Obesity Case 9

A 27 year-old woman with a history of obesity, polycystic ovary syndrome (PCOS) and primary hypothyroidism is referred to you for recent weight gain. She also has a history of recurrent kidney stones. Despite her best efforts to follow a meal plan as prescribed by a registered dietitian and increasing her physical activity by hiring a personal trainer, she has gained 20 pounds in the 6 months prior to her visit with you. She reports recent trouble with portion control. She generally eats three large meals per day and craves salty snacks like potato chips and tortilla chips in the evening while watching TV.

She was evaluated by another endocrinologist who documented a normal 11 pm salivary cortisol, fasting glucose, glycated hemoglobin A1c (HbA1c), and thyroid-stimulating hormone (TSH) level. Her past medical history is unremarkable. Her only medication is levothyroxine 100 mg daily. Her family history is notable for obesity and type 2 diabetes mellitus (T2DM) in her father. Her mother had medullary thyroid cancer but is currently free of disease. She is married, but does not desire to start a family yet, wishing to focus on her personal health first.

On review of systems, she has generalized anxiety and trouble sleeping. Menses are irregular. On physical examination, her heart rate is 88 beats/minute, and her blood pressure is 125/80 mm Hg. Her body mass index (BMI) is 36 kg/m2 (normal, 18.5 to 24.9 kg/m2), and her waist circumference is 96.5 cm. She has mild facial hirsutism on the chin and upper lip. The thyroid gland is minimally enlarged, but there are no palpable nodules. An ultrasound performed 6 months ago also did not show any nodules.

Question 1

  The most appropriate choice of pharmacotherapy for this patient is which of the following?

A. Orlistat
B. Phentermine/topiramate ER
C. Liraglutide
D. NaltrexoneER/bupropion ER
E. Phentermine
Correct Answer
D. NaltrexoneER/bupropion ER

Increasing fat mass is always due to a positive energy balance. In addition to ongoing meal-planning and physical activity, pharmacotherapy plays a role in helping patients adhere to nutrition therapy. Scientifically, there is a growing armamentarium of medications for obesity.

Practically, as of 2017, obesity medications are not covered by the federal government or many third party payers. This results in patients having to incur the cost of medications out-of-pocket. This severely restricts patient access to needed care. Phentermine is an adrenergic agonist. It is approved for short-term use for the treatment of obesity (generally considered 3 months). Although it was originally labelled as having the potential for being habit-forming, tolerance-building, and addictive, we now know it is not. Phentermine is the most commonly used weight management medication because it is generic and cheap. It is safe and effective, but its side effect profile includes hyperadrenergic signs and symptoms. Phentermine use may cause an increase in the heart rate, jitteriness, shakiness, anxiety, palpitations, insomnia, dry mouth, constipation, and anxiety. Therefore, phentermine should be avoided in people who have underlying anxiety.

Phentermine in combination with topiramate is available as Qsymia® in the United States. This combination of medications allows for the phentermine dose to be lower. Although the phentermine dose is lower in Qsymia, its use would still be a concern in a patient with anxiety. Topiramate causes cleft-lip and cleft-palate malformations in women who take it during pregnancy. Topiramate is therefore absolutely contraindicated in women desiring pregnancy. There is also increased risk of nephrolithiasis with topiramate therapy thus not the preferred medication.

Orlistat is a pancreatic lipase inhibitor. For it to be effective, an orlistat capsule has to be taken with each meal containing fat. Orlistat acts entirely within the lumen of the gut. Lipase inhibition causes fat malabsorption. Fat malabsorption in turn may cause loose stools, oily stools, fecal incontinence, and anal leakage. Most of the symptoms of fat malabsorption go away with daily ingestion of soluble fiber (i.e., psyllium seeds), and the ingestion of 500 mg of calcium carbonate with each orlistat capsule.  Calcium carbonate saponifies any oily residue and prevents its irritating effects. The combination of both psyllium and calcium carbonate makes most of the untoward symptoms of fat malabsorption due to orlistat go away, and patients may tolerate it. Over time, orlistat may lead to fat-soluble vitamin malabsorption, and it is recommended to prescribe a multivitamin to be taken apart from meals. Orlistat is probably not the best option due to her regular intake of high fat snacks as well as the increased risk of calcium oxalate stones. In addition, orlistat can block the absorption of levothyroxine, and its dosing would need to be separated from the thyroid medication making it a less optimal choice. Furthermore, orlistat is the only approved weight loss medication that does not work on appetite control which is her primary barrier to dietary adherence.

Liraglutide, 3 milligrams daily, is marketed as Saxenda® in the United States. Liraglutide is a glucagon-like peptide-1 (GLP-1) receptor agonist. It delays gastric emptying, improves insulin secretion in response to postprandial hyperglycemia in people with diabetes, suppresses glucagon release from the pancreas, and stimulates central receptors that promote early satiety. Liraglutide, being a polypeptide, must be injected subcutaneously. It is formulated as a daily injection and is the most costly of the weight-management medications available as of 2017. Liraglutide may cause nausea and other gastrointestinal symptoms. For patients with obesity and hyperglycemic derangements, it may be the preferred option. Due to carcinogenicity studies in rodents, liraglutide is contraindicated in patients with a personal or family history of medullary thyroid cancer or multiple endocrine neoplasia type 2 so this option is incorrect.

The best choice of agents for this patient is the combination of buproprion and naltrexone. Bupropion is a mood stabilizer that also decreases addictive and compulsive behavior. Naltrexone is an opioid receptor blocker and decreases the pleasure of meal intake. The combination of these medications helps to decrease food intake and reduce cravings. The naltrexone component predictably causes nausea, and therefore, the dose is gradually titrated from one tablet daily to two tablets twice daily over time. Most patients tolerate an increase of one tablet a day, once a week.