Obesity and Multiple Sclerosis

Katherine H. Saunders

Mohini Aras

Louis J. Aronne

Introduction

Obesity affects 39.8% of adults (93.3 million) and 18.5% of children and adolescents (13.7 million) in the United States.¹ Obesity is defined as a body mass index (BMI) of greater than or equal to 30 kg/m² in adults and a BMI of greater than or equal to age- and sex-specific 95th percentile of the 2000 Centers for Disease Control and Prevention growth charts in children.² The medical costs associated with obesity are tremendous. The latest published estimate was US$147 billion in 2008.³

Obesity is a multifactorial, chronic disease characterized by an accumulation of visceral and subcutaneous fat, which leads to a predisposition toward a wide variety of comorbid conditions.⁴ Obesity-related comorbidities include many of the leading causes of preventable death, such as heart disease, type 2 diabetes, stroke, and many types of cancer. Mechanisms including abnormalities in lipid metabolism, insulin resistance, inflammation, endothelial function, adipokine balance, and inflammasome activation have been implicated in the development of these weight-related chronic conditions, including multiple sclerosis (MS) among patients with obesity.⁴

Modest weight loss of 5% to 10% body weight is sufficient for significant and clinically relevant improvements in risk factors among patients with overweight and obesity.⁵,⁶ This risk reduction appears to be dose related,
as a 10% to 15% reduction in body weight is associated with even greater odds of clinically significant improvements in most risk factors. The magnitude of weight loss at 1 year is strongly associated with improvements in many parameters including blood sugar, blood pressure, triglycerides, and HDL cholesterol.

Most patients have limited success with weight loss because of the body’s resistance to the effects of lifestyle modifications. Reduced caloric intake and increased energy expenditure are counteracted by a variety of adaptive physiological responses.⁷ Alterations in a range of hormones cause appetite to increase and resting metabolic rate to slow out of proportion to what would be expected based on changes in body composition.⁸ This phenomenon, called metabolic adaptation or adaptive thermogenesis, inhibits weight loss and leads to weight regain.⁹,¹⁰

As a result, successful treatment of obesity requires a multidisciplinary approach to counteract the body’s resistance to weight loss. Although diet, physical activity, and behavioral modifications are the cornerstones of weight management, many patients require additional interventions, such as antiobesity medications and/or bariatric surgery, to achieve and maintain clinically significant weight loss.

In this chapter, we describe how obesity is a risk factor for MS. We also review the available treatment strategies for obesity, including medications and devices approved by the US Food and Drug Administration (FDA), as well as bariatric surgery. Finally, we examine the impact of obesity treatment on MS and present a patient case that illustrates key points.

Obesity as a Risk Factor for Multiple Sclerosis

Epidemiology

MS is a chronic autoimmune disease of the central nervous system (CNS). It is an inflammatory and demyelinating condition that affects both white and gray matter. Symptoms range from fatigue, numbness, and tingling to pain, blindness, spasticity, incontinence, and paralysis. It is estimated that MS affects between 400,000 to 1 million Americans and at least 2.3 million people worldwide.¹¹,¹²,¹³ MS affects twice as many women as men. According to the World Health Organization, rates of MS have increased over the last few years from 2.1 million in 2008 to 2.3 million in 2011.12 The medical costs associated with MS are significant and are estimated to be upward of US$52,000 per patient per year.¹¹

MS is the second leading cause of neurological disease in young people and leads to a wide range of functional debilities.¹² The most common subtype is relapsing-remitting MS, which is associated with numerous brain and spinal cord lesions that resolve either partially or completely between flares.¹⁴ Pediatric MS, and clinically isolated syndrome, which includes
optic neuritis and transverse myelitis, are being reported at increasing rates.¹⁵ Although causes of MS remain unknown, both genetic and environmental factors have been implicated—human leukocyte antigen (HLA)-DRB1*15:01 allele, other non-major histocompatibility complex variants, tobacco exposure, vitamin D deficiency, viral exposures, reproductive history, and obesity.¹¹

The prevalence of obesity in MS is estimated to range from 21% to 37%.¹⁶ The increasing prevalence of obesity over the past few decades could account for increased rates of MS. Numerous studies have confirmed an approximately twofold increased risk of developing MS in women who were obese during late adolescence/early adulthood (age 18-25 y) versus women who had a BMI in the normal range during those years.¹⁷,¹⁸ This association between adolescent/early adult obesity and MS has not been consistently shown in men.

There is also an association between childhood obesity and MS. In 2013, a Danish prospective study of children in the Copenhagen School Health Records Register found that girls who were ≥95th percentile for BMI had a 1.61- to 1.95-fold increased risk of MS compared with girls <85th percentile.¹⁹ Among boys, this association was attenuated and only significant in particular age groups (e.g., among boys aged 8-10 y). Given the strong association between childhood obesity and adult obesity, treating childhood obesity may be an important initiative to reduce the prevalence of MS in adulthood.

Pathophysiology

Genetics

The HLA-DRB*15:01 allele is the most common genetic marker for the risk of developing MS. This allele carries a 2.9-fold increased risk of developing MS among individuals with a normal BMI. The presence of both obesity and the HLA-DRB1*15 allele confers a 9.1-fold increased risk of developing MS compared with noncarriers of the allele with a normal BMI.¹⁴ These findings suggest that obesity is a significant risk factor for developing MS in genetically predisposed individuals.

Inflammation

Previously, it was believed that adipose tissue was metabolically inactive and its main purpose was storage, thermal regulation, and protection of vital organs. However, we now understand that adipose tissue is metabolically active and highly involved in hormonal and immune functions both locally and systemically.²⁰ Adipose tissue consists of the adipocyte as well as supporting cells, including fibroblasts, endothelial cells, and immune cells of both innate (macrophages, neutrophils, eosinophils, and mast cells)
and adaptive (T and B cells) immunity. The adipocyte secretes a variety of adipokines (signaling proteins specific to adipocytes), including leptin and adiponectin. Under conditions of excess weight, adipocytes secrete proinflammatory cytokines, including tumor necrosis factor alpha, monocyte chemoattractant protein 1, and interleukin 6.²⁰ As a result, obesity is considered a chronic proinflammatory state. This chronic inflammation has been associated with a variety of disorders including atherosclerosis, diabetes mellitus, many types of cancer, inflammatory bowel disease, and MS.

On a cellular level, the damage that occurs in MS is due to autoreactive T cells entering the CNS and destroying oligodendrocytes, cells that produce myelin to insulate neurons.²¹ Furthermore, inflammatory dendritic cells and macrophages promote disease by activating these autoreactive T cells and secreting proinflammatory cytokines. The chronic inflammation associated with obesity leads to unrestricted activation of the inflammasome, a multiprotein intracellular complex that secretes proinflammatory cytokines.²¹,²²

Gut Microbiome

The gut microbiome is composed of microbes, such as bacteria, viruses, and fungi, that reside in the bowel.¹⁴,²³ These microorganisms contribute to the development of the immune system, protect against pathogens, and even assist in metabolic functions of the body both locally and systemically. Stool samples from patients with MS reveal significantly increased levels of Methanobrevibacter and Akkermansia and decreased levels of Butyricimonas (phylum: Bacteroidetes) compared with controls without MS.¹⁴,²⁴ Methanobrevibacter and Akkermansia are associated with T cell activation and proinflammatory cytokines, whereas Butyricimonas are associated with anti-inflammatory cytokines. Patients with obesity have also been found to have elevated levels of Methanobrevibacter and reduced levels of Bacteroidetes. These correlations in relative levels of microbiome species support an association between the proinflammatory environments among patients with obesity and MS.

Leptin and Adiponectin

Leptin is one of the peptide hormones secreted by adipocytes. It signals satiety, reduces food intake and regulates fat stores. Patients with obesity are relatively resistant to leptin, so levels are often found to be elevated. Interestingly, leptin has strong proinflammatory effects and is also found to be elevated in patients with MS. Although there are conflicting findings on the utility of leptin as a biomarker of MS disease activity, significantly increased levels have been reported in the cerebrospinal fluid (CSF) of patients during MS flares or relapses.¹⁴,²⁵,²⁶ The rise in leptin is thought
to be related to either increased leptin synthesis in the CSF or increased movement of leptin through a more permeable blood-brain barrier that might occur during an MS flare. In both obesity and MS, leptin modulates the immune system toward a proinflammatory state by secreting proinflammatory cytokines and downregulating anti-inflammatory cells.¹⁴ There are many other hormones that regulate appetite and fat storage, which may be similarly upregulated in both inflammatory conditions.

In contrast to leptin, adiponectin is a hormone produced by the adipocyte that has anti-inflammatory effects. It has been shown in animal studies to be protective in autoimmune CNS inflammation. Mice without adiponectin have greater disease markers for MS, and when these mice are treated with adiponectin, there is improvement in these markers.²⁷ Adiponectin is an important regulator of T cells and could potentially have clinical implications for treating MS.

Vitamin D

Vitamin D is one of the fat-soluble vitamins. As it is sequestered in adipose tissue, circulating levels are often lower in patients with obesity. Vitamin D has been found to have many effects on the immune system, and low levels of vitamin D are thought to be a risk factor for the development of MS. New studies implicate the potential role of vitamin D in neuroprotection and myelin repair, and research is underway to determine if vitamin D supplementation among patients with MS can alter disease progression or rate of relapse.²⁸,²⁹ Whether vitamin D deficiency and obesity are independent risk factors for MS or there are other underlying mechanisms has not yet been elucidated.

Obesity Treatment

Patients with both MS and obesity often suffer more pronounced disabilities than patients with MS who are not obese. In particular, ambulation can be affected early in the disease process and can severely impact quality of life.³⁰ In addition to physical disabilities, patients with MS and obesity also have higher rates of depression and suicide.¹⁶ As a result, treating obesity in patients with MS should be a priority to improve disability and quality of life.

Lifestyle Modifications and Drug-Induced Weight Gain

Lifestyle interventions, including diet, exercise, and behavioral modifications, are the foundation of obesity treatment. Many dietary
strategies can be effective for weight loss. Recommendations should be tailored to a patient’s preferences, as adherence to diet is associated with greater weight loss and greater reductions in cardiac risk factors.³¹ A Mediterranean diet can be a good option for patients at high cardiovascular risk, as it has been shown to reduce the incidence of major cardiovascular events in this population.³² A low-glycemic-index diet can curb hunger and decrease cravings by reducing blood sugar fluctuations.³³ All patients trying to lose weight should be counseled to limit sugary drinks, fast food, junk food, and sweets. Registered dietitians can provide dietary education and customize diet plans.

The American College of Sports Medicine recommends 150 minutes of moderate-intensity aerobic physical activity (such as brisk walking or tennis) per week, 75 minutes of vigorous-intensity aerobic physical activity (such as jogging or swimming laps) per week, or an equivalent combination of moderate- and vigorous-intensity aerobic physical activity.³⁴ Episodes should last at least 10 minutes and, if possible, be spread out through the week. In addition, weight resistance (muscle strengthening) is recommended at least twice weekly. Patients with physical limitations should be encouraged to do what they can even if they cannot meet the recommendations. Exercise physiologists, physical therapists, and trainers can provide additional support for patients.

Behavioral interventions for weight loss include self-monitoring, such as weighing on a scale at regular intervals and keeping a food log to track caloric intake. Stress reduction and adequate sleep can also be helpful for weight loss. Support can be provided to patients by an interdisciplinary team including physicians, dietitians, sports physiologists, physical therapists, psychologists, social workers, and other health care professionals. As weight maintenance can be more difficult than initial weight loss, it is important that patients continue regular follow-up to ensure long-term adherence to their treatment plan.

Medications can have unpredictable and variable effects on a patient’s weight, so it is important to balance the benefits of treatment against the probability of weight gain.³⁵ Multiple medications are associated with weight gain, including certain antidiabetic, antihypertensive, antidepressant, antipsychotic, antiepileptic, and antihistamine agents, as well as steroids, contraceptives, and other hormonal agents.³⁶ Table 11.1 provides an overview of these medications as well as potential alternative options. When possible, practitioners should utilize weight-neutral or weight-loss-promoting medications. If there are no alternative medications, weight gain can be prevented or lessened by selecting the lowest dose required to produce clinical efficacy for the shortest duration necessary.

TABLE 11.1 MEDICATIONS ASSOCIATED WITH WEIGHT GAIN, WEIGHT NEUTRALITY, AND WEIGHT LOSS

	Weight Gain	Weight Neutral/Less Weight Gain	Weight Loss
Antidiabetics	Insulin	α-Glucosidase inhibitors	GLP-1 agonists
	Meglitinides	Bromocriptine	Metformin
	Sulfonylureas	Colesevelam	Pramlintide
	Thiazolidinediones	DPP-4 inhibitors	SGLT2 inhibitors
Antihypertensives	α-Adrenergic blockers β-Adrenergic blockers (atenolol, metoprolol, nadolol, propranolol)	ACE inhibitors ARBs β-Adrenergic blockers (carvedilol, nebivolol) Calcium channel blockers Thiazides
Antidepressants	Lithium MAOIs Mirtazapine SSRIs (paroxetine) Tricyclic antidepressants (amitriptyline, doxepin, imipramine, nortriptyline)	SSRIs (fluoxetine, sertraline)	Bupropion
Antipsychotics	Clozapine Olanzapine Quetiapine Risperidone	Aripiprazole Lurasidone Ziprasidone
Antiepileptics	Carbamazepine Gabapentin Pregabalin Valproic acid	Lamotrigine Levetiracetam Phenytoin	Topiramate Zonisamide
Contraceptives	Medroxyprogesterone acetate	Barrier methods IUDs Surgical sterilization
Antihistamines	First-generation antihistamines	Second- and third-generation antihistamines Decongestants = alternatives
Steroids	Glucocorticoids	Inhaled steroids Topical steroids NSAIDs, DMARDs = alternatives
Adapted from Igel LI, Kumar RB, Saunders KH, et al. Practical use of pharmacotherapy for obesity. Gastroenterology. 2017;152(7):1765-1779. Copyright © 2017 AGA Institute. With permission.
ACE, angiotensin-converting enzyme; ARB, angiotensin II receptor blockers; DMARD, disease-modifying antirheumatic drug; DPP-4, dipeptidyl peptidase-4; GLP-1, glucagon-like peptide-1; IUD, intrauterine device; MAOI, monoamine oxidase inhibitor; NSAID, nonsteroidal anti-inflammatory drug; SGLT2, sodium-glucose cotransporter 2; SSRI, selective serotonin reuptake inhibitor.

Antiobesity Medications

Weight loss achieved by lifestyle modifications alone is often limited and difficult to maintain. As a result, patients may require antiobesity medications, bariatric surgery, devices, or endoscopic bariatric therapies to achieve and maintain clinically significant weight loss.

Antiobesity pharmacotherapy is one strategy to offset the changes in appetite and energy expenditure that occur with weight loss and improve adherence to lifestyle changes. According to the 2013 American College of Cardiology/American Heart Association/The Obesity Society’s guideline for the management of overweight and obesity in adults and the Endocrine Society’s clinical practice guidelines on the pharmacologic management of obesity, pharmacotherapy for obesity can be considered in patients with a BMI ≥ 30 kg/m² or a BMI ≥ 27 kg/m² with weight-related comorbidities, such as hypertension, dyslipidemia, type 2 diabetes, and obstructive sleep apnea.³⁷,³⁸

As obesity is a chronic disease, most antiobesity medications are approved for long-term treatment. Many of the antiobesity medications affect appetite mechanisms, signaling through serotonergic, noradrenergic, or dopaminergic pathways. They primarily target the arcuate nucleus of the hypothalamus to stimulate the anorexigenic pro-opiomelanocortin (POMC) neurons, which promote satiety.

Medications approved for weight management should be viewed as useful additions to diet and exercise for patients who have been unsuccessful with lifestyle changes alone not substitutions for lifestyle changes. The six most widely prescribed antiobesity medications approved by the FDA are phentermine, orlistat, phentermine/topiramate extended release (ER); lorcaserin; naltrexone sustained release (SR)/bupropion SR; and
liraglutide 3.0 mg.³⁹,⁴⁰,⁴¹ Table 11.2 provides an overview of the medications. In addition to producing weight loss, each medication improves metabolic biomarkers, including blood pressure, blood sugar, and lipids. The four agents approved since 2012 have stopping rules, which suggest discontinuing the medication if a certain amount of weight loss has not been achieved after 12 to 16 weeks.

TABLE 11.2 MOST COMMONLY USED MEDICATIONS FOR OBESITY APPROVED BY THE FOOD AND DRUG ADMINISTRATION

Medication

Mechanism, Dosage, Available Formulation

Total Body Weight Loss (%)

Initial FDA Approval

Phentermine

(Adipex,⁴³ Ionamin,⁴⁴ Lomaira,⁴⁶ Suprenza⁴⁵)

Adrenergic agonist

8-37.5 mg daily

(8 mg dose can be prescribed up to TID)

Capsule, tablet

15 mg/d: 6.06

7.5 mg/d: 5.45

Placebo: 1.71

28 wk⁴²

1959

Schedule IV controlled substance

Approved for short-term use

Orlistat

(Alli,⁵¹ Xenical⁵⁰)

Lipase inhibitor

60-120 mg TID with meals

Capsule

120 mg TID: 9.6

Placebo: 5.61

52 wk⁴⁹

1999

Phentermine/topiramate extended release

(Qsymia⁵⁴)

Adrenergic agonist/neurostabilizer

3.75/23-15/92 mg daily

Capsule

15/92 mg daily: 9.8

7.5/46 mg daily: 7.8

Placebo: 1.2

56 wk⁵³

2012

Schedule IV controlled substance

Lorcaserin

(Belviq, Belviq XR⁵⁶)

Serotonin (5-HT)_2C receptor agonist

10 mg BID or 20 mg XR daily

Tablet

10 mg BID: 5.8

Placebo: 2.2

52 wk⁵⁹

2012

Schedule IV controlled substance

Naltrexone/bupropion sustained release

(Contrave¹¹⁰)

Opioid receptor antagonist/dopamine and norepinephrine reuptake inhibitor

8/90 mg daily to 16/180 mg BID

Tablet

16/180 mg BID: 6.1

8/180 mg BID: 5.0

Placebo: 1.3

56 wk⁶¹

2014

Liraglutide 3.0 mg

(Saxenda⁶⁴)

GLP-1 receptor agonist

0.6-3.0 mg daily

Prefilled pen for subcutaneous injection

3.0 mg daily: 8.0

Placebo: 2.6

56 wk⁶³

2014

BID, twice daily; GLP-1, glucagon-like peptide-1; TID, three times daily; XR, extended release.

Phentermine

Phentermine was approved by the FDA in 1959 and is the most commonly prescribed antiobesity medication in the United States. It is an adrenergic agonist that suppresses appetite and increases resting energy expenditure. Phentermine is indicated for short-term use (up to 3 mo), as there are no long-term safety trials of phentermine monotherapy; however, it was approved in combination with topiramate ER for long-term therapy, so many providers prescribe phentermine for longer durations as off-label therapy. In a 28-week randomized controlled trial comparing phentermine, topiramate ER, and the combination of the two medications, participants taking phentermine 15 mg daily lost an average of 6.0 kg compared with 1.5 kg among those assigned to placebo.⁴²

The recommended dosage of phentermine is up to 37.5 mg daily, but dosage should be individualized to achieve adequate response with the lowest effective dose.⁴³,⁴⁴,⁴⁵ In 2016, the FDA approved an 8-mg formulation, which can be prescribed up to three times per day.⁴⁶ Administration of the last dose late in the day should be avoided to prevent insomnia. Phentermine is a schedule IV controlled substance. There seems to be no advantage of continuous compared with intermittent phentermine treatment.⁴⁷ The most common treatment-emergent adverse events (TEAEs) include dry mouth, headache, insomnia, dizziness, irritability, nausea, diarrhea, and constipation. Contraindications include pregnancy, nursing, history of drug abuse or cardiovascular disease, hyperthyroidism, glaucoma, and agitated states.

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