Proactive and Progressive Approaches in Managing Obesity

ABSTRACT

Despite the advice clinicians have been giving patients about the importance of restricting their food intake and increasing physical activity levels, the Centers for Disease Control and Prevention (CDC) states that 78.6 million adults in the United States (US) are still obese. With these statistics in mind, this symposium provided insights on the genetic, cultural, and environmental underpinning of obesity and discussed the latest research on pharmacotherapy, surgery, and the need to individualize treatment.

KEYWORDS:

• Epigenetic dysregulation
• gut/brain crosstalk
• long-term weight management
• obesity
• pharmacotherapy

CME/CE Information

Activity Title:

Proactive and Progressive Approaches in Managing Obesity

Highlights from a CME Symposium held at the Cardiometabolic Health Congress (CMHC), Sheraton Boston Hotel, Boston, MA, October 22, 2015

Activity Format: CME/CE Spotlight

Estimated Time to Complete: 1 hour

Release Date: May 6, 2016

Expiration Date: May 6, 2017

Credit Type(s) Available: ACCME, CDR, ANCC, ACPE

Maximum Credits: 1 AMA PRA Category 1 Credit(s)^TM

Provided By: This activity is jointly provided by and Medical Education Resources, Inc (MER) and Tarsus Cardio Inc. DBA Cardiometabolic Health Congress.

Commercial Supporter:

This activity is supported by educational grants from Takeda Pharmaceuticals International, Inc., U.S. Region and Novo Nordisk.

Program Description:

This activity explores obesity as a multifactorial, recurring disorder, with key genetic and environmental drivers. New genetic and epigenetic insights will provide an understanding of the inheritance, development, and treatment of obesity. The role of CNS pathways and key gastric hormones involved in the regulation of food intake, energy homeostasis, and body weight are also addressed throughout the activity. This article will challenge practitioners to acknowledge obesity as a serious disease, and help overcome common stigmas and barriers to treatment and maintenance.

Purpose Statement:

To improve patient outcomes through communication and intervention strategies regarding obesity management for patients with cardiometabolic disease.

Intended Audience:

This activity is designed for advanced-level clinicians responsible for the prevention, diagnosis, and management of cardiometabolic risk.

Educational Objectives:

Upon completion of this activity, participants should be able to:

• Identify obesity as a serious multifactorial recurring disease that needs to be addressed with a comprehensive obesity management plan

• Describe genetic and epigenetic mechanisms involved in the susceptibility to and development of obesity

• List the hormonal and neural pathways that regulate food intake and how they may contribute to obesity

• Assess the weight dependent and weight independent metabolic effects of obesity treatment and other common comorbidities

• Individualize care for obese and overweight patients by applying established guidelines, best practices, and novel management modalities to improve outcomes and overall quality of life

FACULTY INFORMATION:

Corresponding Author:

Robert H. Eckel, MD (CHAIR)

Professor of Medicine

Professor of Physiology and Biophysics

Charles A. Boettcher II Chair in Atherosclerosis

University of Colorado Anschutz Medical Campus

Aurora, CO

Disclosures:

Grants/Research Support: Janssen, Isis Pharmaceuticals, Esperion

Consulting Fees: Isis Pharmaceuticals, Janssen, Novo Nordisk, Pfizer, Regeneron/Sanofi-Aventis

Co-authors:

Harold E. Bays, MD, FTOS, FACC, FACE, FNLA

Medical Director / President

Louisville Metabolic and Atherosclerosis Research Center

Louisville, KY

Disclosures:

Grants/Research Support: Amarin, Amgen, Ardea, Arisaph, AstraZeneca, Bristol Meyers Squibb, Catabasis, Cymabay, Eisai, Elcelyx, Eli Lilly, Esperion, Gilead, GSK, Hanmi, Hisun, Hoffman LaRoche, Home Access, Janssen, Johnson and Johnson, Merck, Necktar, Novartis, Novo Nordisk, Omthera, Orexigen, Pfizer, Pronova, Regeneron, Sanofi, Takeda, and TIMI

Consulting Fees: Alnylam, Amgen, Eli Lilly, ISIS, Merck, Novartis, Regeneron, Sanofi, and Takeda.

Speakers’ Bureau: Amarin, Amgen, AstraZeneca, Eisai, Regeneron, Sanofi and Takeda

Samuel Klein, MD

William H. Danforth Professor of Medicine and

Nutritional Science

Chief, Division of Geriatrics and Nutritional Sciences

Director, Center for Human Nutrition

Washington University School of Medicine

St. Louis, MO

Disclosures:

Grants/Research Support: Atkins Foundation Charitable Trust, Kilo Foundation

Consulting Fees: Endobar, Takeda Pharmaceuticals, Novo Nordisk, NuSI, Danone/Yakult

Speakers’ Bureau: Merck

Ownership Interest/Shareholder: Aspire Bariatrics, Metro Midwest Biotec, Human Longevity, Inc

Deborah Bade Horn, DO, MPH

Medical Director, University of Texas

Center for Obesity Medicine and Metabolic Performance

Clinical Assistant Professor

University of Texas Medical School

Houston, TX

Disclosures:

Consulting Fees: Novo Nordisk

Speakers’ Bureau: Takeda Pharmaceuticals, Novo Nordisk

DISCLOSURE OF CONFLICTS OF INTEREST:

It is the policy of MER to ensure balance, independence, objectivity, and scientific rigor in all of its educational activities. In accordance with this policy, MER identifies conflicts of interest with its instructors, content managers, and other individuals who are in a position to control the content of an activity. Conflicts are resolved by MER to ensure that all scientific research referred to, reported, or used in a CME activity conforms to the generally accepted standards of experimental design, data collection, and analysis. MER is committed to providing its learners with high-quality activities that promote improvements or quality in health care and not the business interest of a commercial interest.

PROVIDER DISCLOSURES:

The following content managers reported no financial relationships with commercial interests whose products or services may be mentioned in this CME/CE activity:

MER: Julie Johnson, PharmD, Veronda Smith, FNP

CMHC: Erin Franceschini, MS, Karin McAdams, Mary Mihalovic, Melissa Wiles

ACCREDITATION STATEMENTS:

Physician Credit

This activity has been planned and implemented in accordance with the accreditation requirements and policies of the Accreditation Council for Continuing Medical Education through the joint providership of Medical Education Resources and Tarsus Cardio Inc. DBA Cardiometabolic Health Congress. Medical Education Resources is accredited by the ACCME to provide continuing medical education for physicians.

Medical Education Resources designates each enduring material for a maximum of 1 AMA PRA Category 1 credits™. Physicians should only claim credit commensurate with the extent of their participation in the activity.

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Each CE activity provides 1 contact hour of continuing nursing education.

Medical Education Resources is a provider of continuing nursing education by the California Board of Registered Nursing, Provider #CEP 12299, for 1 contact hour per activity.

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Pharmacy Credit

     Medical Education Resources (MER) is accredited by the Accreditation Council for Pharmacy Education as a provider of continuing pharmacy education. MER designates this continuing education activity for 1 contact hour (1 CEU) of the Accreditation Council for Pharmacy Education. (Universal Program Number - 0816-9999-16-064-H01-P)

This activity is certified as Knowledge-based CPE.

DISCLAIMER:

The content and views presented in this educational activity are those of the authors and do not necessarily reflect those of MER, CMHC and/or the various industry supporters. The authors have disclosed if there is any discussion of published and/or investigational uses of agents that are not indicated by the FDA in their presentations. The opinions expressed in this educational activity are those of the faculty and do not necessarily represent the views of MER, CMHC, and/or the various industry supporters. Before prescribing any medicine, primary references and full prescribing information should be consulted. Any procedures, medications, or other courses of diagnosis or treatment discussed or suggested in this activity should not be used by clinicians without evaluation of their patient's conditions and possible contraindications on dangers in use, review of any applicable manufacturer's product information, and comparison with recommendations of other authorities. The information presented in this activity is not meant to serve as a guideline for patient management.

INSTRUCTIONS:

Participants are expected to read the full activity before attempting to complete the post-test and evaluation. Successful completion will lead to the issuance of a certificate for 1 AMA PRA Category 1 Credit(s)™.

To receive credit, the activity must be completed before May 6, 2017. There are no fees for participating in and receiving CME credit for this activity. In order to claim CME credit for this activity, registration is required prior to completing the post-test and evaluation. During the period May 6, 2016 through May 6, 2017, participants must follow these steps in order to receive CME/CE credit:

1. Sign In or Register.

2. Read the full educational activity. Once completed, go to the following posttest and evaluation link: http://www.cardiometabolichealth.org/online/2016obesityspotlight and complete the post-test by recording the best answer to each question in the answer key. Successful completion of the post-test is required to earn CME/CE credit. Successful completion is defined as a cumulative score of at least 70%.

3. Complete the online evaluation form.

4. After successfully completing the post-test and online evaluation form, your CME/CE certificate will be generated and will be available immediately for print.

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THE ROLE OF EPIGENETICS IN PROMOTING FAT WEIGHT GAIN

Presented by Harold E. Bays, MD, FTOS, FACC, FACE, FNLA

Introduction: defining obesity

The Obesity Medicine Association defines obesity as ‘a chronic, relapsing, multi-factorial neurobehavioral disease, wherein an increase in body fat promotes adipose tissue dysfunction and abnormal fat mass physical forces, resulting in adverse metabolic, biomechanical, and psychosocial health consequences.’[1] The Centers for Disease Control estimates 78.6 million U.S. adults remain obese, despite guidelines recommending appropriate caloric intake and physical activity levels.[2] Obesity is a multifactorial disease that includes endocrine, immune, environmental, neurobehavioral, and genetic/epigenetic components and affects numerous organ systems, increasing the risk of hypertension, thromboembolic events, hypertension, asthma, obstructive sleep apnea, stroke, nerve entrapment, psychosocial dysfunction, and a host of other cardiometabolic disorders.

For the majority of patients, obesity is mainly an extragenetic disorder. However, obesity has several inheritance patterns: genetic mutations and alterations, familial/cultural/societal inherited influences, as well as the increasingly recognized importance of epigenetic inheritance.[3] Examples of rare genetic causes of obesity include melanocortin 4 receptor deficiency, Albright’s hereditary osteodystrophy, Prader–Willi syndrome, Bradet–Biedl syndrome, Borjeson–Forssman–Lehmann syndrome, and Cohen syndrome. [3]

Epigenetic factors and regulation in obesity

In contrast to genetic causes of obesity related to gene mutations, or abnormal gene deletions and additions, epigenetics refers to abnormalities in the manner in which genes are expressed. Epigenetic factors may contribute to obesity and its complications, not only in offspring but in future generations.

Epigenetic dysregulation can occur as a result of DNA methylation and histone modification, which often results in suppression of gene expression, as well as acetylation (which often promotes gene expression via transcription activation). Other processes that may influence the epigenetic expression of genes include ubiquitination, phosphorylation, sumoylation, ribosylation, and citrullination.[3] Other contributing factors that influence epigenetic dysregulation include obesogens (e.g. tributyltin, brominated diphenyl ether 47, polycyclic aromatic hydrocarbons), lack of physical activity, infection, medications, and endocrine disruptors (e.g. environmental pesticides, exogenous hormones, estrogenic agents, androgenic agents, anti-estrogenic agents, and anti-androgen agents).[2] Prader–Willi syndrome is generally considered a genetic disorder due to deletion of a portion of chromosome 15. However, in less than 5% of patients, epigenetic dysfunction results in ‘imprinting’ (silencing) of a portion of chromosome 15, as might occur with failure to erase the maternal imprint during spermatogenesis.[4]

During pregnancy, maternal caloric balance may also influence epigenetic expression. In the event of positive caloric balance leading to obesity and adiposopathy in pregnant women, increased placental transport of lipids, amino acids, and other nutrients may affect fetal stem cell fate, and adversely affect postnatal biologic processes involved in substrate metabolism. Similarly, negative caloric balance may also result in increased mobilization of lipids from maternal adipose tissue stores, which again may affect fetal stem cell fate and also adversely affect postnatal biologic processes involved in substrate metabolism. This helps explain why both maternal overnutrition and undernutrition during pregnancy may increase the risk of obesity adiposopathy, dyslipidemia, diabetes mellitus (DM), and other metabolic diseases in offspring later in life. Furthermore, through these in utero maternal nutritional epigenetic mechanisms, subsequent pathogenic biologic changes may not only be clinically expressed in the immediate offspring, but potentially for generations that follow.[5–7]

Early data suggests, however, that maternal health is not the only factor involved in the epigenetic effects that contribute to adverse metabolic effects in offspring. The father may play an important role as well, perhaps through epigenetic transgenerational inheritance of sperm epimutations; toxins and nutritional exposures may result in programming transmissions.[8]

A role for early intensive therapy

An understanding of epigenetics furthers the argument for the need of early intervention to treat obesity. Clinical trial data already suggests that if clinicians wait to implement appropriate and aggressive treatment until patients have end-stage obesity, DM, cardiovascular disease (CVD), and other adiposopathic disorders, then while the metabolic profile of the patient may improve, weight loss may not result in a reduction in CVD events.[9] An exception might be bariatric surgery intervention, which may have cardiovascular benefit in many such patients. But otherwise, the data supports the benefits of early intervention, wherein adiposopathic metabolic diseases (many of which are major CVD risk factors) can be avoided or at least delayed. [3] Similarly, the emerging evidence regarding epigenetics suggests that aggressive and optimal nutritional intervention during pregnancy is not only beneficial for the mother, but also for the offspring and potentially for generations afterwards. So who should be treated and how early should weight management intervention begin? Based upon the potential importance of epigenetics in contributing to individual obesity and metabolic disease in offspring and subsequent generations, and given the potential role of both parents in epigenetic transmission, then one might argue the best time to begin aggressive nutritional and physical activity intervention to prevent and treat obesity would be in both the parents—prior to conception. Afterwards, clinicians should closely monitor and aggressively treat offspring children who may potentially become overweight or obese.

“Obesity is defined as a chronic, relapsing, multi-factorial, neurobehavioral disease, wherein an increase in body fat promotes adipose tissue dysfunction and abnormal fat mass physical forces, resulting in adverse metabolic, biomechanical, and psychosocial health consequences.”[2]

Conclusion

Epigenetic dysregulation before and during pregnancy may promote metabolic disease(s), such as obesity, DM, and heart disease, which can affect offspring and future generations. Factors that influence epigenetic dysregulation include lack of physical activity, infection, medications, and endocrine disruptors, as well as caloric imbalance and parental influence. Both parents may share responsibilities with regard to offspring and generational predisposition to obesity and metabolic disease via extragenetic and epigenetic factors. While efforts to attain ideal body weight among patients with overweight and obesity may improve metabolic diseases, it would seem reasonable to aggressively engage in appropriate nutrition and physical activity as early as possible (e.g. beginning in the parents prior to conception). This may provide the greatest opportunity to prevent (or at least delay) metabolic diseases such as obesity, DM, hypertension, and dyslipidemia, and thus reduce lifetime CVD risk.

GUT/BRAIN CROSS-TALK: HORMONAL AND NEURAL PATHWAY INTERACTIONS

Presented by Samuel Klein, MD

Introduction

Obesity occurs as a result of an imbalance between energy intake and energy expenditure.[2] The mechanisms responsible for that imbalance, however, remain unclear. In any given individual, there is dysregulation between minute-to-minute energy intake and energy expenditure during a 24-hour period.[10–13] But most people maintain a fairly close balance between intake and expenditure over long periods of time. Nonetheless, in the United States, individuals tend to gain weight as they age. From the age of 25 to 55 years old, individuals can gain on average 1–2 pounds of body weight per year.[14] This amount of weight gain represents a very small imbalance between energy consumed and energy expended of ~20 kcal/day, which underscores how easy it is to gain weight in our current modern environment, where there is an abundant availability of food, effective marketing of food products, sedentary lifestyles, and labor-saving devices.

Factors involved in regulating energy balance

The factors involved in regulating energy balance begin with meal initiation, followed by satiety (level of fullness during a meal, which regulates the amount of food consumed) meal termination and satiety (level of hunger after a meal is consumed, which regulates the frequency of eating). However, there are a constellation of other factors that have a strong influence on eating behavior and cause people to initiate or terminate feeding beyond simple satiation and satiety.[15] For example, the desire or request to taste a food (e.g. eat dessert despite being full after dinner), or emotional stress influences food intake.

Regulation of food intake

The regulation of food intake in the brain is extraordinarily complex. The current, overly simplistic theory on the regulation of food intake involves two systems in the brain: a reward system—or mesolimbic dopamine system—which provides pleasure when food is consumed—and a homeostatic system, an appetite and energy balance system that is involved in the regulation of body weight.[16,17]

However, the regulation of food intake is far more complex and involves a variety of hormones in the gastrointestinal tract, adipose tissue, adrenal glands, as well as signals from the eyes, nose, tongue, and ears. Among the hormones and other molecules that send messages to the brain are glucose, cholesystokinin (CCK), glucagon-like peptide-1 (GLP-1), peptide YY, oxyntomodulin, insulin, glucagon, amylin, leptin, ghrelin, and cortisol. These signals travel to the brain and affect a variety of neurochemicals that either stimulate or inhibit food intake. [13–16,18–20] Data from rodent studies demonstrate that even gut bacteria play a role in energy balance and adiposity.[13–16,18–20]

Despite this sophisticated regulatory system, we are all subject to modulating factors that affect food intake that can increase (or decrease) body size beyond healthy levels. The palatability of food, emotions, learned eating cues, habits, stress, portion size, circadian rhythms, environment, and lifestyle influence the consumption of food. People will eat a food if they like it and want to taste it, even when they are not ‘hungry.’ This executive function of the brain can override our bodies’ normal regulatory signals and result in consuming excessive amounts of calories.

In the past, we existed in a very restrictive environment in which nutrients were limited, requiring a constant search for food. In our modern environment, despite an increased availability of nutrients, this innate food-seeking behavior has been maintained, which predisposes individuals to excess adiposity.[19]

Additionally, most species have a preference for sweets, which is part of a hardwired reward and pleasure mechanism. It has been proposed that some individuals even have a ‘food addiction’ which contributes to the likelihood of obesity. Data from studies that used positron emission tomography scanning to evaluate the dopaminergic system which is a key component of the ‘reward system’ suggest that addiction and obesity share similar dopamine abnormalities.[18] Both have impairments in dopaminergic pathways that regulate neuronal systems associated with reward sensitivity, incentive motivation, self-control, and stress reactivity.[20] People with food/drug addiction and people with severe obesity demonstrate decreased binding of dopamine.[20] These data suggest that individuals with obesity may obtain less pleasure from eating the same amount of food than individuals with normal body weight, which could encourage overeating.

Hormonal adaptations to weight loss

The Achilles heel of managing obesity is the inability to maintain long-term weight loss. It is less challenging to disrupt the energy intake/energy expenditure balance with a weight loss regimen over a short period of time compared to maintaining that effort long-term. Effective treatment prevents weight regain common in those who have successfully lost weight. Long-term follow-up of behavioral treatment of obesity has demonstrated that over several years men and women both tend to regain much of the weight they have lost. Several hormonal mechanisms are likely responsible for this phenomenon.

Hormonal adaptations to weight loss facilitate weight regain and are suggested to be involved in recidivism following weight loss. These adaptations may explain why measurements of hunger and the desire to eat increase over time as subjects regain weight. Circulating levels of hormones involved in weight control including ghrelin, amylin, peptide YY, and CCK also change over time following weight loss.[21] Research suggests that these hormone levels return to baseline levels measured prior to weight loss.[19]

Conclusion

In summary, regulation of food intake is complex, involving central and peripheral signals to the brain. Central reward mechanisms likely play a role in the development and maintenance of obesity. Weight loss maintenance is the Achilles heel of obesity therapy; mechanisms responsible for weight recidivism include genetics, hormonal adaptations, and habitual lifestyle behaviors. As researchers unravel the complexities of the food regulation pathways, clinicians will be equipped with practical tools to treat obesity more effectively.

INDIVIDUALIZING THERAPIES FOR THE CARDIOMETABOLIC PATIENT

Presented by Deborah Bade Horn, DO, MPH, FOMA

Introduction

The current challenge is to better define obesity as it affects each individual, and take into consideration how each person uses various strategies to manage their own care.

Defining obesity: individualized parameters to consider

Currently, obesity is most commonly defined by body mass index (BMI).[2] Alternative approaches include waist circumference, waist-to-hip ratio, percent body fat, central versus peripheral fat, and even categorized by an individual’s perceptions about their weight. In addition, to individualize assessment and treatment, multiple factors that influence patients’ weight need to be investigated, including the media; the social and psychological arenas; the economic, medical, and biological factors; as well as physical activity and developmental factors.[20] Medical professionals spend tremendous effort treating obesity from a nutritional perspective, but not addressing important areas such as social psychology, physical activity, and the environment.

Treating obesity: individualizing treatment

When individualizing therapy for patients with overweight and obesity, clinicians should start with intensive lifestyle interventions, including nutrition and physical activity and progress to pharmacotherapy and surgery as needed. A recent meta-analysis of 56 studies revealed that intensive lifestyle intervention improved short-term, intermediate‐term, and long-term systolic blood pressure (SBP).[21] The same intervention produced a small positive change in high-density lipoprotein cholesterol (HDL-C), but changes in low-density lipoprotein cholesterol (LDL-C) varied, increasing in some and decreasing in others, while triglycerides responded very well to intervention. Cardiometabolic responses reported in this analysis also included the following:[20]

• Short-, intermediate‐, and long‐term reductions in waist circumference;

• Short‐term reductions in total serum cholesterol, but not long-term changes;

• Short-term, intermediate-, and long-term improvements in diastolic blood pressure;

• Short-term reduction in fasting blood glucose, but not long term; and

• Long-term reduction in fasting insulin.

The meta-analysis also sheds light on how the frequency of contact between patients and providers affects outcomes in which the authors concluded that as frequency increased, weight, BMI, waist circumference, and SBP decreased.[20] These findings speak to the need for practitioners to decide how often they will see patients and how long the sessions should last, with the ultimate goal of individualizing patient care. The data reinforce guidelines’ recommendations to initiate therapy with intensive lifestyle intervention and to layer other types of therapies as needed.[9,22–24] If the patient does well after modifying their lifestyle, there is no need for higher-level treatments. If not, there may be a role for pharmacologic and/or surgical intervention.

Pharmacologic therapies

There are currently six pharmacologic agents or groups of agents that are FDA-approved for the treatment of obesity in the United States. Phentermine produces weight reduction with a typical dosage of 15–37.5 mg.[25] Unfortunately there are no recent studies for this agent, or for the other similar sympathomimetic agents, which makes it difficult to do adequate comparisons to new anti-obesity agents. The most common side effect of phentermine is dry mouth, and some patients experience sleep disruption or jitteriness.[21]

One of the more recent combination anti-obesity medications pairs phentermine with topiramate. Exact mechanisms for weight loss with topiramate are still unidentified. There is approximately an 8% weight loss with this combination drug when compared to placebo.[26]

Lorcaserin, also a new generation anti-obesity agent, produces a 4% increase in weight loss when compared to placebo. [27] Smith et al. found a gradual regain of body weight over time following the discontinuation of lorcaserin at week 56. This study effectively demonstrates the need for long-term pharmacotherapy in the treatment of patients with obesity. [28]

Liraglutide may be an option not only for weight loss, but for maintenance of weight loss as well. In the SCALE Maintenance trial, Wadden et al. initially placed patients without DM on a low-calorie diet without pharmacotherapy.[29] Participants who lost at least 5% of their body weight were then randomized to either placebo or liraglutide 3 mg once daily for 56 weeks. Study results revealed that those randomized to liraglutide lost an additional 6% of the weight, suggesting that this agent is beneficial in the individualization of weight loss maintenance therapy.[30]

The last of the new-generation anti-obesity agents to consider is a combination of naltrexone and bupropion. In earlier studies of monotherapy with bupropion, weight loss appeared to be limited and transient. However, when combined with naltrexone, the new anti-obesity medication demonstrated stabilization of weight loss. The average placebo‐subtracted weight loss for naltrexone/bupropion is 4.2% compared to placebo. [27]

With several pharmacologic options, the main question is which pharmacotherapy is the best fit for each individual patient. This means taking into account not just efficacy, but also comorbidity treatment, coverage, and whether you are targeting symptom control, abnormal resting metabolic rate, and interaction with other medications. These anti-obesity medications have not been formally compared to each other in a head-to-head trial. However, Wharton et al. did publish an average placebo-subtracted weight loss to allow for general comparisons of efficacy with FDA-approved and non-approved pharmacotherapy options. The authors reported placebo-subtracted weight loss for orlistat, phentermine/topiramate, lorcaserin, liraglutide, tesofensine, bupropion/zonisamide, and pramlintide/metreleptin. They reported pramlintide/metreleptin (currently not FDA-approved for obesity) to be the most effective in terms of weight loss (9.8%) while orlistat was the least effective (3.1%). [31] In addition to weight loss, several studies investigated the cardiometabolic effects of anti-obesity medications. Results are shown in Figure 1 and Table 1.[26,32–34]

Table 1. Cardiometabolic effects of anti-obesity medications (AOM).

AOM	HR (BPM)	SBP (mmHg)	DBP (mmHg)	Glycemic parameter	Insulin level	Waist circumference (cm)	Reference
Phentermine-topiramate ER[34]	+1.3, +1.7 (0.9,1.3)	−4.7	NS	A1C = NS	—	−7.1	Gadde et al. (2011)
Lorcaserin[35]	−2.0 (−0.4)	−1.4	−1.1	—	—	−6.8	Pi-Sunyer et al. (2015)
Liraglutide[26]	2.5	−4.2	−2.6	FPG = −7.9 mg/dL	−12.6%	−8.2	Smith et al. (2010)
Naltrexone/bupropion ER[36]	+1.7	0.6	NS	FPG = NS A1C = −0.6%	−11.4%	−6.7	Apovian et al. (2013)

Source: Adapted from References [26, 34, 35, 36] as a representation of multiple studies for comparison; this is not a head-to-head trial.

A1C, glycosylated hemoglobin A1C; BPM, beats per minutes; cm, centimeter; FPG, fasting plasma glucose; HR, heart rate; NS, non-significant.

Figure 1. Anti-obesity medications (AOM) and cardiometabolic effects. Adapted from References [26,34–36] as a representation of multiple studies for comparison; this is not a head-to-head trial.

LCL-C, low-density lipoprotein cholesterol; HDL-C, high-density lipoprotein cholesterol; ER, extended release

Conclusion

In order to individualize therapy, clinicians need to take into account not only the effect of an agent on obesity/weight loss, but other factors, including adverse medication effects, cardiometabolic effects, patient preference, and coverage of care. Comorbidities should also be considered for contraindications to specific obesity agents as well as identifying if the patient may benefit from an agent that also has an effect on a coexisting disorder. With the advancement of several new medications over recent years, patients should be encouraged to consider pharmacotherapy when intensive lifestyle intervention is insufficient to interrupt abnormal physiology.

EFFECTIVE STRATEGIES FOR LONG-TERM WEIGHT MANAGEMENT

Presented by Robert H. Eckel, MD

Introduction

Losing weight is difficult for most, but equally challenging is the problem of weight regain, which most often follows any degree of weight loss.[35] Once a patient is obese, the body defends the additional fat that has accumulated as the brain senses the amount of fat. This ‘body fat defense’ phenomenon is important because it is a predictor of survival. While humans no longer live in survival mode, there are clear advantages to having excess calories stored when there is not enough food available. There are historical precedents that demonstrate this fact.

Regulating body weight

Body weight is a homeostatically regulated system in humans, and research suggests there is no intervention that can effectively preserve weight loss.[36] The biology of reduced obesity can shed some light on this phenomenon. During weight loss, leptin falls, ghrelin increases, and GLP-1 drops, while appetite increases with a preference for energy-dense foods.[37] Appetite is a major driver of food intake once individuals lose weight.

Insulin sensitivity also increases after weight loss.[34] In an insulin-sensitive environment, lipolysis of adipose tissue triglycerides is reduced, pro-inflammatory cytokines drop, adipose tissue lipoprotein lipase increases while skeletal muscle lipoprotein lipase decreases, and the body preferentially burns carbohydrates and stores fat.[38] There is also a natural tendency to reduce physical activity after weight reduction. All of these mechanisms encourage weight regain.

Maintaining weight loss: interventions

Weight regain is not absolute. Medical literature has documented success stories in maintaining weight loss. In a study that utilized data from the National Weight Control Registry (NWCR), investigators evaluated a self-reported group of 629 women and 155 men who had lost an average of 30 kg and maintained a required minimum weight loss of 13.6 kg for 5 years.[39] Weight loss was achieved in a wide variety of ways: 50% used a formal program and 50% lost weight on their own. Both groups reported having used both diet and exercise, and 77% reported a triggering event that prompted them to lose weight. About 42% of the subjects said that maintaining their weight loss was less difficult than losing weight.

Predictors of weight loss maintenance in the NWCR included avoiding frying foods and substituting low-fat foods for high-fat foods.[40] However, the best predictor of weight loss maintenance in the NWCR was exercise: subjects in this cohort were exercising on average 1.5 hours a day.[37] Their success was also related to the number of sweat episodes per week: sweating simply relates to the intensity of the bout of exercise. Exercise also appears to reduce appetite. Lastly, success was correlated with the ratings on a restraint scale. These individuals were borderline obsessive/compulsive in personality.

A recent meta-analysis examined weight loss maintenance in 20 randomized control trials.[41] The trials included in this review evaluated dietary supplements, a high-protein diet, other macronutrients, exercise, anti-obesity drugs, and meal replacement. Results showed that each intervention produced some initial weight reduction, but weight regain was the least with anti-obesity medications which have been associated with improved weight-loss maintenance after 12 kg of weight reduction.[42] This suggests that once pharmacotherapy-induced weight reduction has been achieved, continuing an anti-obesity agent should be strongly encouraged. Thus, pharmacologic therapy may be necessary throughout a patient’s lifespan, similarly to pharmacotherapy for diabetes, hypertension, or dyslipidemia. Appetite typically increases after successful weight reduction and is a predictor of weight regain. All obesity pharmacologic agents, with the exception of orlistat, work by reducing appetite, thereby causing a decrease in food intake.

In order to influence weight loss, physicians need to

• Be better informed about why patients are unsuccessful in losing weight;

• Increase their knowledge on why patients regain weight initially lost; and

• Consider individual patient profiles to assist in modifying their lifestyles.

Conclusion

Once a patient is obese, weight loss is difficult to achieve and more difficult to maintain. There is a strong metabolic basis for this phenomenon but success can be achieved. Physicians, in addition to other members of the health-care team, must be better informed about why patients are unsuccessful in losing weight and consider individual patient profiles to recommend lifestyle modifications.

PERSONALIZED MEDICINE IN OBESITY CONTROL: CLINICAL CASE DISCUSSION

Moderator: Robert H. Eckel, MD. Discussants: Harold E. Bays, MD; Deborah Bade Horn, MD; Samuel Klein, MD

Patient introduction: A 61-year-old woman with postme-nopausal weight gain who was referred for surgery.

Past medical history: Asthma, arthritis, fibromyalgia.

Physical exam: Weight, 200 lb; height, 5ʹ5″; BMI, 33 kg/m^2; waist circumference, 34 inches; blood pressure, 160/95 mmHg.

Lab results: HbA1c, 5.9%; FPG, 105 mg/dL; total serum cholesterol, 250 mg/dL; LDL-C, 150 mg/dL; HDL-C: 50 mg/dL; triglycerides, 260 mg/dL.

Medication history

• Zafirlukast

• Albuterol (inhaler)

• Metoprolol

• Loratadine

• Etodolac

• Nortriptyline

• Paroxetine

• Vitamins C and B, a multivitamin, and calcium.

Question to consider: given these details, how would you proceed?

Because her BMI is only 33 kg/m², she does not officially meet the criteria for bariatric surgery, which is above 40 kg/m² without comorbidities or 35 kg/m² with comorbidities. She is, however, a candidate for diet, exercise, and behavior therapy, with or without medication.

The expert panel discussed the following issues that needed to be addressed:

• The patient is taking paroxetine, which can cause weight gain; replacing that antidepressant with citalopram or escitalopram will reduce that risk.

• Tricyclic antidepressants like nortriptyline can also contribute to weight gain and should be reconsidered.

• Clinicians can expect a modest weight loss response to eliminating these agents, although the response is expected to fall along a bell-shaped curve, with some patients having a more significant weight loss and others seeing very little benefit.

• The patient has prediabetes based on her lab data, so weight reduction is the best and most practical strategy to reduce the likelihood of progressing to type 2 diabetes.

• After the patient’s medication regimen has been modified, the next step would be to have her accurately record a dietary diary, including everything she eats and drinks, except for water, for a week.

• A 500-calorie deficit may result in a one pound loss per week but it is not possible to restrict 500 calories until a clinician knows what the patient is eating.

To help patients with obesity, both dietary therapy and exercise are important; however, asking a patient to initially change their diet and the amount of physical activity they engage in at the same time may overburden them. It is best to start with nutrition therapy. And in this particular patient, the type of diet is important to consider. She might well benefit from a low-carbohydrate diet, which over the short term would improve her triglyceride and HDL levels more effectively than a low-fat diet.

‘To initially change a patient’s diet and their amount of physical activity at the same time may overburden them … it is best to start with nutrition therapy.’

Program summary

Helping patients lose weight and maintain that weight loss remains a major challenge for clinicians. As the faculty pointed out, obesity is a multifactorial disease that includes endocrine, immune, environmental, neurobehavioral, and genetic/epigenetic components. And while it is well known that weight gain is a result of an imbalance between energy intake and energy expenditure, this explanation is overly simplistic and does not take into account the complex issues that patients must deal with on a daily basis. Addressing those issues requires behavior and lifestyle modifications, an understanding of the benefits versus risks of anti-obesity agents, and a willingness on the part of clinicians to provide individualized therapy.

Financial & competing interests disclosure

This manuscript was funded by Takeda Pharmaceuticals International, Inc., U.S. Region and Novo Nordisk, through support provided to the 2015 Cardiometabolic Health Congress. Editorial support was provided by Robert E. Lamb, PharmD, Mary Mihalovic, Erin Franceschini, MS, and Paul Cerrato, sponsored by Takeda Pharmaceuticals International, Inc., U.S. Region and Novo Nordisk. R Eckel has received grants/research support from Janssen, Isis Pharmaceuticals, and Esperion, and consulting fees from Isis Pharmaceuticals, Janssen, Novo Nordisk, and Regeneron/Sanofi-Aventis. H Bays has received grants/research support from Amarin, Amgen, Ardea, Arisaph, AstraZeneca, Bristol Meyers Squibb, Catabasis,Cymabay, Eisai, Elcelyx, Eli Lilly, Esperion, Gilead, GSK, Hanmi, Hisun, Hoffman LaRoche, Home Access, Janssen, Johnson and Johnson, Merck, Necktar, Novartis, Novo Nordisk, Omthera, Orexigen, Pfizer, Pronova, Regeneron, Sanofi, Takeda, and TIMI, as well as consulting fees from Alnylam, Amgen, Eli Lilly, ISIS, Merck, Novartis, Regeneron, Sanofi, and Takeda. He has also been on the Speakers’ Bureau for Amarin, Amgen, AstraZeneca, Eisai, Regeneron, Sanofi and Takeda. D Bade Horn has received consulting fees from Novo Nordisk and has been on the Speakers’ Bureau for Takeda Pharmaceuticals and Novo Nordisk. S Klein has received grants/research support from Atkins Foundation Charitable Trust, Kilo Foundation, as well as consulting fees from Endobar, Takeda Pharmaceuticals, Novo Nordisk, NuSI, and Danone/Yakult. He has also been on the Speakers’ Bureau for Merck and has ownership interest/shareholder in Aspire Bariatrics, Metro Midwest Biotec, and Human Longevity, Inc . The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.