Tutoring Session 4/12/2017

Obesity

Therapeutics IV

Tutoring Session 4/12/2017

Sara Gordon –

Lecture objectives:

Define short and long term treatment of obesity

Determine if it’s appropriate to treat a patient with medications

Select the best treatment plan for a given patient case

Recall typical adverse effects associated with medications for obesity

Propose adjustment (dose change/discontinuation) of pharmacotherapy based on patient response

Obesity Etiology:

·  Occurs when there is increased energy storage due to energy intake > energy expenditure

·  Cause is usually multifactorial

o  Genetic influences – genetic contributions to BMI and body fat distribution is estimated to be between 40-70%

§  Single-gene mutations causing extreme obesity have been identified, but are rare

o  Environmental factors – easily accessible food, reduction in physical activity

o  Medical conditions

§  Cushing syndrome, growth hormone deficiency, leptin deficiency, some psychiatric disorders – depression, binge-eating disorder, schizophrenia

o  Medications

§  Anticonvulsants, antidepressants, atypical antipsychotics (clozapine, olanzapine, risperidone), hormones (corticosteroids, insulin)

Pathophysiology:

Associated Morbidity: pretty much every organ system – some can improve with weight loss!

·  Cardiovascular

o  HTN, HF, Varicose veins, PE

·  Respiratory

o  Dyspnea, OSA

·  Gastrointestinal

o  GERD, hernias

·  Endocrine

o  Diabetes, dyslipidemia, infertility

·  Integument

o  Cellulitis

·  Genitourinary

o  Stress incontinence, pregnancy complications

·  Musculoskeletal

o  Arthritis, low back pain, immobility

·  Cancer

o  Endometrial, post-menopausal breast, colon, renal cell carcinoma, liver, gallbladder, esophageal, pancreatic

·  Psychosocial

o  Depression, hopelessness, negative self or external perceptions

Defining Obesity:

Body Mass Index (BMI)

Weight (kg)/height (m)2

OR

Weight (lbs) x 703/height (in)2

BMI / Classification
<18.5 / Underweight
18.5-24.9 / Normal
25-29.9 / Overweight
30-39.9 / Obese
>/= 40 / Extreme Obesity

Example: AM is a 45 y/o AAF who presents for obesity follow-up. She weights 234lbs and is 5’4” What is her BMI? How would you classify AM’s obesity?

234lbs = 106.36 kg

5’4” = 162.56 cm = 1.62 m

BMI = 106.36/(1.62)2 = 44.3

Since BMI >40, AM is considered to have extreme obesity

Who needs to lose weight?

BMI >/= 30

OR

BMI 25-29.9 with >/= 1 CVD risk factor(s)

Those patients with BMI 25-29.9 without CVD risk factors should be advised to not gain any weight, but not recommended to lose weight

Patients should lose 5-10% of total body weight within first 6 months; sustained weight loss 3-5% of total body weight reduces TG, BG/A1c, risk of developing DM

Non-pharmacologic weight loss

·  Caloric deficit (diets)

o  Lifestyle modifications

·  Behavioral therapy

o  Goal setting

o  Recording meals, cravings, etc.

·  Exercise

Start with small changes

Pharmacotherapy

Indicated for patients:

·  BMI 27-29.9 with comorbidities (HTN, dyslipidemia, T2DM, OSA)

·  All patients with BMI >/= 30

Short Term Adjunct Therapy / Long Term Therapy
·  Phentermine (Adipex-P, Phentercot, Suprenza)
·  Diethylpropion (Tenuate, Tenuate Dospan) / ·  Orlistat HCl (Xenical, Alli)
·  Lorcaserin HCl (Belviq)
·  Phentermine/Topiramate ER (Qsymia)
·  Naltrexone/Bupropion ER (Contrave)
·  Liraglutide (Saxenda)

Short-Term Therapy:

Phentermine:

·  Phentermine is structurally similar to amphetamine, but less severe CNS stimulation and lower abuse potential – enhances norepinephrine and dopamine neurotransmission, resulting in appetite suppression

o  Effective adjunct to diet, exercise, and behavior modification for producing weight loss

·  Dose: 15-30mg (capsule) daily; 37.5mg (tablet) daily

o  8mg TID before meals

o  Avoid dosing at bedtime d/t insomnia

o  Product labeling indicates short-term (a few weeks) use monotherapy only

·  ADRs: increases in BP, palpitations, and arrhythmias

o  Not recommended for patients with hypertension or underlying cardiac abnormalities

·  Do not use within 14 days of MAOIs due to potential for hypertensive crisis

·  Contraindicated in patients with hyperthyroidism or agitated states

·  Potential for excessive adrenergic stimulation and abuse potential – do not use in patients who abuse substances like cocaine, methamphetamine, etc.

Diethylpropion:

·  Stimulates Norepi release from presynaptic storage granules – increases adrenergic neurotransmitter concentrations which activates hypothalamic centers; results in decreased appetite and food intake

·  Dose 25mg TID before meals or 75mg daily (ER formulation)

o  Insomnia may occur if taken in late afternoon

·  Do not use in patients with severe hypertension or significant cardiovascular disease

Long-Term Therapy:

Orlistat (Xenical, Alli):

·  Lipases are essential for absorption of long-chain triglycerides for dietary fat

·  Lipase also has a role in helping gastric emptying

·  Orlistat is a synthetic lipstatin; reversible inhibitior of intestinal lipases, binds gastric and pancreatic lipases, making them unavailable to hydrolyze dietary triglycerides into absorbable fatty acids

·  Minimally absorbed – reduces dietary fat absorbed through selective inhibition of GI lipase

·  Also results in malabsorption of cholesterol due to lower luminal free fatty acid concentrations

·  Alli (OTC) 60mg TID

·  Xenical (Rx) 120mg TID

o  Achieves up to 30% reduction in fat absorption

o  Must be taken within 1 hour of eating foods containing fat – if meal is skipped or does not contain any fat, the dose can also be skipped

·  Longest clinical safety data is 4 years

o  Decreased the rate of development of type 2 DM, improved lipid profile

·  GI ADRs: soft stool, abdominal pain, flatulence, fecal urgency, incontinence

o  More common in first 1-2 months of therapy, tend to improve with continued use

o  Limiting dietary fat before starting orlistat therapy may help

o  Severe diarrhea may limit absorption of other medications and vitamins

§  Consider multivitamin supplementation

§  Use caution with narrow therapeutic index drugs (warfarin, dig, levothyroxine)

o  Possibility of liver injury – no definite causality to orlistat, but 13 total cases of liver damage with orlistat use. Monitor for s/s of liver injury – yellowing eyes/skin, dark urine, loss of appetite, or light colored stools

Lorcaserin (Belviq):

·  Selective agonist serotonin 2C receptor – anorexigenic neuron

o  Results in appetite suppression, leading to reduced caloric intake and enhanced satiety

·  Dose: 10mg BID (immediate release), 20mg daily (Extended release)

o  Can take with or without food

o  Swallow ER tablet whole – do not crush or chew

o  Class IV due to potential for abuse

·  Improvements in fasting glucose, insulin, total cholesterol, LDL, and TG

·  Modest weight loss, but significantly greater weight loss than placebo

o  **If 5% weight loss not achieved by week 12, agent should be discontinued because it is unlikely that a benefit will be seen

·  ADRs: headache, dizziness, constipation, fatigue, dry mouth

o  Cardiac valvulopathy – heart valves become inflamed and stiff; occurred in clinical trial but was not significantly different between those on lorcaserin v. placebo

§  Though to be related to stimulation of 5-HT2B receptors on cardiac cells; at therapeutic doses of locaserin, selective for central 5-HT2C receptors

§  Use cautiously in patients with congestive heart failure

o  Other rare ADRs include psychiatric disorders, priapism, and elevated serum prolactin concentrations

·  Do not use in combination with other serotonergic and dopaminergic drugs

o  Increased risk of serotonin syndrome or neuroleptic malignant syndrome-like reactions

Phentermine-Topiramate ER (Qsymia):

·  Phentermine – similar to amphentamine, NE & dopamine neurotransmission (see above)

·  Topiramate’s action for weight management is not known, may decrease appetite and increase satiety through multiple pathways

·  Dose: Phentermine 3.75-15mg/topiramate 23-92mg

o  Lower than therapeutic doses of each agent when used as monotherapy

§  **Phentermine short term monotherapy for obesity 37.5mg

o  Start at low dose 3.75/23mg daily and increase after several weeks to a max dose 15/92mg daily

§  When discontinuing therapy, drug should be slowly tapered off to prevent seizures

o  Class IV due to abuse potential

·  ADRs: constipation, dry mouth, paraesthesia, insomnia

o  Increased HR 10-20 beats/min

o  Electrolyte abnormalities – decreased serum bicarbonate, hypokalemia, increased SCr

·  **Contraindicated in pregnancy b/c topiramate is known teratogen – REMS, women must have documented negative pregnancy test before beginning therapy and then monthly

·  Do not administer with MAOIs – potential for hypertensive crisis; d/c 14 days prior

·  **If 5% weight loss not achieved by week 12, agent should be discontinued because it is unlikely that a benefit will be seen

Naltrexone/bupropion ER:

·  Exact mechanism not fully understood – naltrexone is an opioid antagonist, bupropion is an antidepressant with weak inhibitory effects on dopamine and NE neuronal reuptake; increase activation of hypothalamic neurons which depresses appetite and enhances rewards system

·  Dose: naltrexone 8mg/bupropion 90mg once daily, then increase to maintenance dose of 2 tablets BID (max dose)

o  Do not take with a high-fat meal as this increases systemic exposure to both naltrexone and bupropion

o  **If 5% weight loss not achieved by week 12, agent should be discontinued because it is unlikely that a benefit will be seen

·  ADRs: nausea, constipation, headache, vomiting, dizziness, insomnia, dry mouth, diarrhea

o  Increases in HR and BP – do not use in patients with uncontrolled hypertension

o  Naltrexone – hepatotoxicity

o  Bupropion – lowers seizure threshold, associated with neuropsychiatric reactions and increased risk of suicidal thoughts

·  Contraindicated in patients taking chronic opioids (naltrexone)

Liraglutide:

·  GLP-1 analog; GLP-1 is released in response to food digestion and stimulates GLP-1 receptors in the brain to reduce appetite. Also stimulates insulin secretion and reduces glucagon secretion (diabetes)

·  Dose: 0.6mg daily, increased by 0.6mg weekly to maintenance dose of 3mg daily

o  Improves tolerability of GI ADRs – if at any point patient cannot tolerate GI ADRs, dose titration may be delayed by 1 week

o  Subcutaneous administration, available in prefilled, multidose pen

·  ADRs: nausea, diarrhea, constipation, vomiting, abdominal pain

o  Rare cases of acute pancreatitis, potentially leading to fatal hemorrhagic or necrotizing pancreatitis

o  Small increases in HR 2-3 beats/min, some increased by 20 beats/min

·  BBW: Risk of thyroid C-cell tumors, including medullary thyroid carcinoma – contraindicated in patients with personal or family history of thyroid cancer

·  **Discontinue if weight loss of 4% not achieved after 16 weeks of therapy

Theoretically, should be able to use combination therapy of agents – no clinical trials to support; combination therapy not recommended

Patient Case:

SB is a 48 y/o woman with PMH hypertension, sleep apnea, osteoarthritis, and depression. She has struggled with her weight since her teenage years and has progressively gained ~2 kg/year since her 20s. She is 168 cm tall, current weight 98kg. She presents to her PCP for routine physical and complains of dissatisfaction with her weight. She expresses a desire to attempt medication therapy for weight loss. Her current medications include HCTZ, metoprolol, naproxen, and tramadol.

What is SB’s BMI? 34.7

98/(1.68^2)

Which comorbidities that SB has may improve with weight loss?

·  HTN, osteoarthritis, sleep apnea

What would be appropriate goals for weight loss over the next 12 months? What type of nutritional and exercise plan should be recommended?

·  SB (b/c she’s obese) should strive to lose 10% of baseline weight at 1-2 pounds/week with an energy deficit of 500 kcal/day for 6 months

o  Overweight: 0.5 pounds/week with energy deficit 300-500kcal/day

·  Aim for 30 minutes/day moderate intensity physical exercise (increase slowly)

·  Even 5% weight loss is associated with significant improvements in health status

·  Behavioral modifications including support groups, balanced diets, and exercise are most effective

o  Supportive family therapy is desirable

o  Learn new coping skills to avoid over-eating

·  SB should try pharmacologic measures for at least 6 months before considering pharmacologic therapy

What if SB returns the following year for her routine physical. She has managed to lose 14 kg and her BMI is now 29.8. She would like to lose additional weight as she continues to struggle with HTN, depression, OA, and OSA. Would a sympathomimetic agent be a good choice for SB?

·  SB would be a candidate for pharmacologic therapy b/c she is overweight (BMI 29.8) and has obesity-related risk factors of HTN, OSA< and OA. She has had some results with behavioral modification therapy but would benefit from additional weight loss.

o  Pharmacologic agents should not be considered as replacement of non-pharmacologic strategies, but as add-on therapy

·  Due to HTN, sympathomimetic may not be ideal agent

·  Orlistat 120mg TID with meal could be an appropriate agent

o  Counsel on GI effects, usually get better with continued use

o  Initiate multivitamin