Anti-Obesity Medications: Tips and Practical Pearls for ...

DATE: 9 Apr 2021 PRESENTED BY: Jonathan Q. Purnell, MDProfessor, Knight Cardiovascular InstituteDivision of EndocrinologyOregon Health & Science UniversityPortland, Oregon

Anti-Obesity Medications:Tips and Practical Pearls for Use

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Disclosures

Novo Nordisk: Consulting FeeOHSU

Obesity: A Chronic Disease

• Obesity is a Chronic Disease (same as HTN, T2DM)

• Therapy is lifelong:– Lifestyle– Anti-obesity medications– Metabolic-bariatric surgery

• Combination therapy is the norm– Similar to ADA treatment guide for medical management of T2DM– Includes combining weight loss meds and surgery

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Managing Weight as a Chronic Disease

Weight Management Specific Practice Tips:– Use “people-first” language: Patients “with obesity” vs. “are obese.”

– Create a “weight history” to identify:

• Onset of unwanted weight gain

• Sudden jumps and timing to specific meds, medical diseases

• Relationship to pregnancy, menopause

• Lifetime max

• Any previous strategies that had been successful

• Current weight

– Identify and code for any obesity-related complication that is covered

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Obesity is associated with multiple complicationsMetabolic, Mechanical and Mental

CVD, cardiovascular disease; NAFLD, non-alcoholic fatty liver disease;*Including breast, colorectal, endometrial, esophageal, kidney, ovarian, pancreatic and prostate.

Adapted from Sharma. Obes Rev 2010;11:808-9; Guh et al. BMC Public Health 2009;9:88;Luppino et al. Arch Gen Psychiatry 2010;67:220–9; Simon et al. Arch Gen Psychiatry 2006;63:824–30;

Church et al. Gastroenterology 2006;130:2023–30; Li et al. Prev Med 2010;51:18–23; Hosler. Prev Chronic Dis 2009;6:A48.

METABOLIC

Type 2 diabetesPrediabetesGestational diabetes

Cardiovascular diseases• Stroke•Dyslipidaemia•High blood pressure• Coronary artery disease

Atrial fibrillationHeart failure

CANCERS*

Gout

MENTAL

PHYSICALFUNCTIONING

MECHANICAL

Sleep apnoea

Chronic back pain

Infertility

Fatty liver

Asthma

Gallstones

Incontinence

Joint disease

Depression

AnxietyOHSU

• Update on Physiology and of Pathophysiology of Weight Regulation

• Treatment of Overweight and Obesity with Medications

Weight Management: Chronic Disease Model

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Weight Is Regulated Through the Interaction of Three Major Organ Systems

Gastrointestinal (GI)System

Brain: Hypothalamus and Brainstem

Adipose Tissue StoresOHSU

Nutrient Absorption Triggers Secretion of Gut Hormones: “Sensing Food” and Conveying Biologic Appetite Signals to CNS

Ghrelin → hunger

CCK Insulin Amylin PYY GLP-1

→ satietyOHSU

Meal-related Satiety Gut Hormone Appearance: Sensing Food Availability and Calories Consumed

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Time After Meal (Minutes)

SatietyFullnessSatisfaction

Hunger

Normal Meal CaloriesNormal FullnessNormal Hunger SuppressionOHSU

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Time After Meal (Minutes)

SatietyFullnessSatisfaction

Hunger

50% Meal Calories 50% Fullness / Satisfaction 50% Hunger Suppression

and quicker return

Meal-related Satiety Gut Hormone Appearance: Sensing Food Availability and Calories Consumed

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CNS Body Weight Regulation Center “Senses” Adiposity Signal from Fat Depots

Adipose Tissue Stores

LeptinOHSU

CNS Integrates Adiposity and Meal-related Signals to Maintain Body Weight Set Point (Range)

Ghrelin

CCKInsulinAmylinPYY GLP-1 ..others

“Are you weighing what I think you should?”

“Are you eating enough (or too much) to maintain that weight?”

Leptin

+ 5 lbs.

- 5 lbs.OHSU

Hypothalamic control of energy homeostasis by adiposity signals: the set point

Decrease body fat:Food IntakeEnergy Expenditure

PVN

LHA

Arcuate

MCH

Orexins

Increase body fat:Food IntakeEnergy Expenditure

+–

POMC→-MSHCART

MC4R

LEPTIN INSULIN

NPY/AgRP

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Weight Regulation (Patho)Physiology

Overweight and obesity results when leptin resistance (deficiency) occurs, establishing a higher body weight Set Point.

This higher Set Point is tightly regulated to limit weight loss (or gain) and restore baseline weight following caloric restriction (overfeeding).

This occurs in ~70% of the US Population

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• Update on Physiology and of Pathophysiology of Weight Regulation

• Treatment of Overweight and Obesity with Medications

Weight Management: Chronic Disease Model

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Eligible Patients for Pharmacological Weight Management

• BMI 27 - 30 kg/m2 and a weight-related comorbidity:

– HTN

– Dyslipidemia

– Diabetes

– Other

OR

• BMI 30 kg/m2

https://www.nhlbi.nih.gov/files/docs/guidelines/prctgd_c.pdf

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Pharmacological Weight Management

Currently FDA Approved Medications for Weight Loss

• tetrahydrolipstatin (Orlistat) $$$

– (now over the counter as “alli”-60 mg dose)

• phentermine (Fastin, Ionamin, Adipex) $

• phentermine + topiramate (Qsymia) $ or $$

• bupropion + naltrexone (Contrave) $$

• liraglutide 3.0 (Saxenda)

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Weight Loss Medications Enhance CNS Signaling to Meal-related Signals (Fullness) and Diminish Hunger

CNS Hunger Signaling

CNS Satiety Signaling

• phentermine • phentermine + topiramate• bupropion + naltrexone• liraglutideOHSU

Weight Loss with Phentermine + Topiramate (Qsymia)Garvey WT, et al. Am J Clin Nutr. 2012;95:297-308.

-9.3%

-10.5%

-1.8% OHSU

Phentermine: Side Effects and Precautions

Short-Term: Central Adrenergic Agonism• Insomnia• Dry mouth• Increased heart rate and BP• Anxiety

Long-term:• BP stable or reduced with weight loss

• Addictive behaviors not demonstrated

• Can be continued as Qsymia long-term or more than 12 weeks as a single agent off label.

International Journal of Obesity (2014) 38, 292–298.Obesity (2011) 19, 2351–2360.American Journal of Therapeutics (2011) 18, 292–299

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Topiramate: Side EffectsMed Lett. 54(3): 69-71, 2012

• Paresthesias• Cognitive effects

• Concentration• Memory• Word finding

• Metabolic acidosis• Kidney stones• Birth defects (oral clefts)

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Cardiovascular Safety During and After Use ofPhentermine and TopiramateRitchey ME, et al. J Clin Endocrinol Metab. 2019, 104(2):513–522

-9.3%

-10.5%

-1.8%

MACE variables: hospitalization for AMI or stroke and in-hospital CV-related death

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Weight Loss With Buproprion + Naltrexon (Contrave)Nissen SE, et al. JAMA. 2016;315(10):990-1004.

~-4-5 %OHSU

Non-inferior Effect of Buproprion + Naltrexon (Contrave) on MACENissen SE, et al. JAMA. 2016;315(10):990-1004.

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Naltrexone and Bupropion SR (Contrave)Adverse Events and Other Effects

• Nausea (32.5 % vs 6.7%)

– (Forced Titration in studies)

• Vomiting (10.7% vs 2.9%)

• Insomnia

– Take second dose late afternoon, not late evening

• Dry mouth

• Constipation, Headache, Dizziness

• Taper off to reduce likelihood of seizures

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Liraglutide 3.0 for Weight Management and Type 2 Diabetes Risk Reduction in Pre-diabetesle Roux, et al. Lancet 2017; 389: 1399–409

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~80% risk reduction for diabetes

Liraglutide 3.0 for Weight Management and Type 2 Diabetes Risk Reduction in Pre-diabetesle Roux, et al. Lancet 2017; 389: 1399–409

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LEADER: Liraglutide 1.8 mg Improves Cardiovascular Outcomes and All Cause Mortality in Type 2 DiabetesMarso SP et al. N Engl J Med 2016;375:311-322.

Nonfatal MI or stroke or death from CV causes.OHSU

Liraglutide 3.0Adverse Events and Other Effects

• Nausea - 40.2%

– Titrate slowly

• Vomiting - 16.3%

• Elevated pancreatic enzymes

• Pancreatitis 0.2% vs. Placebo 0.0%

• Diarrhea – 20.9%

• Constipation – 20.0%

• Acceptable to use in patients with CAD, CKD

• Do not use:

– Personal history of pancreatitis

– Personal or family history of medullary thyroid cancer (MEN)

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Pharmacological Weight Management: Tips

• Lifestyle is always attempted first and continued during treatment.

• All drugs are Category X for Pregnancy and Lactation.

• All drugs have been shown to improve cardiometabolic risk factors.

• Weight loss is variable.

• Continue treatment long-term (do not stop) unless:

– Side effect(s) emerge

– Pregnancy is planned or occurs

• Avoid use of phentermine, phentermine/topiramate ER, and buproprion/naltrexone SR in patients with:

– Active CAD/CHF/Arrhythmias

– Untreated HTN

– Untreated hyperthyroidism

– MAO inhibitors

• Hypoglycemia is a risk in patients with diabetes treated with oral hypoglycemic med and insulin

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Reasons for Underutilization of Weight Management Medications

• Previous weight loss drugs had poor safety record (fenfluramine, sibutramine, rimonabant)

• Perceived need for frequent follow-ups needed for AE monitoring

• Some are controlled substances:

– Phentermine is a DEA schedule IV (low potential for abuse and low risk of dependence)

– Compared to Adderall, Concerta, and Vyvanse (all schedule II)

• Lack of understanding of current guideline recommendations

• Misperception that meds are only used “short-term,” leading to weight regain

• Variable response among patients, including many “non-responders”

• Poor and inconsistent insurance coverage

Slide credit: clinicaloptions.com

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Weight Curve: Example of Using Rx for Weight Stability

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MediFastDaily exercise

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150

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Phentermine:18.75 → 37.5 mg

Weight Curve: Example of Using Rx for Weight StabilityMediFastDaily exercise

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150

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239 241

160 168 165 166

0 3 10 11 12 13 14 15

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Phentermine:18.75 → 37.5 mg

Weight Curve: Example of Using Rx for Weight StabilityMediFastDaily exercise

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Pharmacological Weight Management

(Endocrine Reviews. 39: 79 – 132, 2018)

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Thank YouOHSU

Weight Curve

150

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239 241261

287

2005 2006 2013 2015 2016 May-17 Oct-17 Apr-18

Bo

dy

Wei

ght

(lb

s)24 hour urineCortisol, TSH—NL

48 yo womanBMI: 44 kg/m2

OSA, OA knee

TSH-NL

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Weight Curve

150

200

239 241261

287

2005 2006 2013 2015 2016 May-17 Oct-17 Apr-18

Bo

dy

Wei

ght

(lb

s)24 hour urineCortisol—NL

Phentermine:18.75 → 37.5 mg

TC: 204TG: 319LDL: 147HDL: 25A1c: 6.4%

48 yo womanBMI: 44 kg/m2

OSA, OA knee

TSH-NL

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Weight Curve

150

200

239 241261

287266

2005 2006 2013 2015 2016 May-17 Oct-17 Apr-18

Bo

dy

Wei

ght

(lb

s)24 hour urineCortisol—NL

Phentermine:18.75 → 37.5 mg

TC: 204TG: 319LDL: 147HDL: 25A1c: 6.4%

TC: 190TG: 202LDL: 121HDL: 29OHSU

Weight Curve: Next Steps

150

200

239 241261

287266

2005 2006 2013 2015 2016 May-17 Oct-17 Apr-18

Bo

dy

Wei

ght

(lb

s)24 hour urineCortisol—NL

Phentermine:18.75 → 37.5 mg

TC: 204TG: 319LDL: 147HDL: 25A1c: 6.4%

TC: 190TG: 202LDL: 121HDL: 29

Topiramate:25 → 100 mg BID

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Weight Curve: Next Steps

150

200

239 241261

287266

245

2005 2006 2013 2015 2016 May-17 Oct-17 Apr-18

Bo

dy

Wei

ght

(lb

s)24 hour urineCortisol—NL

Phentermine:18.75 → 37.5 mg

TC: 204TG: 319LDL: 147HDL: 25A1c: 6.4%

TC: 190TG: 202LDL: 121HDL: 29

TC: 196TG: 134LDL: 135HDL: 34A1c: 5.5%

BP: 107/55

Topiramate:25 → 100 mg BID

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