Module 8 Obesity Biology and FDA-Approved Weight-Loss ...

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Module 8Obesity Biology and FDA-Approved Weight-Loss MedicationsObesity Biology and FDA-Approved Weight-Loss Medications..............................................................4

Introduction............................................................................................................................................. 4

Think Ahead: Effects of Weight Loss.................................................................................................5

Case #1: Ms. Clements.......................................................................................................................... 6

Biological Weight-Loss Difficulties..........................................................................................................7

Discussing Biological Weight-Loss Difficulties ..................................................................................8

Genetics and Obesity ........................................................................................................................ 8

Biology of "Food Addiction"................................................................................................................ 9

Addictive Eating Cycle..................................................................................................................... 10

Biological Factors in Weight Loss Maintenance ..............................................................................11

Discussing Biological Adaptations of Obesity .................................................................................12

Biology of Appetite and Weight Regulation ..........................................................................................12

CNS Pathways ..................................................................................................................................... 13

Orexigenic Appetite Pathways (1st and 2nd Order).........................................................................13

Anorexigenic 1st Order Appetite Pathway.......................................................................................14

Anorexigenic 2nd Order Appetite Pathway......................................................................................15

Reward Pathways ........................................................................................................................... 16

Reward Brain Regions..................................................................................................................... 17

Quiz: CNS Hormones & Brain Structures........................................................................................18

Gut Hormones...................................................................................................................................... 19

Gut Hormones and Hunger.............................................................................................................. 19

Gut Hormones and Satiety............................................................................................................... 21

Proximal Small Intestine...................................................................................................................22

Distal Small Intestine and Colon......................................................................................................23

Food Influences on Gut Hormones..................................................................................................24

Pancreatic Hormones – Beta Cells..................................................................................................25

Other Pancreatic Hormones.............................................................................................................26

Liver Hormone Effects...................................................................................................................... 27

Quiz: Gut Hormones ....................................................................................................................... 28

of 72 June 14, 2018 Update – Module 8 Obesity Biology and FDA-Approved Weight-Loss Medicationswww.obesity.ClinicalEncounters.com

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Adipocyte Hormones............................................................................................................................ 28

Quiz: Adipocyte Hormones............................................................................................................... 31

Cannabinoid System............................................................................................................................. 31

Quiz: Cannabinoids.......................................................................................................................... 32

Recap of the Biology of Appetite......................................................................................................33

Weight Loss Pharmacotherapy ............................................................................................................34

Indications for Pharmacotherapy VS Other Treatments..................................................................35

Quiz: Considering Qualifications......................................................................................................36

Is Pharmacotherapy Appropriate for Ms. Clements?.......................................................................37

Quiz: Discussing Pharmacotherapy.................................................................................................37

Talking About Medications................................................................................................................ 37

Current Weight Loss Medications....................................................................................................38

Initiating and Continuing Pharmacotherapy.....................................................................................39

Poll: Pharmacotherapy Prescribed?.................................................................................................40

Weight Loss Supplements............................................................................................................... 40

Determining Medication Choice ...........................................................................................................41

Poll: Considering Orlistat.................................................................................................................. 41

Orlistat Description and Evidence ...................................................................................................42

Orlistat Side Effects, Contraindications, Precautions.......................................................................43

Ms. Clements: Discussing Side Effects............................................................................................44

Follow-Up......................................................................................................................................... 45

Case #2: Mr. Williams........................................................................................................................... 45

Talking with Mr. Williams.................................................................................................................. 46

Mr. Williams: One Year Later............................................................................................................47

Lorcaserin Description and Evidence ..............................................................................................47

Lorcaserin Side Effects, Contraindications, Precautions.................................................................48

Poll: Prescribe Lorcaserin?.............................................................................................................. 49

Further Discussion........................................................................................................................... 49

Bupropion / Naltrexone Description & Evidence .............................................................................50

Bupropion / Naltrexone Side Effects.....................................................................................................51

Bupropion / Naltrexone Contraindications/Precautions...................................................................52

Mr. Williams: Progress..................................................................................................................... 53

Case #3: Mr. Akins................................................................................................................................ 53


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Poll: Treatment Options........................................................................................................................ 54

Discussing Treatment....................................................................................................................... 55

Liraglutide Description & Evidence..................................................................................................55

Liraglutide Side Effects, Contraindications, Precautions.................................................................56

Discussing Pharmacotherapy..........................................................................................................58

Phentermine and Phentermine / Topiramate ER Description..........................................................58

Phentermine / Topiramate Evidence ...............................................................................................60

Phentermine / Topiramate ER Side Effects......................................................................................60

Phentermine / Topiramate ER Contraindications & Special Precautions.........................................61

Mr. Akins: Progress ......................................................................................................................... 62

Lifestyle Management and Followup................................................................................................62

Quiz: Review Weight-Loss Medications 1............................................................................................63

Quiz: Review Weight-Loss Medications 2............................................................................................64

Clinical Protocol Steps in This Module.................................................................................................64

Module Summary.................................................................................................................................. 65

Resources available through this module:............................................................................................66

References used in this module:..........................................................................................................66


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Module 1

OBESITY BIOLOGY AND FDA-APPROVED WEIGHT-LOSSMEDICATIONS

Goal:

To prepare the learner to determine which patients meet criteria for prescribing FDA-approved weight-loss medications, make an informed decision about prescribing these medications, and, when prescribing weight-loss medications, using them as an adjunct to a comprehensive weight-loss treatment plan.

After completing this module participants will be able to:• Explain the biological modifications that occur in chronic obesity that contribute to perpetuating

the condition

• Describe the biological pathways and hormones involved in regulating appetite and weight

• Identify which patients meet guideline criteria for prescribing weight-loss medication as an adjunct to routine weight management

• Educate patients on the need for comprehensive weight-loss treatment in conjunction with weight-loss medication

• If prescribing FDA-approved weight-loss medications, select medications for individual patients based on the each medication's pharmacological profile

• Discuss the potential side effects and effectiveness of FDA-approved weight-loss medications with patients

Professional Practice GapsEvidence-based practice guidelines recommend that, in order to promote weight loss and long-term weight maintenance, physicians should use approved weight loss medications (over no pharmacological therapy) to help ameliorate comorbidities and amplify adherence to behavior

changes needed for weight loss in individuals with a BMI ≥ 30 kg/m2 or in individuals with a BMI ≥

27kg/m2 and at least one associated comorbidity (Apovian et al., 2015).

However, in our needs analysis survey of primary care providers (N=25), 88% said they needed further training regarding the use of pharmacotherapy in weight management, while 32% of providers were not confident with the use of pharmacotherapy in weight management (Tanner, 2011).

INTRODUCTION

Biology Underlying Obesity and FDA-Approved Medications for Weight LossStudying the biology underlying obesity contributes to an understanding of how to treat it. Exploration of the biological mechanisms involved has led to the development of a number of weight-loss medications. The relevant biology includes factors regulating appetite and weight management, as


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well as the physiological adaptations that help perpetuate obesity. The FDA has approved several medications that can be used as adjuncts to a comprehensive treatment plan for weight loss.

Understanding of the relevant biology and current guidelines on weight-loss pharmacotherapy will help providers:

• select which patients might benefit from weight-loss medications • provide patients with realistic expectations • select which medications to prescribe.

Meet the Patients:We will follow the stories of these patients in order to illustrate the effectiveness and limitations of FDA-approved medications for weight-loss. Their stories will illustrate how to guide patients for optimal weight loss if weight-loss medications are prescribed:

MS. CLEMENTS Wants to discuss weight-loss drugs How would you discuss weight-loss medications with her and select the best medication?

MR. WILLIAMS Has weight-related erectile dysfunction Can weight-loss pharmacotherapy help him lose enough weight to help this problem?

MR. AKINS Requests weight-loss pharmacotherapy so that he does not have to "go on a diet" Is pharmacotherapy appropriate in his case?

THINK AHEAD: EFFECTS OF WEIGHT LOSSThink Ahead: Which of the following commonly occurs following significant weight loss?

Choose one

1. Decrease in circulating leptin levels • Feedback: • Correct! This topic is discussed in Biological Difficulties After Weight Loss.

2. Increase in resting energy expenditure • Feedback: • Incorrect. This topic is discussed in Biological Difficulties After Weight Loss.

3. Decrease in circulating ghrelin levels


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• Feedback: • Incorrect. This topic is discussed in Biological Difficulties After Weight Loss.

4. Stimulation of anorexigenic pathways • Feedback: • Incorrect. This topic is discussed in Biological Difficulties After Weight Loss.

5. All of the above• Feedback: • Incorrect. This topic is discussed in Biological Difficulties After Weight Loss.

CASE #1: MS. CLEMENTSThe first case illustrates how a patient can attempt to follow recommended weight-loss treatment, but still struggle to lose weight. Understanding the biological basis for such struggles is key to understanding the effort needed to lose weight and the role of pharmacological adjunctive treatments in weight loss.

Meet Your PatientPatient Name: Marcy Clements Age: 30 y/o

Height: 5'6” Weight: 192 lbs BMI: 31 kg/m2 Waist: 39"

BP: 135/93 Pulse: 75 Respiration: 16/min

Chief Complaint: Wishes to discuss weight-loss drugs, especially OTC medications

History of Present Illness: Following a recommendation to lose weight 3 years ago, she met with a dietitian for several months and lost moderate weight initially. She then stopped all weight-loss efforts for 2 years and regained most of the weight.

Medical History: Patient being treated by headache specialist who referred her for weight-loss management. Last physical exam, 3 years ago. Blood test by neurologist was significant as follows:

Test Result (Reference Range)

HDL 30 mg/dL (above 40 mg/dL)

LDL 165 mg/dL (below 100 mg/dL)

Total cholesterol 240 mg/dL (below 200 mg/dL)

Triglycerides 175 mg/dL (below 150 mg/dL)

Weight History: Lost a moderate amount of weight working with a dietitian several years ago. Her weight loss stopped and she then regained most of the weight.

Physical Activity Level: Moderately low: 80 minutes of moderately intense physical activity per week. (Target is 150 minutes/week)

Weight Related Diagnoses: E66.9 Obesity, unspecified; E65 Localized Adiposity (central)

DIDACTIC AND CASE OBJECTIVESThe didactic content on the biology of obesity and appetite regulation and weight management will cover the following objectives:


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• Explain the biological modifications that occur in chronic obesity that contribute to perpetuatingthe condition.

• Describe the biological pathways and hormones involved in regulating appetite and weight.

This case will cover the following objectives:

• Identify patients for whom prescribing weight-loss medication is appropriate as an adjunct to routine weight management.

• Educate patients on the need for comprehensive weight-loss treatment in conjunction with weight-loss medication.

• If prescribing FDA-approved weight-loss medications, select medications for individual patients based on the each medication's pharmacological profile.

• Discuss the potential side effects of FDA-approved weight-loss medications with patients.

BIOLOGICAL WEIGHT-LOSS DIFFICULTIES

Ms. ClementsMs. Clements, who has chronic obesity, lost a moderate amount of weight working with a dietitian several years ago. Her weight loss stopped and she then regained most of the weight. Is there a biological basis for her weight loss difficulties that might be treatable?

The basic behavior needed for weight loss is clear: Reduced energy intake and increased physical activity. However, many patients struggle to adhere to this plan, even with behavioral supports. The reasons include:

• Conflict between the patient's desire to lose weight and adaptive biological responses to prevent starvation that is triggered by reduced energy intake

• (Apovian et al., 2015)

Biological adaptations to long-term chronic obesity also decrease weight loss, enhance weight gain, and contribute to weight-related comorbidities. These adaptations include:

• Increased fat storage capacity due to a proliferation of preadipocytes (Ochner et al., 2015; ) • Chronic hypersecretion of insulin, a potent hunger trigger, in response to increased fat mass

and insulin resistance (Isganaitis, et al., 2005)


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• Chronic over-consumption of highly palatable foods results in habituation to the rewarding effects of neural dopamine signaling (Ochner et al., 2015; ). When food intake is restricted, a feeling of reward deficit is experienced.

• Low-grade chronic inflammation in metabolic tissues and chronic pain are seen with chronic obesity. Tissues affected include adipose, liver, muscle, pancreas, and brain, which contributes to insulin resistance and metabolic dysfunction (Gregor & Hotamislagil, 2011). The worsening of chronic inflammatory processes is beyond the load-bearing effects of excess weight. Multiple chemical mediators are under investigation as possible links between obesity and symptoms of fibromyalgia, rheumatoid arthritis, lupus, psoriasis, and many others.

Evidence points to these biological adaptations persisting even after a healthy BMI is obtained (Ochner et al., 2015). With gastric bypass surgery, however, some of the changes of chronic obesity are reversed, including gut hormone levels and neural responsivity.

PRACTICE TIPWhile none of the approved weight-loss medications produces sufficient weight loss on their own, they do help promote weight loss in combination with standard treatment. Weight-loss medications can provide a small boost to weight loss efforts.

DISCUSSING BIOLOGICAL WEIGHT-LOSS DIFFICULTIES

Ms. Clements

Provider: You asked about why it was so difficult for you to maintain your weight loss. One problem is that the body eventually adapts to excess weight making it harder to lose weight, in some ways permanently or at least for a very long time. The body's hormones basically sent you messages encouraging weight gain. Fortunately there are some answers so you don't re-gain the weight next time.

Ms. Clements: Please, tell me.

Provider: You can raise the amount you exercise and perhaps work with a trainer for a few sessions to make sure you are getting an effective workout for at least a half hour a day. You can review your dietary patterns with a dietitian to look for ways you might be slipping in following an effective weight loss plan. Sometimes, due to conditioning, people find ways of getting foods with a lot of sugar, for example, and fool themselves into thinking they are not having any sugar.

Ms. Clements: Both of those might help. It doesn't sound easy, but I'm willing to do what is necessary.

GENETICS AND OBESITY


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Food Cravings and DNACertain genes may play a part in people craving foods high in fatand sugar. Some people may be predisposed to obesity due to afew genetic variants, located near the following genes (NLM NCBI,2015; Preidt, 2015):

• FTO gene: Associated with body mass index and obesity • DRD2 gene: Associated with dopamine reception

People with the FTO gene variant have an activation in a part of the brain (striatum) when shown high-calorie foods. The effect depends their variant of a gene affecting the brain's dopamine system - the DRD2 gene. People with the gene combination are more likely to be obese, due to the brain's reward response to foods high in fat and sugar which boosts cravings (Preidt, 2015).

Better understanding of the biological basis of obesity may help identify those who are predisposed toobesity and may better guide treatment (Preidt, 2015).

Epigenetics and ObesitySome evidence points to epigenetic (abnormal gene expression without altered genetic code) factors operating for some families with obesity and the metabolic effects of obesity. Thus, epigenetics apparently is one factor that contributes to obesity being a transgenerational disease for some families. Offspring of affected obese individuals may benefit from intensive prevention. The potential for an intergenerational effect may motivate obese women of childbearing age to lose weight.

BIOLOGY OF "FOOD ADDICTION"

Ms. Clements: Sometimes I crave ice cream or something sweet, and it gets so strong I feel like I just have to have it. There's a tension that will only go away if I indulge in food. It's a bit like the feeling I had when I used to smoke and wanted a cigarette, but not quite as strong.

A number of commonalities between addiction and obesity have been describedand may suggest possible approaches to obesity treatment (Volkow et al., 2013;Shriner & Gold, 2014):

• Addictive-type processing in the CNS has been observed in associationwith overeating that resembles addiction.

• Neuroimaging studies of individuals experiencing "food addiction" symptoms have revealed increased activation in reward-related brain regions, such as the striatum and the medial orbitofrontal cortex, consistent with other addictive disorders (Gearhardt et al., 2011).

• Additional brain regions involved in pleasure and self-control involving the neurotransmitter dopamine are dysfunctional in both food and drug addictions. This leads to reduced ability to resist temptation and decreased enjoyment of the addictive substance, whether a drug or food.


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• Specific dopamine receptors, D2, are reduced in both drug addiction and obesity (Volkow et al., 2013).

• A decrease in D2 receptor activity also seems to contribute to less sensitivity to leptin (Volkow et al., 2013). Leptin is a hormone produced in the stomach that increases after eating and signals a feeling of fullness, leading to less eating. Leptin also may be involved in modifying the rewarding effects of alcohol and drugs.

ADDICTIVE EATING CYCLE

Ms. ClementsMs. Clements describes a cycle of starting to crave ice cream orsweetened yogurt around 4 pm, especially on stressful days atwork. She often binges on these foods when she gets home. Shefeels good at first, but later she regrets her binge and her moodcomes down from the sugar high. She vows never to bingeagain. But the next day, the same cycle repeats. Is she addicted to these foods?

Behavior in response to certain foods, for some individuals,resembles the compulsiveness of drug addictions (Volkow et al., 2013; Shriner & Gold, 2014). The addictive-like behavior is cyclical:

• High fat / high sugar foods raise dopamine levels • These foods are sought out and even "craved" for their stimulating effect on opioid and

dopamine levels (Gearhardt et al., 2011; Shriner & Gold, 2014). • The positive effect becomes muted in a response resembling drug tolerance (Gearhardt et al.,

2011). • Individuals consume more or even binge in order to experience the pleasure they once

received (Gearhardt et al., 2011). • As with drug addiction, people may feel unpleasant "withdrawal" when they go without high fat

or sugar foods. A low mood may be a part of these symptoms. • Eating the desired food helps raise the mood. • The response by opioid receptors is further muted like drug tolerance, resulting in cravings,

repeated indulgence, etc., in a cyclical pattern.

Foods and food attributes that are implicated in addictive-like eating were identified based on a study of 120 undergraduates (Schulte et al, 2015). This study found that not all foods are equally implicatedin addictive-like eating; the foods at the top of the list were:

1. Processed foods 2. Foods high in fat and glycemic load

. The authors noted that highly processed foods share certain characteristics with abused drugs: concentrated dose and rapid rate of absorption.


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PRACTICE TIPS• Assess how your patients feel about foods they over-consume and their eating patterns. • Pharmacological treatments may help break the addiction-like cycle, or at least decrease it

enough to increase success in weight loss. Some medications affect the reward center and others work on appetite-regulating hormones.

• Encourage periodic change rather than sudden abstinence (Shriner & Gold, 2014). The sudden removal of a food source from the patient's usual diet may trigger binge-eating in compensation, which has an overall negative effect on weight loss.

BIOLOGICAL FACTORS IN WEIGHT LOSS MAINTENANCE

Difficulties in Weight Loss MaintenanceAltered and dysfunctional physiology due to chronic obesity is maintained even afterweight loss and promotes weight regain (Apovian et al., 2015). Energy expendituredecreases and appetite increases as described below:

• Total energy expenditure falls, especially resting energy (BMR), out ofproportion to the change in lean body mass (Apovian et al., 2015). Thedecrease appears to persist indefinitely. The decrease in BMR is partially due toan increase in skeletal muscle efficiency after weight loss. Muscle lossdecreases energy expenditure beyond that expected by decreased weight itself(Rosenbaum, et al., 2003).

• Changes in appetite-related hormones caused by low caloric intake duringweight loss persist for at least 1 year after weight reduction and include:

• Increase in circulating levels of the orexigenic (promoting eating, weight gain) hormoneghrelin

• Reduction in the level of the anorexigenic (reducing eating, causing weight loss) hormones (e.g., peptide YY (PYY), cholecystokinin (CCK), leptin, and insulin

• (Apovian et al., 2015) • Weight loss reduces the size of adipocytes, which changes their metabolic and inflammatory

characteristics and leads to more energy being stored than is needed (Maclean et al., 2015).

Effective Approaches for Weight Loss MaintenanceAlthough exercise is not very effective at promoting weight loss, it is very important in maintenance ofweight loss. Fairly high amounts of time spent exercising are needed (~200 to 300 minutes/week) (Jensen et al, 2013)

Caloric intake must be maintained at a new level, lower than before the diet, indefinitely (Jensen et al,2013)

Did You Know? Brown Fat and ObesityBrown fat shows some potential as a medical target in supporting weight loss maintenance. Brown fatmediates energy metabolism and helps to keep animals warm. People who are obese have less brown fat, than slender individuals (Ravussin, 2015). Brown fat metabolism increases in response to cold, even in humans, but less so in humans who are obese or have diabetes (Kern, et al, 2014). Pharmacological manipulation of brown fat to increase calories burned has only helped a little with weight loss because the amount of brown fat in humans is small (Ravussin, 2015).


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DISCUSSING BIOLOGICAL ADAPTATIONS OF OBESITY Ms. Clements: Is there something wrong with me that I feel hungrier more often than my

slender sister? And why does she get full after eating smaller portions than me?

Provider: Your gut makes a number of hormones that regulate appetite and feeling full. They also affect the amount of energy you expend and cause changes in your blood sugar. These hormones actually get out of balance when there is excess fat in the body and cause you to feel more hungry and less full than when you were thinner.

Ms. Clements: It sounds like I'm stuck being heavy!

Provider: It is true that through these hormonal changes, the excess body fat actually is somewhat self-perpetuating. That is why I like to recommend extra support in weight loss for someone who has struggled with a lot of excess weight for a long time.

BIOLOGY OF APPETITE AND WEIGHT REGULATION

Ms. ClementsMs. Clements has described that she struggles with fairly strong craving for something sweet, especially certain foods such as ice cream. Could there be a biological reason for her cravings?

An understanding of the biological pathways and hormones involved in regulating appetite and weightprovides a biological foundation for understanding:

• The complex hormonal and neuroendocrine processes at work in weight regulation. • The dysregulation responsible for the body's resistance to weight loss in obesity. • The propensity for weight regain after weight loss. • How weight loss medications work.

The biological units involved in regulating appetite and weight are:

• CNS Appetite Regulation and Reward Pathways: How the CNS, especially the hypothalamus and brainstem, works with signals from the gastrointestinal system to up-regulate or down-regulate food intake and body-fat mass.

• Gut Hormones: How hormones secreted by the stomach, small and proximal large intestines,pancreas, and liver affect body mass through regulating food intake and energy storage and use.

• Adipocyte Hormones: How the body's fat mass acts like an endocrine organ to secrete hormones affecting fat deposition.

• Cannabinoid System: How this system, working in the CNS and peripherally, works to stimulate appetite.


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CNS PATHWAYS The appetite and controlling centers of the Central Nervous System(CNS), especially the hypothalamus and brainstem, receive signalsfrom the gut, adipose tissue, liver, and pancreas. In response, theCNS regulates food intake and body fat mass.

The CNS Pathways:Two main pathways control this process:

1. APPETITE REGULATION PATHWAYS:

• Orexigenic pathway: Leads to weight gain and food intake • Anorexigenic pathway: Leads to weight loss, satiety, and decreased food intake

1. Gut and adipose hormones plus energy substrates signal first order neurons in the CNS in both pathways, especially in the hypothalamus.

2. The first order neurons in each of these pathways signal the second order neurons 3. Second order neurons control feeding behavior and metabolism.

(Broussard, 2014; Coll, 2007; Lenard, 2008)

2. REWARD PATHWAYS: Neurological pathways involved in feeding and associated with reward and emotions, especially the mesolimbic dopamine reward pathway, are involved in promoting eating. The pathway rewards high caloric food intake. Food-related stimuli trigger the release of the neurotransmitters dopamine and serotonin, which produce a pleasure response which reinforces eating.

OREXIGENIC APPETITE PATHWAYS (1ST AND 2ND ORDER)

Lead to Weight Gain, Food Intake

First order orexigenic pathway

Neuropeptide Y (NPY) & Agouti-relatedprotein (AgRP)Action: Decrease energy expenditure, oxygenconsumption, and thyrotropin releasing hormone.Promotes hunger and food-seeking behavior.

• CNS location: Arcuate nucleus of thehypothalamus

• Stimulated by: Ghrelin • Inhibited by: Insulin, leptin, PP, PYY, nd

serotonin • Inhibit: MC3R and MC4R at second order

neurons

(Lenard, 2008; Broussard, 2014)


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Second order orexigenic pathways

Melanin Concentrating Hormone (MCH)Action: Increases food intake and adipogenesis. Stimulates cognitive function; regulates mood and sleep-wake cycle

• CNS Mechanism: Stimulated by NPY and AgRP • CNS Location: Lateral hypothalamus • Inhibited by: Leptin (indirectly)

(Coll, 2007; Stanley, 2005; Broussard, 2014)

Orexin A & BAction: Increases arousal and food seeking

• Inhibited by: Leptin

(Coll, 2007; Lenard, 2008; Stanley, 2005; Broussard, 2014)

POTENTIAL CLINICAL APPLICATIONS:These 2nd order orexigenic hormones and signaling pathways that promote eating theoretically couldbe targets for weight-loss drugs to block them.

ANOREXIGENIC 1ST ORDER APPETITE PATHWAY

First Order Anorexigenic Pathway

Proopiomelanocortin (POMC) & Cocaine andAmphetamine Regulated Transcript (CART)Action: Promotes feelings of satiety

• CNS Action: POMC releases the anorexigenichormone, Alpha-Melanocyte Stimulating Hormone(α-MSH). A precursor of peptides with roles in painand energy homeostasis, melanocyte stimulation,and immune modulation

• CNS Location: Arcuate Nucleus of thehypothalamus

• Stimulated by: Serotonin, leptin and insulin • Inhibited by: NPY (Y-1) and GABA

(Stanley, 2005; Coll, 2007; Broussard, 2014)

CLINICAL APPLICATIONS:Several weight-lossdrugs exert their effects by stimulating POMCneurons:

1. The weight-loss medication bupropion is a dopamine and norepinephrine reuptake inhibitor that releases feedback inhibition of POMC neurons. Naltrexone, an

opioid blocking

medication, is added to bupropion to potentiate the effect.



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2. Phentermine is a noradrenergic and possibly dopaminergic sympathomimetic amine weight-loss medication that stimulates POMC neurons to promote satiety.

3. Liraglutide is a GLP-1 agonist weight-loss medication that affects POMC neurons.

(Apovian et al., 2015)

ANOREXIGENIC 2ND ORDER APPETITE PATHWAY

Second Order Anorexigenic Pathways

SerotoninAction related to appetite regulation: Reduces foodintake

• CNS Location: Hypothalamus • CNS Mechanism: Stimulates serotonin (5-HT)

receptors, which mediate the following: • Activates POMC and MC3R/MC4R, which

reduces food intake • Inhibits NPY and AgRP in the arcuate

nucleus, which reduces food intake

(Coll, 2007; Broussard, 2014) CLINICAL APPLICATION: Lorcaserin, an FDA approved weight-loss drug, actsthrough stimulation of a serotonin receptor. (Apovian etal., 2015)

Melanocortin Receptors (MCR 3 & MCR 4) &Brain derived neurotrophic factor (BDNF)

• CNS Mechanism: Reduces food intake by reducing hypothalamic neuron activity. Increases energy expenditure.

• Cholecystokinin (CCK) activates POMC signaling MC4Rs, which promote satiety

CLINICAL RELEVANCE: PRADER-WILLI SYNDROME Genetic deficiencies of these hormones cause 1-3% of obesity. A mutation in the melanocortin-4 receptor in the hypothalamus is seen in Prader-Willi syndrome, a rare genetic syndrome which is characterized by:

• Hyperphagia due to not feeling full • Obesity • Weak muscle tone • Incomplete sexual development

(Broussard, 2014; Genetics Home Reference, 2015)



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REWARD PATHWAYS

Ms. Clements

Ms. Clements: So, why do I have food cravings? Am I just weak-willed? Am I doomed to always crave sweets and gain weight?

Provider: Good questions! Your brain does cause you to crave sweets and other high energy foods. It's a survival mechanism. Your brain rewards you with feelings of pleasure and a good mood if you eat these foods. The good news is there are some things you can do: For example, you may crave sweets less with a low carbohydrate diet. There are also some medications that may help some.

The CNS reward center plays a major role in appetite regulation by rewarding eating. The mesolimbic dopamine reward path, an important component of the reward pathway, links the back of the brain to the front (Bardo, 2013). It runs from the ventral tegmental area (VTA) to the nucleus accumbens. The pathway is driven by the neurotransmitters dopamine and serotonin.

When we eat, dopamine and serotonin are released, which is pleasant and therefore reinforcing. Reinforcement happens early during the eating process, in response to seeing, smelling, tasting, and chewing of food, as opposed to later, during digestion. Neurological appetite responses also occur



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when a person encounters something they associate with eating rewarding food, such as an image ofa favored food, especially high calorie or high-fat food.

DopamineDopamine is the main neurotransmitter used by the reward pathway. Functions include:

• Reward (motivation) • Pleasure, euphoria • Compulsion

• Craving • Perseveration • Fine motor function

(Bardo, 2013)

SerotoninSerotonin plays a role in many brain processes including:

• Mood • Appetite • Cognition & memory

• Body temperature regulation • Sleep

(Bardo, 2013)

CLINICAL APPLICATIONS:In the FDA-approved weight loss medication bupropion/naltrexone, bupropion is a weak inhibitor of dopamine reuptake, which activates the satiety-producing POMC neurons in the hypothalamus (Apovian et al., 2015; Takeda, 2014). Naltrexone blocks opioid receptors throughout the CNS.

Selective serotonin reuptake inhibitor (SSRI) antidepressants have been used with some effectiveness in treating binge eating disorder and bulimia (Sim et al., 2010).

REWARD BRAIN REGIONSAreas of the brain involved in the reward and emotional pathways that affect feeding and body mass include:


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Nucleus AccumbensAction in reward pathway: Involved with reward, cravings, and addiction - pleasure center.

(Lenard, Berthoud, 2008)

HippocampusAction in reward pathway: Encoding and storage of explicit memory (conscious memory) and learning. Vital for conscious, logical, and cooperative social functioning.

(Cozolino, 2010)

AmygdalaAction in reward pathway: Generates dread, anxiety, and fight-or-flight impulse. When activated, asin states of distress and fear, produces difficulty being rational, logical, and in control of self (Cozolino, 2010).

• Mechanism of action: Controls locus coeruleus, a primary location for norepinephrine synthesis.

• Stimulated by: Norepinephrine and sympathetic stimuli

(Cozolino, 2010)

QUIZ: CNS HORMONES & BRAIN STRUCTURESMatch the following CNS hormones and brain structures to their function in feeding, energy, or body mass regulation. Make your selection by clicking on each drop down menu:

1. Nucleus Accumbens • Suggested Answer: Decreases energy expenditure & oxygen consumption • Feedback: NPY decreases energy expenditure & oxygen consumption, as well as

decreasing thyrotropin releasing hormones.



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2. Neuropeptide Y (NPY) • Suggested Answer: Increases arousal & food seeking • Feedback: Orexin A & B increases arousal and food seeking, and is inhibited by leptin.

3. Proopiomelanocortin (POMC) • Suggested Answer: Promotes satiety • Feedback: Stimulated by serotonin, leptin, and insulin, POMC promotes satiety.

4. Orexin A & B • Suggested Answer: Involved with reward, cravings, & addiction • Feedback: The Nucleus Accumbens acts as a pleasure center, involved with reward,

cravings, & addiction.

GUT HORMONES

OVERVIEW

• Stomach & Small Intestine Hormones:• Orexigenic Gut Hormone leads to weight gain and food

intake. Ghrelin is the main hormone in this category. • Anorexic Gut Hormones leads to weight loss by producing

feelings of satiety. Multiple hormones are involved, such as cholecystokinin (CCK), glucagon-like peptide (GLP-1), and peptide YY (PYY)

(Kim et al., 2011; Cummings & Overduin, 2007)

• Pancreatic Hormones:• Pancreatic Polypeptide (PP) slows gastric emptying • Amylin reduces meal size and food intake • Insulin lowers blood glucose. Increases uptake of glucose into muscle, adipose, and

other tissues except when an individual has developed insulin resistance. • Glucagon raises blood glucose (in opposition to insulin), increases energy

expenditure, and reduces appetite.

(Suzuki, et al., 2011; Woods, et al, 2006; Tattikota, et al., 2014)

• Liver Hormone:• Fibroblast Growth Factor increases energy expenditure (Woo, et al., 2013) • Fetuin-A elevated in obesity; impairs glycemic control (Trepanowski et al, 2015)

GUT HORMONES AND HUNGER

Orexigenic (weight gain) Hormones - A Signal to EatThese gut hormones are perceived by the body as a signal to eat (hunger) or to store calories as fat (Cummings & Overduin, 2007, Furguson, 2014).

Ghrelin A gut hormone that increases eating and thus, contributes to weight gain. Surges prior to meals and increases with time since the last meal. Rapidly suppressed by nutrient intake, especially


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carbohydrates. Note that ghrelin is not the only hormone involved in producing hunger: A decrease in leptin, which is made by adipose tissue, also signals increased hunger.

GHRELIN ACTION:

Increases food intake, gut motility, generation of fat, and weight gain. Inhibits the opposite effects.

GHRELIN CNS MECHANISM:

Via NPY and AgRP neurons

GHRELIN PERIPIHERAL MECHANISM:

Via vagus afferent nerves. Decreases insulin.

CLINICAL APPLICATION:An FDA-approved device is implanted under the skin with electrodes to the stomach region. It blocks vagus nerve signals which were stimulated by these gut hormones.

CLINICAL RELEVANCE:Ghrelin is increased in Prader-Willi Syndrome, a genetic syndrome characterized by constant hunger and obesity.

GHRELIN EFFECT OF WEIGHT LOSS:

Ghrelin response increases with non-surgical weight loss, leading to increased hunger.

GHRELIN CLINICAL APPLICATIONS:1) Weight loss gets increasingly difficult as more weight is lost; 2) Attempts to block or control ghrelin pharmacologically have not worked to date.

GHRELIN PRODUCED IN:

The gastric fundus and proximal small intestine.

GHRELIN CLINICAL APPLICATION:The fundus of the stomach is removed in gastric sleeve weight loss surgery which reduces the amount of tissue producing ghrelin; therefore ghrelin is especially reduced with this surgery.


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GHRELIN SECRETED IN RESPONSE TO:

• meal times • habits • and potentially nutrient sensors

GHRELIN EFFECT OF OBESITY:

The normal postprandial fall in ghrelin is suppressed in obesity, and thus there is less decrease in hunger in response to a meal.

(Ferguson, 2014; Kim et al., 2011; Cummings & Overduin, 2007)

PRACTICE TIPThe higher response to ghrelin after weight loss can be counteracted with a higher plant based diet orincreasing satiety through a ketogenic diet (Blackburn, 2004a,b)

GUT HORMONES AND SATIETY

Anorectic (Weight Loss) Gut Hormones - A Signal to Stop EatingThe anorexic effects of gut hormones signal fullness or satiety. Satiety involves a more complicated system than appetite stimulation. Characteristics of anorectic gut hormones include:

ACTIONS: Anorectic gut hormones increase satiety, especially PYY, CCK, and also GLP-1. Most anorectic gut hormones (CCK, GLP-1, OXM, PYY) delay gastric emptying (Ferguson, 2014).

• Effect of Obesity: Obese persons produce less anorectic gut hormones and thus feel less satiety. For example, PYY normally increases in response to a meal leading to feeling less hungry, but this response is blunted in obesity.

• CNS Mechanism: Anorectic gut hormones act via MSH, POMC and CART to mediate satiety

(Ferguson, 2014)

• Peripheral Mechanism: Two of the anorectic gut hormones, GLP-1 and PYY, delay emptying of the ilium ("ileal brake")

(Ferguson, 2014)

CLINICAL APPLICATION:Delayed emptying → More gut nutrients/lipids→ satiety →diabetes control & weight loss. This is the mechanism for several weight loss and antidiabetes medications.

Weight-loss surgery reduces the ileal "brake" thus decreasing transit time, leading to hypoglycemic hyperinsulinemia


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The Anorectic Gut HormonesProduced in Proximal Small Intestine

• Cholecystokinin (CCK): Produces short acting satiety; peaks quickly • Glucose-Dependent Insulinotropic Peptide (GIP): Promotes nutrient storage rather than satiety

Produced in Distal Small Intestine/Colon

• Glucagon-Like Peptide-1 (GLP-1): A potent antihyperglycemic hormone • Dipeptidyl Peptidase-4 (DPP-4): Degrades GLP-1 • Oxyntomodulin (OXM): Lessens hunger. Reduced buffet meal intake • Peptide YY (PYY): Reduces appetite

(Cummings & Overduin, 2007; Kim et al., 2011; Ferguson, 2014)

Other hormones with anorectic effects1) Leptin, secreted in adipose tissue also is anorectic.

2) The orexigenic hormone from the stomach, ghrelin, has an anorectic effect when levels are low.

PROXIMAL SMALL INTESTINE

Anorectic hormones produced in the proximal small intestine

Cholecystokinin (CCK)ACTION: Produces short acting satiety; peaks quickly

• Produced by: I cells in duodenum/jejunum • Stimulated by: Dietary fat, proteins and gastric distention • CNS Mechanism: CCK2 acts via the Arcuate Nucleus of the hypothalamus • Peripheral Mechanism: CCK 1 acts mostly in GI tract

CLINICAL APPLICATION:Attempts at modulating CCK pharmacologically fail because of more frequent eating in compensation.

(Ferguson, 2014)

Glucose-Dependent Insulinotropic Peptide (GIP)Secretion responds to calorie density of glucose and lipids

ACTION: Promotes nutrient storage rather than satiety

• Secreted in: Proximal small intestine by K cells • Peripheral Mechanism: Acts via incretin-mediated insulin release • Effect of Obesity: Elevated chronically in obesity and further increased by weight-loss diet


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CLINICAL APPLICATION:May be reduced after gastric bypass surgery

(Cummings & Overduin, 2007; Kim, 2011; Ferguson, 2014)

DISTAL SMALL INTESTINE AND COLON

Anorectic hormones produced in the distal small intestine and L cells inthe colon

Glucagon-Like Peptide-1 (GLP-1) (an Incretin)ACTION: A potent antihyperglycemic hormone

• Stimulated by: Triglycerides/fats in the small intestine; also in response to proteins and carbohydrates

• CNS Mechanism: Acts via the Arcuate Nucleus of the hypothalamus • Peripheral Mechanism: Delays gastric emptying, suppresses glucagon and enhances insulin

release

GLP-1 CLINICAL APPLICATION:

• A GLP-1 agonist that is FDA-approved for treatment of both diabetes and obesity is liraglutide (Victoza for diabetes; Saxenda for obesity)

• Example GLP-1 agonist that is FDA-approved for diabetes but not FDA approved for treatmentof obesity is exenatide (Byetta)

• Increased post-gastric surgery, especially bypass surgery

(Apovian et al., 2015; Ferguson, 2014)

Dipeptidyl peptidase-4 (DPP-4)ACTION: Degrades GLP-1 CLINICAL APPLICATION:DPP-4 inhibitors are weight-neutral oral hypoglycemics approved for type 2 diabetes, e.g. sitagliptin (Januvia™) and saxagliptin (Onglyza™). They prolong the action of incretins via GLP-1 and GIP.

(Davidson, 2010; Apovian et al., 2015; Ferguson, 2014)

Oxyntomodulin (OXM)ACTION: Lessens hunger. Reduced buffet meal intake CLINICAL APPLICATION:

• No associated medications have been developed. • Increased post-gastric bypass surgery


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(Cummings & Overduin, 2007; Ferguson, 2014)

Peptide YY (PYY)ACTION: Reduces appetite

• Released in response to: Eating • Peripheral Mechanism: Delays gastric emptying (like GLP-1) and intestinal transit • CNS Mechanism: May act via the Arcuate Nucleus of the hypothalamus

CLINICAL APPLICATION:

• PYY reduced buffet meal intake without compensatory increased eating frequency in studies. Giving PYY centrally may increase food intake. No associated medications have been developed.

• Increased after gastric surgery, especially bypass surgery

(Kim et al., 2011; Ferguson, 2014)

FOOD INFLUENCES ON GUT HORMONESMs. Clements: Is there anything I can do so I won't feel so hungry when I try to lose weight,

like just eating meat?

Provider: The type of food you eat can make some difference, but your body needs some of the basic nutrients, fat, carbohydrate, and protein. For some people, a diet that is low carbohydrate and alittle higher in protein can decrease hunger.

Types of food ingested affect hunger in various ways via the gut hormones. Regions of the gut most affected are the small intestine and L cells of the colon. The three main categories of macronutrients, lipids, proteins, and carbohydrates, increase satiety via the following hormones:

Biological response to:

EATING LIPIDS

CHOLECYSTOKININ (CCK)

Short acting, peaks quickly in terms of increasing satiety.

GLUCAGON-LIKE PEPTIDE-1 (GLP-1)

Delays gastric emptying, suppresses glucagon and enhances insulin release.

PEPTIDE YY (PYY)

Delays gastric emptying (like GLP1) and intestinal transit. May also inhibit NPY/AGRP.



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EATING PROTEINS

CCK

Short acting, peaks quickly in terms of increasing satiety.




EATING CARBOHYDRATES




Notes:

A very low carbohydrate/high-fat diet produces more satiety than a very low-fat diet

GLP-1 is stimulated by all three types of nutrients, carbohydrates, lipids, and proteins. It is targeted inboth anti-obesity and anti-diabetic drugs.


PANCREATIC HORMONES – BETA CELLS

Pancreatic HormonesPancreatic hormones play a complicated role in regulation of food intake and fat mass. Hormones produced in the pancreatic beta cells include the following:

Amylin - made in beta cellsACTION: Reduces meal size and food intake PERIPHERAL MECHANISM: Inhibits gastric emptying and inhibits glucagon CLINICAL APPLICATION: Synthetic amylin (pramlinitide) is FDA-approved for diabetes treatment (lowers glucose/body weight). Not approved for treatment of obesity.

(Woods et al., 2006; Ferguson, 2014; Apovian et al., 2015)


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Insulin - made in beta cellsACTION:

1. Lowers blood glucose levels 2. Increases glucose storage by muscle, adipose, and liver except with insulin resistance 3. Increased hunger and food intake 4. Increased pleasure from sweets 5. In the CNS:

• Decreases energy intake by decreasing drive for food intake • Decreases pleasure response to food

(Isganaitis, et al., 2005; Banks, et al., 2006).

STIMULATED BY: High blood glucose. Influenced by other hormones: Increased by GIP, GLP-1, amylin DECREASED BY: Fibroblast growth factor 21 (FGF21) produced in the liver CNS MECHANISM: Anorexigenic effect on arcuate nucleus PERIPHERAL MECHANISMS:

• Increases glucose uptake in liver and muscle, production of glycogen, and amino acid uptake to produce proteins

• Inhibits gluconeogensis by inhibiting hormone sensitive lipase and protein conversion

EFFECT OF OBESITY: Increased insulin levels, which is a potent hunger trigger, in response to increased fat mass/insulin resistance EFFECT OF WEIGHT LOSS: Decreases with weight loss along with CCK, leptin, and PYY, making satiety more elusive

(Tattikota et al., 2014; Ferguson, 2014)

Note: The pancreas has cannabinoid-1 receptors, along with adipose tissue, liver, muscle, and thyroid.

OTHER PANCREATIC HORMONESPancreatic hormones play a complicated role in the regulation of food intake and fat mass. Hormonesproduced in the pancreatic cells other than the beta cells include the following:

Pancreatic Polypeptide (PP) - made in F islet cellsACTION: Slows gastric emptying STIMULATED BY: Caloric load CNS MECHANISM: Acts on Y4 receptor on NPY/AgRP neurons EFFECT OF OBESITY: Reduced levels Peripheral administration: decreases feeding short and long term; Central administration increases feeding


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CLINICAL APPLICATIONS:1) Vagotomy reduces its anorectic effect; 2) No associated medications at this time

(Suzuki et al., 2011; Ferguson, 2014)

Glucagon - made in alpha cellsACTION: Raises blood glucose (opposite to insulin), increases energy expenditure, and reduces appetite STIMULATED BY: Low glucose; inhibited by high glucose PERIPHERAL MECHANISM: Stimulates gluconeogenesis in liver CLINICAL APPLICATION: Mechanism by which glucose is obtained in very low carbohydrate diets.

(Suzuki et al., 2011; Ferguson, 2014)

LIVER HORMONE EFFECTS

Liver Hormones

Fibroblast growth factor 21 (FGF21)ACTION: Increases energy expenditure PERIPHERAL MECHANISMS:

• Decreases insulin level • Decreases gluconeogenesis

• Stimulates glucose uptake by adipocytes but not other tissues • Increases fat utilization and lipid excretion in animals

(Woo et al., 2013; Ferguson, 2014)

Fetuin-AACTION: A binding protein. Elevation causes impaired glucose control. Also secreted by adipocytes PERIPHERAL MECHANISMS:

• Plays a role in insulin resistance induced by free fatty acids

• Elevated in Type 2 diabetes mellitus, nonalcoholic fatty liver disease, and metabolic syndrome• Increased in obesity • Potential marker for obesity-related complications

(Trepanowski et al., 2015)


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QUIZ: GUT HORMONES Match the following gut hormones to their function. Make your selection by clicking on each drop down menu:

Response:1. Ghrelin

• Suggested Answer: Increases eating, and thus contributes to weight gain • Feedback: Increases food intake, gut motility, generation of fat, and weight gain.

Produced in the gastric fundus and proximal small intestine. 2. Cholecystokinin (CCK)

• Suggested Answer: Produces short-acting satiety; peaks quickly • Feedback: Stimulated by dietary fat, proteins and gastric distention, CCK produces

short acting satiety and peaks quickly. Produced in proximal small intestine. Produced in distal small intestine and L cells in the colon.

3. Pancreatic Polypeptide (PP) • Suggested Answer: Slows gastric emptying • Feedback: Stimulated by caloric load, PP slows gastric emptying. Produced in f islet

cells. 4. Glucagon-Like Peptide-1 (GLP-1)

• Suggested Answer: Potent antihyperglycemic hormone • Feedback: A potent antihyperglycemic hormone that is stimulated by triglycerides/fats

in the small intestine (also stimulated by proteins and carbohydrates). 5. Amylin

• Suggested Answer: Reduces meal size and food intake • Feedback: Reduces meal size and food intake and inhibits both gastric emptying and

glucagon. Produced in pancreatic beta cells

ADIPOCYTE HORMONESProvider: Another reason it is difficult to lose excess weight is that the fat itself makes hormones thatend up making you hungrier.

Ms. Clements: I didn't know that! That motivates me even more to lose it!

Cytokines secreted by abdominal adipose cells and macrophages in adipose tissue alsocontribute to the low-level inflammation associated with obesity. (Gammone & D'Orazio, 2015).

Leptin The main hormone secreted by adipose tissue affecting fat deposition.


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LEPTIN ACTION:

An anorectic hormone, meaning decreased food intake and increased energy expenditure. However, the anorectic effect is weak. Leptin's most important action occurs when it is low and triggers feeding.High levels of leptin do not confer high levels of satiety.

LEPTIN CNS MECHANISM:

Activates anorectic pathways (CART and POMC in the arcuate nucleus); inhibits orexigenic CNS neurons (AgRP and NPY), which reduces energy intake.

LEPTIN PERIPHERAL MECHANISM:

Decreases ghrelin. Exhibits lypolysis activity.

LEPTIN EFFECT OF OBESITY:

Increases circulating leptin proportional to amount of fat mass, decreases response to exogenous leptin. Leptin exhibits "resistance" resembling insulin resistance. That is, it becomes less effective at reducing hunger and ghrelin.

(POTENTIAL) CLINICAL APPLICATION: Leptin's lypolysis activity is inhibited by insulin and increased by catecholamines, phosophodiesterase inhibition (caffeine, thyroid hormone), glucagon, testosterone, growth hormone, adiponectin, and HCG. Potential ways to control these factors and thus help with weight control include:

• Use of adrenergic agents • Use of caffeine • Optimizing thyroid function • Reducing insulin • Avoiding beta blockers

LEPTIN EFFECT OF WEIGHT LOSS:

Dieting and weight loss decrease leptin levels, producing more hunger and less satiety.

(Apovian et al., 2015; Stanley, 2005; Westman, 2014)

Adiponectin

ACTION:

An anorexigenic hormone (reduces eating and produces weight loss).

ADIPONECTIN CNS MECHANISM:

Insulin-sensitizing.


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ADIPONECTIN PERIPHERAL MECHANISM:

Increases lipolysis (increased triglyceride uptake and fatty acid oxidation, decreased gluconeogenesis).

ADIPONECTIN EFFECT OF OBESITY:

Decreases adiponectin levels proportionally to the amount of fat mass.

(Lindberg et al., 2014; Westman, 2014)

(POTENTIAL) CLINICAL APPLICATION: Low levels are associated with Type 2 diabetes mellitus.Inflammation may decrease serum adiponectin levels. Effective treatment of inflammation may raise adiponectin levels (Cansu et al., 2011).

Resistin

ACTIONS:

Raises LDL, plays a role in the inflammatory response, may play a role in insulin. Secreted in adiposetissue in rodents, endothelial and immune cells in primates.

PERIPHERAL MECHANISM:

Increases pro-inflammatory cytokines (e.g., interleukins, TNF, intracellular and vascular cell adhesion molecules).

EFFECT OF OBESITY AND DIABETES:

Increased levels in obesity and Type 2 diabetes mellitus.

CLINICAL RELEVANCE: May be part of a link between chronic inflammation and insulin resistance.

(Westman, 2014)

Uncoupling Protein (UCP1)

ACTIONS:

Induction leads to the oxidation of fatty acids and heat production in abdominal white adipose tissue (WAT).

(Gammone & D'Orazio, 2015)

CLINICAL RELEVANCE: Fucoxanthin, a carotenoid derived from plants, induces UCP1 activity. Fucoxanthin improves insulin


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resistance and decreases blood glucose by regulating WAT cell cytokine secretion. Potential as a nutritional additive for weight loss treatment.

QUIZ: ADIPOCYTE HORMONESMatch the following Adipocyte hormones to their function. Make your selection by clicking on each drop down menu:

Response:1. Letpin

• Suggested Answer: The main hormone secreted by adipose tissue affecting fat deposition

• Feedback: Leptin is the main hormone secreted by adipose tissue and triggers feeding when low.

2. Adiponectin • Suggested Answer: An anorexigenic hormone, reducing eating and producing weight

loss • Feedback: An anorexigenic hormone that is insulin-sensitizing and increases lipolysis.

3. Resistin • Suggested Answer: Raises LDL and may play a role in insulin resistance • Feedback: Raises LDL, plays a role in the inflammatory response, and may play a role

in insulin resistance.

CANNABINOID SYSTEM

Ms. Clements

Ms. Clements: My husband and I sometimes smoke a little marijuana. Is it true that it increases appetite? It sure seems to have that effect on me!

Provider: Yes. It actually does cause changes in chemicals in your brain that signal you to eat more. So, reducing or stopping marijuana would be likely to support your weight-loss efforts.

Endocannabinoids (endogenous cannabinoids) act both centrally and peripherally.

• In the CNS, endocannabinoids increase appetite and produce craving of palatable food (Davis& Perkins, 2007).

• Peripherally, endocannabinoids increase lipogenesis, size of adipocytes, insulin resistance, and dyslipidemia and decrease adiponectin.

Anandamide An endogenous cannabinoid neurotransmitter that stimulates appetite


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ACTION:

Has an orexigenic effect (increased appetite) and decreases satiety

CNS MECHANISM:

Acting in the hypothalamus, mesolimbic system. Its actions are similar to THC, which is found in marijuana.

• via CB1 receptors are found in high amounts in CNS reward centers, such as the Nucleus Accumbens

• Appetite stimulation (orexigenic) • Reward, euphoria and motivational processes

(Pagano, 2008)


Blunts the vagus nerve's satiety signal. Increases lipogenesis. Produces insulin resistance.

PRODUCED:

Multiple pathways, including a pathway associated with fat digestion

• via CB2 receptors found in GI, adipose, liver, muscle, thyroid, heart, & pancreas

• Immunosuppressant • Anti-inflammatory

CLINICAL APPLICATION: Mechanism of weight-loss drug Rimonobant (Acomplia), which was withdrawn from the market

(Pagano, 2008; You, 2011; Iversen, 2008; Gieringer, 2008)

Research: Cannabinoids target the same receptors in the hypothalamus as THC in marijuana, the pro-opiomelanocortin (POMC) neurons, increasing the appetite (Koch et al., 2015). Cannabinoids block POMC neurons, which normally suppress the appetite via α melanocyte stimulating hormone (α-MSH), and direct POMC neurons to stimulate appetite instead (Koch, et al., 2015). POMC neuronsalso encode opioid peptide β-endorphin. The opioid antagonist, naloxone, blocks acute cannabinoid receptor-induced feeding. Further research is needed to understand their actions in humans.

DID YOU KNOW?Although no currently approved weight-loss medications address the cannabinoid system, it may be atarget for future pharmacological interventions. Furthermore, use of cannabinoids is widespread and so their orexigenic properties should be considered when treating obese patients who use them.

QUIZ: CANNABINOIDSThe endogenous cannabinoid, anandamide, is: (Check all that apply)


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Response:1. Orexigenic

• Feedback: Correct! Endocannabinoids such as anandamide have an orexigenic effect (increase appetite) and decrease satiety.

2. Anorexigenic • Feedback: Incorrect. Endocannabinoids such as anandamide act both centrally and

peripherally, have an orexigenic effect, and decrease satiety. 3. Centrally acting

• Feedback: Correct! Endocannabinoids such as anandamide act in the CNS to increaseappetite and produce cravings of palatable foods.

4. Peripherally acting • Feedback: Correct! Endocannabinoids such as anandamide act peripherally by

increasing lipogenesis, size of adipocytes, insulin resistance, and dyslipidemia, as well as decreasing adiponectin.

RECAP OF THE BIOLOGY OF APPETITECNS Appetite Regulation and Reward Pathways: The CNS, especially the hypothalamus and brainstem, works with signals from the gastrointestinal system to up-regulate or down-regulate food intake and body-fat mass. Two main pathways control this process:

• Orexigenic pathway: Leads to weight gain and food intake. Key hormones: Neuropeptide Y (NPY) & Agouti-related protein (AgRP)

• Anorexigenic pathway: Leads to weight loss, satiety, and decreased food intake. Key chemicals: Propiomelanocortin (POMC) & Cocaine and Amphetamine Regulated Transcript (CART)

• Reward center: Key biochemicals: Serotonin and dopamine

Gut Hormones: Hormones secreted by the stomach, small and proximal large intestines, pancreas, and liver affect body mass through regulating food intake and energy storage and use.

• Stomach & Small Intestine Hormones: Orexigenic gut hormones that lead to weight gain and food intake. Key hormone:

• Ghrelin - increases eating and thus, contributes to weight gain. Surges prior to meals and increases with time since the last meal. Rapidly suppressed by nutrient intake, especially carbohydrates.

• Anorexic Gut Hormones leads to weight loss by producing feelings of satiety. Multiple hormones, such as cholecystokinin (CCK), glucagon-like peptide (GLP-1), and peptide YY (PYY) (Kim et al., 2011; Cummings & Overduin, 2007)

• Pancreatic Hormones:Pancreatic Polypeptide (PP) slows gastric emptying • Amylin reduces meal size and food intake • Insulin lowers blood glucose. Increases uptake of glucose into muscle, adipose, and

other tissues except with insulin resistance. • Glucagon raises blood glucose (opposite to insulin), increases energy expenditure,

and reduces appetite.(Suzuki, et al., 2011; Woods, et al, 2006; Tattikota, et al., 2014)


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Liver Hormone: Fibroblast Growth Factor increases energy expenditure (Woo, et al., 2013)Fetuin-A elevated in obesity, which impairs glycemic control (Trepanowski et al, 2015)

Adipocyte Hormones: The body's fat mass acts like an endocrine organ to secrete hormones affecting fat deposition. Key hormone:

• Leptin - An anorectic hormone, meaning decreased food intake and increased energy expenditure. However, the anorectic effect is weak. Leptin's most important action occurs when it is low and triggers feeding. High levels of leptin do not confer high levels of satiety.

Cannabinoid System: This system, by working in the CNS and peripherally, works to stimulate appetite.

WEIGHT LOSS PHARMACOTHERAPY

SECTION TOPICS• Which patients meet criteria for weight-loss medication • The need for comprehensive weight-loss treatment in conjunction with weight-loss medication • Selecting weight-loss medications based on the pharmacological profile • Potential side effects and effectiveness of FDA-approved weight-loss medications.

Treatment Protocol Step: Discuss the option of prescribing medications to support a comprehensiveweight-loss program, if indicated.

MS. CLEMENTS

Ms. Clements has a history of being moderately successful with a weight loss attempt, reaching a weight plateau, and then regaining most of her weight. She wants to try again but asks about pharmacotherapy.

Would pharmacotherapy help her be more successful in her weight loss?

Pharmacotherapy that targets the biological processes affecting food intake, energy expenditure, andfat deposition can be an adjunct to comprehensive lifestyle interventions for weight loss.

The following section highlights some of the significant prescribing information for FDA-approved weight-loss medications, but current medication information guides should be consulted before prescribing. Weigh the potential risks of the medication being considered against the potential benefits of successful weight loss for the individual patient.

How Pharmacotherapy HelpsWeight-loss pharmacotherapy is used as an adjunct to a comprehensive weight lossplan. These medications may help patients who are struggling with weight loss byinterrupting biological adaptations to obesity that help perpetuate the condition.

Patients taking the medications typically experience additional weight loss of around2.9% to 8.6% compared to those who do not take the medications. The added weight


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loss may make a difference in terms of encouraging patients that have previously had unsuccessful weight-loss attempts.

The effects of these medications on underlying physiology are typically sustained only as long as theyare taken (Apovian et al., 2015). Gradual weight gain tends to occur when the medications are stopped.

NOTE THAT:• A restricted-calorie diet, increased physical activity, and psychosocial support must be used

along with pharmacotherapy. The greater the lifestyle change, the greater the weight loss (Apovian et al., 2015; WIN, 2013).

• Small, sustained weight changes of around 5% or more can have a measurable effect on some aspects of health, especially cardiovascular and blood sugar.

• Side effects are often experienced.

PRACTICE TIPWeight should be treated at the same time as comorbidities in order to help ameliorate the comorbidities. This may, in turn, improve physical functioning and allow for greater physical activity, thereby adding a small increase to weight loss.

INDICATIONS FOR PHARMACOTHERAPY VS OTHER TREATMENTS

PHARMACOTHERAPY INDICATIONPharmacotherapy for weight loss is indicated in:



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• Obese patients with a BMI ≥30 • Overweight patients with a BMI ≥27 and at least one comorbidity, such as hypertension,

dyslipidemia, diabetes mellitus type 2, andobstructive sleep apnea.

(Jensen et al., 2013; Apovian et al., 2015)

Additionally, for patients who meet the qualifications above, they must also:

• Be willing to take the medication in addition to a reduced-calorie diet and increased exercise • Have a realistic understanding of potential weight loss with medication • Have been unable to lose weight despite serious attempts at diet, exercise, and behavioral

changes

(WIN, 2013)

CAUTION TIPContraindication for all weight-loss medications: Do not use any of these weight-loss medications with pregnant women or women who are breastfeeding.

PHARMACOLOGICAL GUIDELINESThe Pharmacological Management of Obesity(Apovian, 2015) by the Endocrine Society, works together with the AHA/ACA/TOS Guideline for the Management of Overweight and Obesity (Jensen, 2013) to complete a current set of guidelines for obesity management.

QUIZ: CONSIDERING QUALIFICATIONSWhich patient scenario falls within the guidelines for pharmacotherapy consideration?

Choose one1. Sally still has a BMI of 32 kg/m2, despite changing her diet, exercising, and going to a weight-

loss program. • Feedback: Correct! Pharmacotherapy is indicated for all patients having a BMI ≥30

kg/m2. 2. Wanda is currently pregnant, but is classified as obese.

• Feedback: Incorrect. Weight-loss medication should not be used by pregnant women.

3. Ted has a BMI of 28 kg/m2 and no weight-related comorbidities. He wants to take a weight-loss medication to avoid having to "go on a diet."

• Feedback: Incorrect. With a BMI between 27 and 30 kg/m2, pharmacotherapy is indicated only when there is at least one weight-related comorbidity. Furthermore, he does not understand that with weight-loss pharmacotherapy, you still need to make a long term change in your diet.

4. John has a BMI of 25 kg/m2 and has been unable to lose weight with dietary change alone.

• Feedback: A BMI of 25 kg/m2 is below the cut points for pharmacotherapy.


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IS PHARMACOTHERAPY APPROPRIATE FOR MS. CLEMENTS?Ms. Clements falls within the criteria for considering weight loss pharmacotherapy by virtue of:

1. having a BMI of 31 mg/kg2, and 2. having tried a standard approach to weight loss without success.

Provider: You wanted to discuss weight-loss medications as a treatment option?

Ms. Clements: Yes, I changed my eating habits with the help of a dietitian and lost some weight, but then I couldn't seem to lose more. Eventually, I returned to some of my old eating patternsand regained most of the weight. I thought medication might help kick-start weight loss again.

Provider: You do meet the medical criteria for weight-loss medications and they can be of help, but you will still have to diet and exercise. A weight-loss program might be a good idea since you already worked with a dietitian.

QUIZ: DISCUSSING PHARMACOTHERAPYDiscussion Topics: What topics should be discussed with patients when initiating pharmacotherapy for weight loss?

Response:

SUGGESTED ANSWER: Topics such as how the medication works, side effects, expected weight loss, and long-term effectiveness should be reviewed with the patient.

TALKING ABOUT MEDICATIONS

MS. CLEMENTSThe provider responded to Ms. Clements' question about how weight-loss pharmacotherapy works. What other information should the provider provide about weight-loss pharmacotherapy?

Advise patients for whom a weight-loss medication is being considered of the following:

• How the medication works • Expected and possible side effects • The weight-loss expectations for the weight-loss medication. They typically add 3 to 5%

weight loss to whatever weight loss is achieved through diet and physical activity lifestyle change.

• Burden and cost of medications


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• That you will be monitoring their progress on the pharmacological treatment for weight loss. The weight reduction should be seen by 6 months, if it is going to be effective.

• That after stopping weight-loss medication, weight regain is a common occurrence, unless they develop lasting lifestyle changes.

(WIN, 2013; Apovian et al., 2015)

Patient preferences and opinions should also be considered.

Similarly, before replacing medications that might cause weight gain or loss, this should be discussedwith patients along with possible alternatives.

PRACTICE TIPA key component of weight-loss treatment is determining what your patients have tried in the past. Consider both successes and failures, including prescriptions possibly obtained illegally or weight-loss supplements.

CURRENT WEIGHT LOSS MEDICATIONS

OverviewCurrently, several medications are FDA-approved forweight loss. Most act through central and peripheraleffects on appetite, hunger, satiety, and response to foodcues to improve adherence to a weight-loss diet. Forexample, one medication blocks fat absorption, as wellas reinforces avoidance of high-fat foods.

The current FDA-approved medications are thefollowing:

• ORLISTAT: LIPASE INHIBITOR.

Blocks absorption of fat.

• LORCASERIN: SEROTONIN RECEPTOR AGONIST.

Increases feeling of fullness.

• PHENTERMINE/TOPIRAMATE: COMBINATION ANORECTIC AND ANTICONVULSANT MEDICATION.

A combination of the anorectic medication, phentermine, and the anticonvulsant, topiramate, may help avoid the compensation by the brain seen when medications target a single pathway. Phentermine acts to decrease the appetite – topiramate also decreases the appetite and mimics the satiety effects of leptin.



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• BUPROPION/NALTREXONE: COMBINATION ANTIDEPRESSANT AND OPIOID RECEPTOR BLOCKER.

A combination of the antidepressant medication, bupropion, and the opioid receptor blocker, naltrexone, may help avoid the compensation by the brain seen when medications target a single pathway. The combination of these medications was approved for weight loss in September 2014.

• LIRAGLUTIDE: GLP-1 AGONIST.

Has dual benefit of weight loss and glycemic control. Approved for weight loss in December, 2014.

• Sympathoamines have been approved for weight loss for many years. They include: Phentermine, diethylpropion, phendimetrazine, benzphetamine and act by increasing satiety. Side effects include those of stimulants including tachycardia and high blood pressure (Bays, 2018)

(Huizinga, 2007; Domecq et al., 2015; Apovian et al., 2015; )

Other medications are in the pipeline for approval.

CAUTION TIPS• Short-term use medications, such as phentermine and diethylpropion, are approved, but their

safety and effectiveness long-term is not yet known (Apovian et al., 2015). • The Endocrine Society's guidelines made a strong recommendation against using these

medications in patients with uncontrolled hypertension or a history of heart disease, including advanced arteriosclerosis or coronary artery disease (Apovian et al., 2015).

INITIATING AND CONTINUING PHARMACOTHERAPY

Recommendations for Initiating PharmacotherapyGuidelines suggest dose escalation based on efficacy and tolerability,but not exceeding the approved upper dose limit (Apovian et al.,2015).

Recommendations for Ongoing Management ofPharmacotherapy

GUIDELINES FOR PHARMACOLOGICAL WEIGHT-LOSS TREATMENTGuidelines recommend the following approach to pharmacological weight-loss treatment:

• Monthly or more frequent assessment for efficacy and safety and adherence to weight-loss programs for the first 3 months, then at least every 3 months

• At 3 months, continue if safe and at least 5% weight loss has been achieved. Otherwise, discontinue and consider alternatives or improving lifestyle change/behavioral supports.


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• If there are no clinical improvements on weight-loss pharmacotherapy after 12 weeks, consider switching to another treatment. Alternatively, the dose may need to be increased, but the maximum dose should not be exceeded.

• For best results, include lifestyle change therapy in diet and physical activity with weight loss pharmacotherapy.

(Apovian, 2015; Jensen et al., 2013)

Provider: Weight-loss medication, in combination with a diet and exercise program, can help a little by influencing some of the biological factors we have been talking about.

Ms. Clements: And then I should start to see some weight loss?

Provider: We will be evaluating your progress for the first three months and then, if we do not see at least a 5% weight loss, we will consider other options.

POLL: PHARMACOTHERAPY PRESCRIBED?Question: Among your patients who are overweight / obese, for approximately what percentage do you currently prescribe weight-loss medication?

1. 0%• 40% (36 votes)

2. 1-10%• 32% (29 votes)

3. 11-20%• 9% (8 votes)

4. 21-30%• 7% (6 votes)

5. 31-40%• 2% (2 votes)

6. 41-50%• 3% (3 votes)

7. More than 50%• 0% (0 votes)

8. Not sure• 7% (6 votes)

Total votes: 90

WEIGHT LOSS SUPPLEMENTSMany people trying to lose weight turn to dietary supplements that claim to promote weight loss. These include products marketed as "appetite suppressants", thermogenic products/"fat burners", and digestion inhibitors. The National Center for Complementary and Integrative Health reviewed common weight-loss supplements with the following findings (NCCIH, 2016):


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• Many of these supplements (fish oil, green tea extracts, Chinese herbs, and others) have not been scientifically proven to affect weight loss.

• Weight loss supplements may have poorly understood and potentially dangerous side effects. For example: Ephedra, an ingredient in many weight loss supplements, was banned by the FDA due to frequent cardiovascular complications with potentially fatal outcomes. High amounts of caffeine and herbs that contain caffeine have replaced Ephedra in many weight-loss supplements; however, high dosage amounts of caffeine can lead to increased heart rate and arrhythmia.

• Contents of these supplements are not regulated. The FDA has found weight loss products that were contaminated with prescription ingredients. Adverse reactions can be reported to theFDA via the MedWatch system and to the manufacturer.

Patients who are looking for more natural alternatives to support weight loss could be directed to mind and body practices, such as yoga, meditation, and mindful eating which are considered safer and have some evidence for efficacy in supporting weight loss (NCCIH, 2016).

DETERMINING MEDICATION CHOICE

SECTION TOPICS• Selecting weight-loss medications based on the pharmacological profile. • Potential side effects and effectiveness of FDA-approved weight-loss medications.

Ms. Clements meets criteria for pharmacotherapy and she has been educated about the benefits. The next step is choosing the best and most clinically appropriate medication to support her weight loss goals.

Provider: Do you have any questions or concerns about weight-loss medications?

Ms. Clements: I heard there is a medication that makes you not digest fat. Fats are my biggest problem. I eat a lot of fat, so that might help.

Provider: There is a medication called orlistat that blocks fat absorption. It might fit your needs. It hasunpleasant effects if you eat a lot of fats, though. And you will need to take a supplement.

POLL: CONSIDERING ORLISTATQuestion: At this point, are you inclined toward recommending that Ms. Clements try over the counter orlistat?

1. Yes• 44% (38 votes)

2. No• 30% (26 votes)

3. Unsure• 26% (23 votes)

Total votes: 87


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ORLISTAT DESCRIPTION AND EVIDENCE Prescription orlistat , Over-the-counter orlistat

ACTION:

Blocks 1/3 of the fat consumed from being absorbed by the small intestines, thus promoting malabsorption of calories from fat. Also reinforces the behavior of eating a low-fat diet through unpleasant effects of eating a high-fat diet. The only FDA-approved obesity management drug that does not act on the appetite (Apovian et al., 2015).


A gastric and pancreatic lipase inhibitor

INDICATIONS:

May be used long-term up to 4 years for weight loss or for weight-loss maintenance in adult obese patients. Pediatric indication is for 12-16 y/o obese adolescents (the only weight-loss drug approved for children 12 and older) (WIN, 2013).

DOSE:

Prescription:

120 mg 3 times/day

Over-the-Counter:

Half-strength, 60-mg, blocks 25% of fat

(WIN, 2013)

Clinical StudiesEffectiveness of orlistat (120 mg) on weight loss, maintenance, and regain was demonstrated in seven multicenter, double-blind, placebo-controlled trials:

EXPECTED WEIGHT LOSS:

Average weight loss is 2.9 to 3.4% more than placebo at 1 year (Apovian, 2015). After 1 or 2 years of taking orlistat, patients may lose about 5-7 lbs (WIN, 2013). Weight loss was greater than placebo in most 2-year studies and in a 4-year study.

In a 4-year study, mean weight loss was 5.17% vs. 2.75% for placebo (see Figure). Nearly half (45%)of the orlistat group lost > 5% of body weight vs. 28% of the placebo group (Genentech, 2013).


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EFFECT ON DIABETES:

Orlistat reduced incidence of diabetes better than placebo in a 4-year study. Prevalence for type 2 diabetes was decreased more among individuals taking orlistat than controls (Torgerson et al., 2004).Orlistat is not, however, FDA-approved for treating diabetes.

ADVANTAGES:

• Non-systemic. • Approved by the FDA for long-term use. • Over-the-counter orlistat is less expensive.


DISADVANTAGES:

• Relatively less weight loss (2-3%) • Patients must avoid foods that are more than 30% fat or they can experience unpleasant

changes in bowel movements

(Kushner & AMA, 2011)

ORLISTAT SIDE EFFECTS, CONTRAINDICATIONS, PRECAUTIONS

Side EffectsCommon side effects include (Based on 360 mg Total Daily Dose):

• Headaches (30.6%) • Nausea (8.1%) • Menstrual Irregularity (9.8%) • Urinary Tract Infection (7.5%)



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• Back Pain (13.9%) • Oily Spotting (26.6%)

• Flatus with Discharge (23.9%) • Fecal Urgency/Frequency (22.1%) • Fatty/Oily Stool (20%) • Fecal Incontinence (7.7%) • Chronic malabsorption syndrome

(Genentech, 2013)

Psyllium, a dietary supplement, may have some benefit in managing the GI side effects of Orlistat (Cavaliere, 2001).

***Information on this page is not a comprehensive list of side effects, contraindications, or precautions. This partial list was up to date as of June 10, 2014. For the most up-to-date information, view the medication's latest package insert.***

• Because vitamins and minerals may be lost with the unabsorbed fat, a multivitamin with vitamins A, D, E, K, and beta-carotene may be needed (Genentech, 2013)

• Rare cases of severe liver injury have also been reported (Genentech, 2013).

Contraindications• Chronic malabsorption syndrome • Cholestasis • Nephrolithiasis (Calcium oxalate stones) • Hepatic impairment • Pregnancy and breastfeeding

(Genentech, 2013; Garvey et al., 2016-2017)

Special Precautions/Drug Interactions• Convulsions have been reported in combination with antiepileptic drugs. • Warfarin • Exposure to cyclosporine is reduced • Monitor patients on levothyroxine for changes in thyroid function

(Genentech, 2013)

PRACTICE TIPBecause of the common gastrointestinal side effects, tell patients to try this medication for the first time on a day off.

MS. CLEMENTS: DISCUSSING SIDE EFFECTS

Ms. ClementsThe provider describes the following information to Ms. Clements, due to her interest in taking orlistat:


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• Side effects • Potential weight-loss outcomes • Requirement for meals to include less than 15 grams of fat and no more than 45 grams of

fat/day

Ms. Clements is willing to try OTC orlistat in addition to her reduced calorie diet and exercise plan. The provider reminds her to work with her dietitian to learn about fats in the foods she eats, keeping some healthy fats in her diet, and adding lean proteins so that carbohydrate increase is limited.

Provider: Because of the side effects of this drug, I would try it for this first time when you can stay athome.

Ms. Clements: That's a good point.

Provider: I'd also like you to take a multivitamin supplement because some vitamins will be lost along with the fat. Let's schedule a follow-up in a month.

FOLLOW-UP

Three Months Later

At her three-month follow-up Ms. Clements has lost 7 pounds and her BMI is down to 28.

Ms. Clements: The monthly visits really helped me stick to the plan. The side effects were unpleasant at first, but they got better.

Provider: I'm happy to hear you're in good spirits. I'm also happy to tell you that your LDL cholesterolis down to 155 mg.

PRACTICE TIP• Focus on attainable weight-loss goals • Frequent contacts with the patient helps promote weight loss and weight-loss maintenance

CASE #2: MR. WILLIAMSThis case illustrates a patient whose medical condition would benefit from weight-loss and for whom pharmacotherapy might be considered.

Meet Your Patient

Patient Name: Xavier Williams Age: 38 y/o

Height: 6'0” Weight: 302 lbs BMI: 41 kg/m2 Waist: 50"


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Chief Complaint: Erectile dysfunction and fatigue.

History of Present Illness: Symptoms are mild with gradual onset over past year

Medical History: Treated for adjustment disorder with depressive features for over a year with counseling and antidepressant. Currently asymptomatic.

Medication: Sertraline (anti-depressant)

Weight History: Multiple past weight-loss attempts, but all have failed. He has become despondent over weight and his lack of success.

Physical Activity Level: Low - 1 hour of moderately intense physical activity per week intermittently, decreased in past few months.

Weight Related Diagnoses: E66.01 Morbid Obesity; E65 Localized Adiposity (Central)

CASE OBJECTIVESThe learner will be able to:

• Identify patients for whom prescribing weight-loss medication is appropriate as an adjunct to routine weight management.


• Discuss the potential side effects of FDA-approved weight-loss medications with patients.

TALKING WITH MR. WILLIAMSMr. Williams has been evaluated for his chief complaint of erectile dysfunction and possible other causes have been discussed. The provider next brings up the topic of Mr. Williams' weight.

Provider: Excess weight could contribute to your erectile dysfunction, fatigue, and depressed feelings. Depression and fatigue can also contribute to excess weight. Can we talk about a plan to lose some weight?

Mr. Williams: I've tried to lose weight several times without much success. I didn't last long. I just get tired all the time and then I don't feel like doing anything. That gets my emotions down, too, so it feels like I'm stuck in a downward spiral.

Provider: Losing some weight could help break that cycle. It sounds like you could use some additional support with it. Eating a healthy diet can help depression, too. We have a dietitian who canwork with you.

Mr. Williams: That sounds good.

Because Mr. Williams BMI is over 40 kg/m2, potential adjunctive treatments of pharmacotherapy, surgery, or very low-calorie meal replacements are suggested, but he is not interested at this time. Together, the provider and Mr. Williams come up with some diet and physical activity changes Mr. Williams will work on over the next month. The provider finalizes a treatment plan for Mr. Williams' erectile dysfunction and schedules him for monthly appointments with the practice's dietitian.


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Foods and DepressionMany dietary interventions have been shown to improve or help prevent depression (Opie et al, 2014). For example, Mediterranean diet has been shown to reduce the risk of developing depression 40 to 60% (Sánchez-Villegas et al, 2009). It can also be adapted for weight loss. Whole food diets, asopposed to processed foods, have also been linked to reduced depression rates.

Testosterone and WeightChronic obesity is often associated with low testosterone and vice versa (Swerdloff & Anawalt, 2014).Sex hormone-binding globulin (SHBG), the protein that carries testosterone in the blood, is also lowered in obesity. Symptoms include increased body fat, impaired libido, decreased bone mineral density, decreased muscle mass, and lowered vitality. Physical findings might include hypogonadism. Low serum testosterone level is associated with increased risks for hypertension, metabolic syndrome, type 2 diabetes, and cardiovascular disease. Weight loss generally raises testosterone levels.

MR. WILLIAMS: ONE YEAR LATER

One Year LaterThe practice dietitian saw Mr. Williams every month at first and then every three months for the past year to help him lose weight. He returns one year later for follow-up of several weight-related comorbidities. He has lost only 11 pounds so far, despite mild success with lifestyle changes, and his erectile dysfunction has improved. He no longer takes the SSRI, sertraline.

Mr. Williams: I don't know if I can keep this up. I try so hard and I haven't lost any weight. Youknow, my mother's doctor prescribed her lorcaserin and it made it easier to lose weight. Can I try that,too?

LORCASERIN DESCRIPTION AND EVIDENCE

Lorcaserin

ACTION:

Works by inducing satiety.

CNS MECHANISM:

A selective serotonin agonist stimulating the 2creceptor (Eisai, Inc., 2014).



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Patients can expect to lose 3.6% of body weight at one year beyond placebo (Apovian, 2015).

DOSE:

10 mg, twice/day. Discontinue if 5% weight loss is not achieved at 12 weeks.

ADVANTAGES:

Fairly good side effect profile; Long term data available.

DISADVANTAGES:

High cost


Clinical StudiesIn several studies, lorcaserin plus reduced-calorie diet and increased physical activity produced greater weight loss than placebo plus reduced-calorie diet and increased physical activity (O'Neil et al., 2012).

In conjunction with reduced caloric intake and increased physical activity, weight loss at the end of 2 years was greatest for patients who took lorcaserin both years 1 and 2 (6.0 kg), followed by the groupthat took it only for the first year (3.8 kg), and lastly the placebo group (2.6 kg). (See Figure) Patients in all groups regained weight in the second year but mean weight after year 2 remained under baseline weight (Eisai Inc., 2014).

EFFECT IN DIABETES:

Lorcaserin helped control glucose levels in patients with Type 2 diabetes resulting in the need for lessdiabetes medication (O'Neil et al., 2012).

LORCASERIN SIDE EFFECTS, CONTRAINDICATIONS, PRECAUTIONS

Side EffectsCommon side effects include (Based on 20 mg Total Daily Dose):

• Headaches (16.8%) • Dizziness (8.5%) • Nausea (8.3%)

• Constipation (5.8%) • Diarrhea (6.5%) • Dry Mouth (5.3%)

• Fatigue (7.2%) • Back Pain (6.3%)

(Eisai, Inc., 2014)


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***Information on this page is not a comprehensive list of side effects, contraindications, or precautions. This partial list was up to date as of December 2014. For the most up-to-date information, view the medication's latest package insert.***

The serotonergic agonists, fenfluramine and dexfenfluramine, withdrawn due to valvulopathy, acted on different receptors, so the risk of valvulopathy is said to be greatly reduced (Smith et al., 2010). Nostatistically significant difference in the development of FDA-defined valve abnormalities between lorcaserin and placebo-treated patients were reported (FDA, 2012).

Lorcaserin is a schedule IV drug due to its hallucinogenic properties and the potential for users to develop psychiatric dependencies on the drug (DEA, 2013).

Contraindications• Patients with valvular heart disease should NOT take lorcaserin (Eisai, Inc., 2014) • Pregnancy and breastfeeding (Apovian et al., 2015) • Severe hepatic impairment (Garvey et al., 2016-2017) • Severe chronic kidney disease - urinary clearance of metabolites (Garvey et al., 2016-2017) • Avoid combining serotonergic drugs

Special Precautions/Drug InteractionsMonitor patients for serotonin syndrome or neuroleptic malignant syndrome (NMS)-like reactions, including agitation, hallucinations, coma, tachycardia, labile blood pressure, hyperthermia, hyperreflexia, incoordination, nausea, vomiting, diarrhea, and muscle rigidity (Eisai, Inc., 2014).

Avoid prescribing lorcaserin with selective serotonin reuptake inhibitors (SSRIs) or serotonin-norepinephrine reuptake inhibitors (SNRIs) due to potential for serotonin syndrome (Apovian et al., 2015). Also contraindicated with St. John's wort, triptans, bupropion, and dextromethorphan. The safety of coadministration with other serotonergic or antidopaminergic agents has not been established (Eisai, Inc., 2014).

POLL: PRESCRIBE LORCASERIN?Question: Would you prescribe lorcaserin to Mr. Williams?

1. Yes• 51% (46 votes)

2. No• 24% (22 votes)

3. Unsure• 24% (22 votes)

Total votes: 90

FURTHER DISCUSSIONUpon looking up lorcaserin, the provider sees that over half of weight lost in the first year on the drug is re-gained in the year after stopping the medication, on the average. Lorcaserin is also contraindicated in patients using an SSRI, but Mr. Williams has stopped taking sertraline, which is an SSRI.


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Provider: Lorcaserin actually should not be taken with the antidepressant medication you were on previously. It could present a problem if I prescribed lorcaserin and you had to go back on that antidepressant.

Mr. Williams: Ok...I do get down at times still, so maybe that's a good idea.

Provider: One weight-loss medication combines an antidepressant with a drug that helps treat addiction. Together they have been shown to help people lose more weight and it does not cause erectile dysfunction.

Mr. Williams: Well, that actually sounds promising.

The provider discusses with Mr. Williams:

• How bupropion/naltrexone works • Expected weight loss

• Drug interactions, special precautions, contraindications, and side-effects

PRACTICE TIPAdditionally, bupropion is approved for smoking cessation (Zyban®) and as an antidepressant (Wellbutrin®) in the U.S. Be sure to ask patients about both potential uses to make sure they are not already taking bupropion.

BUPROPION / NALTREXONE DESCRIPTION & EVIDENCE

Bupropion/Naltrexone

ACTION:

Bupropion is an antidepressant. Naltrexone is an opioid antagonist. The combination in extended-release tablets is FDA-approved for weight loss (FDA, 2014).

CNS MECHANISM:

Bupropion weakly inhibits reuptake of dopamine and norepinephrine, which activates POMC neurons in the hypothalamus (first order anorexigenic pathway). Naltrexone potentiates feedback inhibition of POMC neurons (Apovian et al., 2015; Takeda, 2014). The medication also reduced food intake in mice when injected into an area associated withregulation of reward pathways. Targeting two targets mayget around the brain's compensation when only onemechanism is targeted.

DOSAGE:

Supplied as 8 mg naltrexone HCl/90 mg bupropion HClextended release tablets. Titrated over a month up to twotablets, tid with meals (Apovian et al., 2015). Discontinueif 5% weight loss not achieved at 12 weeks.



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ADVANTAGES:

Addresses food addiction; Long term data available.

MODERATE:

Modest weight loss (> 3 to 5%); Moderate cost

DISADVANTAGES:

Side effect profile

(Apovian et al., 2015). Safety studies required by FDA at approval need to be completed (Sharfstein & Psaty, 2016; Nissen et al, 2016).

Clinical StudiesEffectiveness on weight loss, maintenance, and regain was demonstrated in several trials in conjunction with lifestyle modification (Takeda, 2014):

• Mean weight loss in a 56-week trial was 4.8% more body weight than placebo at one year (Apovian, 2015). A reduction of 5% body weight was achieved by the treatment group more often than placebo (42% vs. 17%)

• Cardiovascular and metabolic parameters (triglycerides, HDL, LDL, heart rate, and blood pressure) were also improved in earlier studies (Apovian, 2015). However, at approval, the FDA requested further studies on cardiovascular safety and these were stopped at the midpoint when there was not significantly less cardiovascular risk in the group taking the medication compared to placebo (Sharfstein & Psaty, 2016; Nissen et al, 2016).

EFFECT IN DIABETES:

Weight loss in a trial of patients with Type 2 diabetes mellitus was similar. Furthermore, HbA1c(-0.6% treatment group vs. -0.1% for control) and fasting glucose (-11.9 mg/dL treatment group vs. -7.9 mg/dL control) were improved.

BUPROPION / NALTREXONE SIDE EFFECTS

Side Effects and RisksCommon side effects include (Based on 32 mg/360 mg Total Daily Dose):

• Nausea (32.5%) • Constipation (19.2%) • Headache (17.6%) • Vomiting (10.7%)

(Takeda, 2014)

• Dizziness (9.9%) • Insomnia (9.2%) • Dry Mouth (8.1%)


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• Diarrhea (7.1%)

***Information on this page is not a comprehensive list of side effects, contraindications, or precautions. This partial list was up to date as of September 2014. For the most up-to-date information, view the medication's latest package insert.***

Rare, but serious associated risks to consider, include:

• Increases in both heart rate AND blood pressure* • Can cause seizures, risk is dose-related • Hepatotoxicity has been observed with naltrexone

In clinical trials, 24% of patients discontinued treatment because of an adverse reaction (vs. 12% for placebo) (Takeda, 2014).

* The significance of elevated blood pressure and heart rate is not clear because patients having significant cardiovascular history were excluded from clinical trials. (FDA, 2014).

Warnings Regarding Opioid UseNaltrexone blocks the effects of opioids. Alternative pain medications will be needed. Increasing opioid dose to try to overcome the effects of naltrexone is dangerous and could result in serious injury, coma, or death. The medication should not be started while physically dependent on any opioid. See Prescribing Guide for details.

BUPROPION / NALTREXONE CONTRAINDICATIONS/PRECAUTIONS

Contraindications• Do not use in patients with uncontrolled high blood pressure. Monitor blood pressure and

pulse at regular intervals • Boxed warning for bupropion: Be alert to increased risk of suicidal thoughts and behaviors that

may be associated with antidepressants. Some serious neuropsychiatric events have been reported with use of bupropion for smoking cessation (FDA, 2014)

• Do not use/discontinue in patients having seizures • Contraindicated with eating disorders • Contraindicated with drug or alcohol withdrawal • Contraindicated with pregnancy/trying to become pregnant or breastfeeding • Severe kidney disease - urinary clearance of drug • Contraindicated with monoamine oxidase inhibitors (MAOI) • Contraindicated with uncontrolled hypertension • Contraindicated with severe hepatic impairment • Contraindicated with glaucoma - may trigger angle closure

(Takeda, 2014; Garvey et al., 2016-2017)

Special Precautions/Drug Interactions• Monitor heart rate with hypertension, cardiovascular disease • Avoid in adolescents and young adults • Bupropion: Do not use with other medications containing bupropion, such as Wellbutrin or

Zyban


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• Naltrexone: Do not use with opioids or treatments for opioid dependence, or during acute opiate withdrawal

• Do not use in patients having abrupt discontinuation of alcohol, benzodiazepines, barbiturates and antiepileptic drugs; do not use in alcoholism/addiction due to seizure risk.

(Takeda, 2014; Garvey et al., 2016-2017)

MR. WILLIAMS: PROGRESSMr. Williams steadily loses a little weight while on the medication. He only partially followed his comprehensive weight loss plan at first and has not followed it at all for the past few weeks.

Medication OutcomesTime Elapsed

(From Medication Start)Current Weight

(Loss)BMI

(Current)

0 Weeks 291 (0 lbs) 39.5

2 Weeks 289.5 (1.5 lbs) 39.3

4 Weeks 289 (2 lbs) 39.2

6 Weeks 289 (2 lbs) 39.2

8 Weeks 288 (3 lbs) 39.1

10 Weeks 288 (3 lbs) 39.1

12 Weeks 288 (3 lbs) 39.1

At his three month follow-up, Mr. Williams has lost 3 pounds and his BMI remains at 39.1.

Mr. Williams: I was doing really well with my diet until Thanksgiving. It's hard not to indulge during the holidays.

Provider: I understand, it can be hard at holidays! I'd like to help you get back on track, because what is needed for your health is a permanent change in diet and activity level. Would you be open tomeeting with a dietitian again, or joining a weight loss group for support?

Mr. Williams: I know. I think joining a weight loss group would be good for me.

Provider: Good! We'll set you up with a good referral on your way out. Just give them a call to schedule your first session.

CASE #3: MR. AKINSThis case illustrates use of pharmacotherapy when weight-loss surgery is contraindicated.

Meet Your Patient


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Patient Name: Tom Akins Age: 48 y/o

Height: 6'2" Weight: 336 lbs BMI: 43.1 kg/m2 Waist: 53"


Chief Complaint: He wants pharmacotherapy "instead of dieting." The cardiologist says I have to lose weight.

History of Present Illness: He has not been able to sustain efforts to follow a reduced calorie diet and increased exercise. The cardiologist recommends against weight-loss surgery at this time. He was diagnosed with Class I angina and early coronary artery disease, after visiting an emergency department with mild chest pain from exertion 2 months ago. Stress EKG and echocardiogram were within normal limits and a minimal amount of blockage was evident on angiogram. He was referred toprimary care for follow-up and weight management.

Medical History: Class I angina and early coronary artery disease were diagnosed by cardiologist. He is currently being treated for dyslipidemia, high blood pressure. History of being treated for atypical depression.

Medications: Lipitor, Azor, Nitroglycerin (not used since initial episode).

Weight History: Overweight since childhood. Weight increase of 5 lbs/year in his 30s, and 10 lbs/year after age 40.

Physical Activity Level: Does not like to exercise, very sedentary. Walks 2x/week for < 10 minutes each.

Weight Related Diagnoses: E66.01 Morbid Obesity; E65 Localized Adiposity (Central)

CASE OBJECTIVESThis case will cover the following objectives:


• Discuss the potential side effects of FDA-approved weight-loss medications with patients

POLL: TREATMENT OPTIONSQuestion: What weight-loss treatment are you most inclined toward at this time?

Responses:

1. Pharmacotherapy plus routine weight-loss management • 57% (50 votes)

2. Diet, exercise, and weight-loss program only • 28% (25 votes)

3. Explore other combinations / options • 11% (10 votes)

4. Give pharmacotherapy-only a try. It's better than nothing. • 3% (3 votes)

Total votes: 88


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DISCUSSING TREATMENT

Treatment Protocol Step: Discuss the option of prescribing medications to support a comprehensiveweight-loss program if indicated.

The provider discusses the possibility of using adjunctive treatments to support Mr. Akin's weight loss efforts:

Provider: I see that your cardiologist has recommended that you lose weight, but does not want you to have weight-loss surgery at this time.

Mr. Akins: I guess my heart is still being evaluated, but my weight makes my heart worse. I tried dieting before and after the first 10 lbs, I only lost about a pound a week.

Provider: There are meal replacement programs that produce more rapid weight loss. Some have a liquid you drink to replace one or more meals.

Mr. Akins: No way I'm going to drink my food or starve myself! Can I try those weight-loss medicines? I get too hungry when I try to diet, so I figure just taking a pill would be easier.

Provider: Weight-loss medications can help. There are some new medications that might help with that hunger. Additionally, some medications could help with your tendency toward slightly increased blood sugar. You would still have to make a long-term change in your diet, however, and get enough exercise. Medications just give your weight-loss efforts a little help.

Mr. Akins: That sounds good. Maybe I would be more successful with a little help like you say. I'd like to give that a try.

The provider consults a drug reference, looking up liraglutide, a medication with which the provider is familiar from using it in another form to treat diabetes. The provider's rationale is that this might be a good choice with Mr. Akin's slightly elevated blood sugar.

LIRAGLUTIDE DESCRIPTION & EVIDENCE

Liraglutide

ACTION:

Produces satiety. FDA-approved for adult chronic weight treatment as an adjunct to a reduced-caloriediet and increased physical activity (FDA, 2014).

CNS MECHANISM:

GLP-1 agonists acting on the POMC neurons in a first order anorexigenic pathway (Apovian et al., 2015).


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DOSAGE:

Injectable subcutaneous medication. For weight loss, used once per day, starting at a dose of 0.6 mg/day, increasing weekly by 0.6 mg/day up to a maximum of 3 mg/day

ADVANTAGES:

Side effect profile relatively better than other weight-loss medications. Long term data available.

DISADVANTAGES:

Expensive. Administered by injection


Clinical StudiesEffectiveness of 3 mg dose on weight loss with patients nothaving diabetes mellitus, in combination with a caloriereduction diet and increased physical activity (FDA. 2014):

• Mean weight loss after 1 year was 4.5% more thanplacebo.

• At least 5% more of body weight lost than placebo(62% vs. 34%).

• Cardiovascular and metabolic risk factors, includingsystolic and diastolic blood pressure, heart rate,and serum lipids, were improved more than withplacebo control.

• A study published after FDA approval also foundthat weight loss was independent of serum glucosestatus (Pi-Sunyer, et al, 2015). Additionally, in non-diabetics, there was a slightly greater reduction in glycated hemoglobin, fasting glucose, and fasting insulin levels than in the placebo group.

EFFECT IN DIABETES:

Had a similar effect on weight loss in patients with type 2 diabetes mellitus. FDA-approved in a different product (Victoza®) at a different dose to improve glycemic control (FDA, 2013). This formulation is used as an adjunct to diet and exercise for adults with type 2 diabetes mellitus.

LIRAGLUTIDE SIDE EFFECTS, CONTRAINDICATIONS, PRECAUTIONS

Side Effects and RisksCommon side effects include (Based on 3 mg Total Daily Dose):

• Nausea (39.3%) • Diarrhea (20.9%)



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• Hypoglycemia (w/ Type 2 Diabetes) (23%) • Constipation (19.4%) • Vomiting (15.7%)

• Headache (13.6%) • Decreased appetite (10%) • Dyspepsia (9.6%) • Fatigue (7.5%) • Dizziness (6.9%)

(Novo Nordisk, 2015)

***Information on this page is not a comprehensive list of side effects, contraindications, or precautions. This partial list was created to highlight some effects as of December 2014. For the mostup-to-date information, view the medication's latest package insert.***

Rare, but serious associated risks to consider, include:

• Elevated heart rate • Increased risk for medullary carcinoma in animals (FDA, 2014b). • Acute pancreatitis (fatal and non-fatal) has been observed (FDA, 2014b). • Additional serious side effects include: gallbladder disease, renal impairment, and suicidal

thoughts (FDA, 2014a).

Note: Effects on cardiovascular morbidity and mortality, as well as coadministration with other weight-loss products, have not yet been established (Novo Nordisk, 2014).

Contraindications• History or family history of thyroid cancer or elevated risk (multiple endocrine neoplasia

syndrome) • Pregnancy. (Package insert says "presence in breast milk is not known." Avoid with breast

feeding. • Severe hepatic impairment • Avoid with prior or current pancreatitis

(Novo Nordisk, 2014; Garvey et al., 2016-2017)

Special Precautions/Drug Interactions• Discontinue with sustained increase in heart rate • Do not use with insulin • Can cause serious hypoglycemia with insulin secretagogue, e.g., a sulfonylurea) • Do not use with other GLP-1 receptor agonists, including Victoza for diabetes, which is the

same drug at a different dose • Monitor heart rate at regular intervals

(Novo Nordisk, 2014)


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DISCUSSING PHARMACOTHERAPY

The provider has reviewed the drug information for liraglutide and another weight-loss medication, phentermine/topiramate, and discusses them with Mr. Akins.

Provider: There is one medication, liraglutide, that requires a daily injection. Another new one is pretty effective, phentermine/topiramate; it has some side effects we would need to discuss. And some other possibilities.

Mr. Akins: No way I'd give myself a shot! These other ones, are they pills?

Provider: Yes, phentermine/topiramate has produced somewhat good results. There are some warnings about phentermine and cardiovascular disease. I would need to get your cardiologist's opinion on its safety, given your recent heart problems. Meanwhile, it is important to start working on your diet and exercise. Medication helps a little, but you still have to make changes in what you eat and increase your physical activity. I have the name of someone who can help you with that if you arewilling.

Mr. Akins: Okay, sounds good.

Discussion of Pharmacotherapy Options for Mr. AkinsPhentermine/topiramate has fairly good weight loss compared to other medications but has a side effect of increased heart rate that increases with higher dose. It should not be used with patients having recent or unstable cardiac disease.

Weight-loss medications that are not sympathomimetics, such as lorcaserin and/or orlistat, might have been considered for Mr. Akins.

The Endocrine Society's guidelines made a strong recommendation against using the sympathomimetic agents, phentermine or diethylpropion, in patients with uncontrolled hypertension ora history of heart disease, including advanced arteriosclerosis or coronary artery disease (Apovian et al., 2015). But it is not clear whether this applies to the dosage of phentermine in the combination drug, phentermine/topiramate.

PHENTERMINE AND PHENTERMINE / TOPIRAMATE ER DESCRIPTION

1) Phentermine hydrocloride2) Phentermine and topiramate extended release

ACTIONS:

Phentermine suppresses appetite (anorectic effect). Primarily a noradrenergic and possibly dopaminergic action in hypothalamus and limbic system (Apovian et al., 2015). A sympathomimetic amine with activity similar to amphetamine activity in obesity (Drugs.com, 2016).


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Topiramate decreases appetite and causes feelings of satiety to last longer after eating (AHFS, 2012), but action is not fully understood (Vivus, 2013). May target addiction centers, since there is also a decrease in drug and alcohol seeking; may affect reward center (Mental Health Daily, 2016). May affect leptin and cortisol, reduce taste through saliva decrease, promote ketosis. Pharmacologic effects include "augmenting the activity of the neurotransmitter gamma-aminobutyrate, modulation of voltage-gated ion channels, inhibition of AMPA/kainite excitatory glutamate receptors, or inhibition of carbonic anhydrase" (Drugs.com, 2016).

Phentermine / topiramate combined: The components potentiate each other's effects (Vivus, 2013). Improvements in leptin sensitivity, thermogenesis, and basal metabolic rate.


Phentermine HCL: At doses of 30-37.5 mg, the average weight loss above diet and lifestyle alone was 3.6 kg (7.9 lbs) (Apovian, 2015).

Phentermine / topiramate combined: At the recommended dose, the average weight loss above diet and lifestyle alone was 6.6 kg 14.5 lbs), a 6.6% weight loss on average (Apovian, 2015).

Phentermine was approved by itself in the 1960s for short-term use in weight loss at a relatively higher dose (Apovian et al., 2015).

REMS: Due to teratogenic risks of phentermine, a Risk Evaluation and Mitigation Strategy (REMS) requires manufacturers to provide training for prescribers and informing prescribers of changes to therisk-benefit profile (Vivus Inc., 2013b).

DOSING:

1) Phentermine: The usual dose is one 37.5 capsule daily, not recommended for use in children (Drugs.com, 2016); 2) Phentermine/topiramate is available in several doses to allow titration between doses.

• Recommended dose: Phentermine 7.5 mg/topiramate 46 mg ER per day • Maximum dose: Phentermine 15 mg/topiramate 92 mg ER per day

Begin with low dose for 2 weeks, thenrecommended dose. After 12 weeks, if weightloss is less than 3%, increase dose in 2-weekincrements to maximum or discontinue with ataper.


ADVANTAGES:

Relatively better weight loss (>5%); Long-termdata available.

DISADVANTAGES:

High cost; phentermine is a teratogen



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PRACTICE TIPS• When prescribing phentermine/topiramate ask the patient if they have tried or are currently

using phentermine. • Only certified pharmacies can dispense this medication (FDA, 2012).

PHENTERMINE / TOPIRAMATE EVIDENCE Phentermine/topiramate resulted in significantly more weight loss than placebo (both groups had reduced calorie diet/increased physical activity) in 1 year randomized trials (Vivus Inc., 2013) (see figure). More patients on phentermine/topiramate than placebo achieved 5% and 10% weight loss.

OTHER FINDINGS:No change to blood pressure or heart rate was seen in the above studies. Patients treated with phentermine for up to 21.5 years do not develop phentermine abuse, addiction, cravings, or withdrawal after cessation. Similar results would be expected for the combination drug.

EFFECT ON DIABETES:In studies of type 2 diabetes, phentermine/topiramate produced better glycemic control with less needfor diabetes medications and a decrease in the progression of diabetes (Garvey et al., 2014). It is not FDA-approved for diabetes treatment, however.

PHENTERMINE / TOPIRAMATE ER SIDE EFFECTS

Side EffectsCommon side effects include (Based on 7.5 mg/46 mg Total Daily Dose):

• Paraesthesia (13.7%) • Dizziness (7.2%) • Insomnia (5.8%)

• Headaches (7%) • Diarrhea (6.4%) • Constipation (15.1%)

• Dry Mouth (13.5%) • Dysgeusia (7.4%)

(Vivus Inc., 2013)

***Information on this page is not a comprehensive list of side effects, contraindications, or precautions. This partial list was up to date as of June 2014. For the most up-date information, view the medication's latest package insert.***

Serious, but rare side effects include:

• Allergic reactions (such as rash, hives, difficulty breathing)

(Vivus Inc., 2013)

• Thoughts of suicide


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• Pulmonary hypertension, palpitations (2.4%)

• Memory problems • Changes to vision (4.0%)

The combination may cause fetal toxicity, increased heart rate, metabolic acidosis, elevated creatinine, hypoglycemia, cognitive impairment, and mood disorders (Vivus Inc., 2013). There is also a risk for suicidal behavior and ideation with topiramate use.

PHENTERMINE / TOPIRAMATE ER CONTRAINDICATIONS & SPECIAL PRECAUTIONS

ContraindicationsThe combination of phentermine/topiramate is contraindicated in patients with glaucoma or hyperthyroidism, pregnancy, or breastfeeding (Apovian et al., 2015; Vivus Inc., 2013a).

Not recommended with severe hepatic impairment or severe kidney disease (urinary drug clearance) (Garvey et al., 2016-2017).

The manufacturers emphasize the need for pregnancy prevention for females of reproductive potential (FDA, 2013). Discontinue the drug immediately if pregnancy occurs due to teratogenic risk.

Because the drug has not been studied in patients with recent or unstable cardiac or cerebrovascular disease, it is not recommended for these patients (Vivus, 2013b).

The Endocrine Society's guidelines for pharmacological management of obesity made a strong recommendation against using the sympathomimetic agents, phentermine or diethylpropion, in patients with uncontrolled hypertension or a history of heart disease (Apovian et al., 2015). The latter include advanced arteriosclerosis or coronary artery disease.

Phentermine by itself is also contraindicated in agitated states, history of known drug abuse, and all of the conditions listed for the combination medication. The dose of phentermine is much lower in the combination phentermine/topiramate (7.5 mg recommended dose in the combination medication vs. 30 to 37.5 mg in phentermine alone) (Vivus Inc., 2014).

Note that a boxed warning for phentermine/topiramate states that it "is a federally controlled substance (CIV) because it contains phentermine and can be abused or lead to drug dependence." It recommends keeping the medications "in a safe place, to protect it from theft" and recommends never giving it "to anyone else, because it may cause death or harm them. Selling or giving away this medicine is against the law" (Vivus Inc., 2014)

Special Precautions/Drug InteractionsRegular measurement of resting heart rate is recommended for all patients, but especially in the presence of cardiac or cerebrovascular disease.

Nephrolithiasis - Calcium phosphate stones (Garvey et al., 2016-2017)

The Endocrine Society's pharmacological guidelines recommend caution and monitoring of blood pressure in patients taking phentermine who have any history of hypertension. Presumably, this applies to the combination phentermine/topiramate as well, even though the dose of phentermine is relatively low.


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Package insert info as of 10/2014 said the effect "on cardiovascular morbidity and mortality has not been established" (Vivus Inc., 2014). The guidelines also advised caution in prescribing phentermine in patients with a history of cardiac arrhythmia or seizures. They recommend a serotonin receptor agonist, such as lorcaserin, for patients with cardiac disease, hypertension, or seizures instead of phentermine.

Do not use in patients using monoamine oxidase inhibitor or sympathomimetic amines.

(Apovian et al., 2015; Vivus Inc., 2013a)

MR. AKINS: PROGRESS

After 6 weeks of monitoring Mr. Akins, the cardiologist approved phentermine/topiramate ER for Mr. Akins. Over the next 12 weeks, Mr. Akins steadily lost weight while on the medication and strictly adhering to a reduced calorie DASH diet and a daily walking regimen of 30 minutes per day.

Medication OutcomesTime Elapsed

(From Medication Start)Current Weight

(Loss)BMI

(Current)

0 Weeks 336 (-0 lbs) 43.1

2 Weeks 334 (-2 lbs) 42.9

4 Weeks 331 (-5 lbs) 42.5

6 Weeks 329 (-7 lbs) 42.2

8 Weeks 326 (-10 lbs) 41.9

10 Weeks 325 (-11 lbs) 41.7

12 Weeks 322 (-14 lbs) 41.3

Mr. Akins reports being pleased with his steady progress and looks forward to long-term weight-loss. He continues to be followed bimonthly (twice monthly) for another 3 months in order to achieve 6 months of intensive supports. Thereafter, he will still be seen monthly to continue weight loss and then to support maintenance. Adjustments will be made to his lifestyle (diet and activity level) to continue to lose weight.

LIFESTYLE MANAGEMENT AND FOLLOWUP

Include Lifestyle ManagementWhen considering pharmacotherapy for weight loss, it shouldbe part of a comprehensive weight-management plan.

Pharmacological management of obesity does not replacelifestyle modifications.


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Patients receiving pharmacological management of obesity also need to make lifelong and comprehensive lifestyle change including:

• DIET Consumption of a reduced calorie diet • EXERCISE High levels of physical activity (at least 150 minutes per week, but 200 to 300

minutes/week is better) • BEHAVIORAL SUPPORT This support is for achieving the above steps. Ideally, it should be

face-to-face and regular. Two possible approaches can meet this need: 1) Meeting with a trained interventionist, such as a dietitian or a counselor specializing in weight loss; and/or 2) A structured, evidence-based weight-loss program.

• CONTINUED MEDICAL FOLLOW UP

(Jensen et al., 2013)

Stopping Pharmacological TreatmentTreatment Protocol Step: Plan for transition from pharmacological treatment, very low calorie diets, or meal replacements to a long term weight loss/weight maintenance program.

If patients wish to stop the medication or stopping is indicated medically, it is important to modify their weight loss plan, in order to avoid weight regain. For example, they may need additional behavioral support, a more structured diet, and/or more physical activity. Without such adjustments, weight regain is very likely.

PRACTICE TIPIf a patient is not ready to alter their lifestyle, then they are not ready for pharmacotherapy or weight-loss surgery.

QUIZ: REVIEW WEIGHT-LOSS MEDICATIONS 1Question: Ms. Castillo, whose BMI remains at 31 despite trying conventional weight lossmethods, wishes to avoid medications that reduce the appetite. Which of thesemedications does not reduce the appetite?

Choose one1. Liraglutide

• Incorrect • Feedback: Liraglutide does reduce the appetite; however, orlistat does not.

2. Phentermine with topiramate ER • Incorrect • Feedback: Phentermine with topiramate does reduce the appetite; however, orlistat

does not. 3. Orlistat

• Correct • Feedback: Orlistat does not reduce the appetite.

4. Lorcaserin • Incorrect • Feedback: Lorcaserin does reduce the appetite; however, orlistat does not.


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QUIZ: REVIEW WEIGHT-LOSS MEDICATIONS 2Question: Mr. Perez, who has a BMI of 43.5, as well as type 2 diabetes, may benefitfrom weight loss pharmacotherapy. Which of the following FDA-approved weight-lossmedications is also approved for diabetes treatment?

Choose one1. Orlistat

1. Incorrect 2. Feedback: Orlistat is not approved for diabetes treatment. Liraglutide is currently

approved for diabetes treatment at a different dosage. Different products are approved for each purpose (Victoza for diabetes; Saxenda for obesity).

2. Lorcaserin 1. Incorrect 2. Feedback: Lorcaserin is not approved for diabetes treatment. Liraglutide is currently

approved for diabetes treatment at a different dosage. Different products are approved for each purpose (Victoza for diabetes; Saxenda for obesity).

3. Phentermine with Topiramate ER 1. Incorrect 2. Feedback: Phentermine/Topiramate is not approved for diabetes treatment. Liraglutide

is currently approved for diabetes treatment at a different dosage. Different products are approved for each purpose (Victoza for diabetes; Saxenda for obesity).

4. Liraglutide 1. Correct 2. Feedback: Liraglutide (Saxenda) is approved for chronic weight management and in a

different product (Victoza) at a different dose for adults with type 2 diabetes mellitus to improve glycemic control (FDA, 2013). It should be used as an adjunct to diet and exercise and behavioral support as indicated.

5. Bupropion/Naloxone1. Incorrect 2. Feedback: Liraglutide is currently approved for diabetes treatment.

CLINICAL PROTOCOL STEPS IN THIS MODULEThe following Clinical Protocol Steps for patients with obesity were illustrated in this module:

Treatment

• Discuss the option of prescribing medications to support a comprehensive weight-loss program, if indicated.

• Plan for transition from pharmacological treatment to a long-term weight loss/weight maintenance program.


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MODULE SUMMARY

Approved Medications for Treating Obesity or Overweight + Comorbid ConditionCurrent FDA-approved weight-loss medications include:

• Orlistat: Lipase inhibitor • Lorcaserin: Serotonin receptor agonist • Phentermine plus Topiramate: Combination anorectic/anticonvulsant • Bupropion/Naltrexone: Combination antidepressant (dopamine blocker) plus

opioid antagonist • Liraglutide: Glucagon-like peptide-1 (GLP-1) agonist; injectable • (Jensen et al., 2013; Apovian et al., 2015)

Criteria For Prescribing Medication for Weight Loss and StoppingWhen considering pharmacotherapy for weight loss, the following criteria should be met for patients:

• Obese (BMI ≥30) with no comorbidities or overweight (BMI ≥27) with at least one comorbidity • Willing to take the medication in addition to a reduced-calorie diet and increased exercise • Has a realistic understanding of potential weight loss with medication • Unable to lose weight despite serious attempts at diet, exercise, and behavioral changes • (Apovian et al., 2015; Jensen et al, 2013; WIN, 2013)

• Pharmacotherapy is considered effective if weight loss of ≥ 5% of body weight is achieved by 3 months and it is well tolerated, it can be continued (Aprovian et al., 2015). If not, it should bediscontinued.

Medication Cautions and PrecautionsPatients should be informed of the following factors in weight-loss medications:

• Expected and possible side effects • Realistic weight-loss expectations for the weight-loss medication (4 to 6% more than placebo,

depending upon the medication prescribed) • Burden and cost of medications • 6-month window of weight loss, and the need to readjust if the particular medication is not

working • Weight regain is common after stopping medication • Potential for other medications to affect weight as well • (Apovian et al., 2015; WIN, 2013)

GI Hormones Regulating AppetiteHormones that increase hunger are:

• Ghrelin • Neuropeptide

The following hormones decrease hunger and promote satiety after eating:

• Somatostatin • Cholecystokinin • Motlin


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• Insulin • Glucagon • Pancreatic polypeptide • Amylin • Fibroblast growth factor19 • Glucagon like peptide-1 • Oxyntomodulin • Peptide YY • Leptin

(Bays et al., 2017)

RESOURCES AVAILABLE THROUGH THIS MODULE:• 2013 AHA/ACC/TOS Guideline for the Management of Overweight and Obesity in AdultsEdit

These are the newest guidelines written by experts from the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and The Obesity Society. The guidelines also include a detailed treatment algorithm - The Chronic Disease Management Model for Primary Care of Patients with Overweight and Obesity. This algorithm is intended to guide providers in the evaluation, prevention and management of patients who are overweight or obese. Endorsed by the American Association of Family Physicians.

• Natural Medicines in the Clinical Management of Overweight and ObesityEdit Includes brief descriptions and research on many weight loss supplements.

• Orlistat 60 mg Information Edit Orlistat 60 mg (Alli) Information

• Orlistat 120 mg Package InsertEdit Orlistat 120 mg Package Insert

• Pharmacological management of obesity: an endocrine society practice guidelineEdit Practice guideline for obesity management by the Endocrine Society

REFERENCES USED IN THIS MODULE:

Practice Gap ReferencesApovian CM, Aronne LJ, Bessesen DH. Pharmacological management of obesity: an endocrine society practice guideline. J Clin Endocrinol Metab. 2015. Available at: http://press.endocrine.org/doi/pdf/10.1210/jc.2014-3415 Accessed on: 2015-01-23. Tanner B, Metcalf M. Needs Analysis . Improving Obesity Outcomes Through Interactive Web-Based Clinical Skills Training. . 2011. Accessed on: 2015-02-23.

Module Content ReferencesAHFS Consumer Medication Information. Orlistat. Bethesda (MD): American Society of Health-System Pharmacists, Inc.; ©2008. 2010. Available at: http://www.nlm.nih.gov/medlineplus/druginfo/meds/a601244.html Accessed on: 2014-04-07.


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https://local.impactobesity.com/node/3791/edit



http://www.gene.com/download/pdf/xenical_prescribing.pdf


https://dailymed.nlm.nih.gov/dailymed/drugInfo.cfm?setid=a2d3bd73-f3af-4ea5-a57c-66b0004cfe4f


http://naturaldatabase.therapeuticresearch.com/ce/ceCourse.aspx?s=ND&cs=&pm=5&pc=15-112


http://circ.ahajournals.org/content/early/2013/11/11/01.cir.0000437739.71477.ee.long

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AHFS Consumer Medication Information. Phentermine and Topiramate. Bethesda (MD): American Society of Health-System Pharmacists, Inc.; ©2008. 2012. Available at: http://www.nlm.nih.gov/medlineplus/druginfo/meds/a612037.html Accessed on: 2014-04-07. Apovian CM, Aronne LJ, Bessesen DH. Pharmacological management of obesity: an endocrine society practice guideline. J Clin Endocrinol Metab. 2015. Available at: http://press.endocrine.org/doi/pdf/10.1210/jc.2014-3415 Accessed on: 2015-01-23. Apovian CM. Pharmacotherapy For The Management Of Obesity. Medscape CME. 2013. Available at: http://www.medscape.org/viewarticle/809408_6 Accessed on: 2014-04-03. Banks WA. The blood-brain barrier as a regulatory interface in the gut-brain axes.. Physiol Behav. 2006. Available at: https://www.ncbi.nlm.nih.gov/pubmed/16904139 Accessed on: 2015-08-17. Bardo MT . The mesolimbic dopamine reward system and drug addiction . Biological research on addiction: comprehensive addictive behaviors and disorders . 2013; 2: 209-216. Available at: https://books.google.com/books?hl=en&lr=&id=ZUeCgcrNjOUC&oi=fnd&pg=PA209&dq=mesolimbic+dopamine+reward+pathway+review&ots=EffNWXIinA&sig=q99NfPDrLD2_wZJ31L9SXS7SI6Q#v=onepage&q&f=false Accessed on: 2015-03-20. Bays H, Scinta W. Adiposopathy and epigenetics: an introduction to obesity as a transgenerational disease. Curr Med Res Opin. 2015; 28: 1-11. Available at: http://www.ncbi.nlm.nih.gov/pubmed/26331354 Accessed on: 2015-10-29. Bays HE, Seger JC, Primack C, et al. Obesity Algorithm, presented by the Obesity Medicine Association. . 2016-2017. Available at: https://obesitymedicine.org/obesity-algorithm/ Accessed on: 2017-08-17. Blackburn GL. Making Scientific Sense of Different Dietary Approaches, Part 2: Evaluating Diets. . Medscape. Diabetes & Endocrinology. 2004; 6(1): . Available at: http://www.medscape.org/viewarticle/470747 Accessed on: 2015-01-29. Blackburn GL. Making Scientific Sense of Different Dietary Approaches, Part-1: Meeting Dietary Needs, Achieving Weight Loss. Medscape Diabetes & Endocrinology. 2004; 6(1): . Available at: http://www.medscape.org/viewarticle/469768 Accessed on: 2014-12-30. Broussard C. CNS Regulation of Weight. ASBP Obesity Medicine Review Course. 2014. Accessed on: 2015-01-29. Cansu B, Cansu DU, Kasifoglu T, et al.. Disease-modifying antirheumatic drugs increase serum adiponectin levels in patients with rheumatoid arthritis. J Clin Rheumatol. 2011; 17(1): 14-7. Available at: http://www.ncbi.nlm.nih.gov/pubmed/21169855 Accessed on: 2015-03-11. Cavaliere H, Floriano I, Medeiros-Neto G. Gastrointestinal side effects of orlistat may be prevented byconcomitant prescription of natural fibers (psyllium mucilloid).. Int J Obes Relat Metab Disord. 2001; 25(7): 1095-9. Available at: http://www.ncbi.nlm.nih.gov/pubmed/11443512?dopt=Abstract Accessed on: 2016-05-23. Coll AP, Farooqi IS, O'Rahilly S. The hormonal control of food intake . Cell. 2007; 129: 251-262. Available at: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2202913/ Accessed on: 2015-01-09. Colman E, Golden J, Roberts M, et al. The FDA's Assessment of Two Drugs for Chronic Weight Management. N Engl J Med. 2012; 367: 1577-1579. Available at: http://www.nejm.org/doi/full/10.1056/NEJMp1211277#t=article Accessed on: 2014-06-05.


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Module 8 Obesity Biology and FDA-Approved Weight-Loss ...

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