized controlled trials have demonstrated the effectiveness of rimo-nabant as a weight loss agent.²⁸ Taken as a 20 mg dose, subjects lost an average of approximately 6.5 kg compared to approximately 1.5 kg for placebo at 1 year. Concomi-tant improvements were seen in waist circumference and cardiovascular risk factors. The most common reported side effects include depression, anxiety and nausea. Rimonabant is approved for use in Europe and other countries outside the US.

4.6 WEIGHT LOSS SURGERY

Bariatric surgery can be considered for patients with severe obesity (BMI=40 kg/m²) or those with moderate obesity (BMI=35 kg/m²) associated with a serious medical condition such as OSA.²⁹ Surgical weight loss functions by reducing caloric intake and, depending on the procedure, macronutrient absorption. The improvement in co-morbid conditions is the result of multiple factors including weight and body fat loss, change in diet, and for the malabsorptive procedures, anatomical changes of the gastrointestinal tract that effect altered responses of several gut hormones involved in glucose regulation and appetite control.

Weight loss surgeries fall into one of two categories: restrictive and restrictive malabsorptive. Restrictive surgeries limit the amount of food the stomach can hold and slow the rate of gastric emptying. The laparoscopic adjustable silicone gastric banding (LASGB) is the most commonly performed restrictive operation. The first banding device, the LAP-BAND, was approved for use in the United States in 2001. In contrast to previous devices, the diameter of this band is adjustable by way of its connection to a reservoir that is implanted under the skin (Fig. 8.3). Injection or removal of saline into the reservoir tightens or loosens the band’s internal diameter, respectively, thus changing the size of the gastric opening. Since there is no rerouting of the intestine with LASGB, the risk for developing micronutrient deficiencies is entirely dependent on the patient’s diet and eating habits.

Fig. 8.4 The Roux-en-Y gastric bypass (RYGB) is the most commonly performed and accepted restrictive-malabsorptive procedure. It involves formation of a 10–30 ml proximal gastric pouch by either surgically separating or stapling the stomach across the fundus. Outflow from the pouch is created by performing a narrow (10 mm) gastrojejunostomy. The distal end of jejunum is then anastomosed 50–150 cm below the gastrojejunostomy.

The Roux-en-Y gastric bypass (RYGB) is the most commonly performed and accepted of the restrictive-malabsorptive bypass procedures. It involves formation of a 10–30 ml proximal gastric pouch by either surgically separating or stapling the stomach across the fundus (Fig. 8.4). Outflow from the pouch is created by performing a narrow (10 mm) gastrojejunostomy. The distal end of jejunum is then anastomosed 50–150 cm below the gastrojejunostomy. ‘Roux-en-Y’ refers to the Y-shaped section of small intestine created by the surgery; the Y is created at the point where the pancreo-biliary conduit (afferent limb) and the Roux (efferent) limb are connected. ‘Bypass’ refers to the exclusion or bypassing of the distal stomach, duodenum and proximal jejunum. RYGB may be performed with an open incision or laparoscopically.

Fig. 8.3 Laparoscopic adjustable silicone gastric banding (LASGB) is the most commonly performed restrictive operation. The diameter of the band is adjustable by way of its connection to a reservoir that is implanted under the skin. Injection or removal of saline into the reservoir tightens or loosens the band’s internal diameter, respectively, thus changing the size of the gastric opening.

Although no recent randomized controlled trials compare weight loss after surgical and non-surgical interventions, available data from meta-analyses and large databases primarily obtained from observational studies suggest that bariatric surgery is the most effective weight loss therapy for those with severe obesity. These procedures are generally effective in producing an average weight loss of approximately 30–35% of total body weight that is maintained in nearly 60% of patients at 5 years. In general, mean weight loss is greater after the combined restrictive-malabsorptive procedures compared to the restrictive procedures. An abundance of data supports the positive impact of bariatric surgery on obesity-related morbid conditions including diabetes mellitus, hypertension, OSA, dyslipidemia and non-alcoholic fatty liver disease.

If surgery is considered, the patient should be evaluated by a high patient volume multidisciplinary team that incorporates medical, nutritional and psychological care. Significant and rapid improvement in diabetes control, OSA, gastroesophageal reflux disease and urinary incontinence, among others, is typically seen following surgery. For patients who undergo LASGB, there are no intestinal absorptive abnormalities other than mechanical reduction in gastric size and outflow. Therefore, selective deficiencies occur uncommonly unless eating habits remain restrictive and unbalanced. In contrast, the restrictive-malabsorptive procedures produce a predictable increased risk for micronutrient deficiencies of vitamin B₁₂, iron, folate, calcium and vitamin D based on surgical anatomical changes. Patients require lifelong supplementation with these micronutrients.