1. Weight Regulation: Discovery Timeline
Pre-modern
Modern
“Gluttony”
“Sloth”
Weight Regulation
Physiology / Pathophysiology
1994

2. Weight Regulation Physiology
The body weight Set Point is tightly regulated:
Sensing mechanisms detect environmental changes in food intake (type, quantity) and activity level, as well as adipose tissue content.

3. Weight Regulation Physiology
The body weight Set Point is tightly regulated:
Sensing mechanisms detect environmental changes in food intake (type, quantity) and activity level, as well as adipose tissue content.
Effector systems respond (adapt) with changes in appetite and energy expenditure.
Weight loss (or gain) is limited and baseline weight eventually restored

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

5. Weight Regulation (Patho)Physiology
Overweight and obesity results when the body establishes 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).

6. Overweight and Obesity: Take Home Message
Obesity is a Chronic Disease (same as HTN, T2DM):
Weight is physiologically (homeostatically) regulated to remain within a normal set range of body weight (set point).
Pathophysiologic alteration in set point leads to defense/maintenance of higher body weight.
Accumulation of excess body fat proportional to body size that leads to impaired health.

7. Overweight and Obesity: Take Home Message
To achieve sustained weight loss, any therapy must ultimately “interfere” with the way that the brain senses and responds to feedback signals, preventing counter-regulatory appetite and energy expenditure adaptions from restoring baseline weight. (and be continued long-term)

8. Recommendation For Consideration of Pharmacological Weight Management
BMI kg/m2 and a weight-related comorbidity:
HTN
Dyslipidemia
Diabetes
Other OR
BMI  30 kg/m2

9. 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)
lorcasarin (Belviq)
bupropion + naltrexone (Contrave)
liraglutide 3.0 (Saxenda)

10. Weight Loss Medications Enhance CNS Signaling to Meal-related Signals
phentermine
phentermine + topiramate
lorcasarin
bupropion + naltrexone
liraglutide
 CNS Hunger Signaling
 CNS Satiety Signaling

11. Weight Loss With Phentermine Monroe, et al. BMJ. 1:352-54. 1968.
8 and 37.5 mg tablets
15 and 30 mg capsules
~ 9-10% wt loss

12. Phentermine: Side Effects and Precautions
Short-Term: Adrenergic stimulation
Insomnia
Dry mouth
Increased heart rate and BP
Anxiety
Long-term:
BP stable or reduced with weight loss
No addictive behavior demonstrated
Can be continued more than 6-12 weeks per Qsymia package insert: “…an adjunct to a reduced-calorie diet and increased physical activity for chronic weight management in adult patients…”
International Journal of Obesity (2014) 38, 292–298.
Obesity (2011) 19, 2351–2360.
American Journal of Therapeutics (2011) 18, 292–299

13. Weight Loss with Phentermine + Topiramate (Qsymia) Garvey WT, et al
Weight Loss with Phentermine + Topiramate (Qsymia) Garvey WT, et al. Am J Clin Nutr. 2012;95:
-1.8%
-9.3%
-10.5%

14. Weight Loss With Lorcaserin (5-HT2C agonist) Smith, et al. NEJM
-6 %

15. Weight Loss Medications Enhance CNS Signaling to Meal-related Signals: Lorcaserin
Discontinuation rates due to Drug AE’s*
Placebo – 6.7 %
Lorcaserin – 8.6 %
Headache 1.3% vs 0.8%
Depression 0.9% vs 0.5%
Dizziness 0.7% vs. 0.2%
No stimulating effects  can be used in the cardiovascular patient
If patient on SSRI or other serotonin medications then use with “extreme caution” due to serotonin syndrome risk.
*Lorcaserin (Prescribing Information) Woodcliff Lake, NJ Eisai Inc. 2012

16. Naltrexone and Bupropion SR: Weight Loss Greenway FL, et al. Lancet
-8 %

17. Naltrexone and Bupropion SR Adverse Events and Other Effects
Nausea (32.5 % vs 6.7%)
(Forced Titration in studies)
Vomiting (10.7% vs 2.9%)
Constipation
Headache
Dizziness
Insomnia
Take second dose late afternoon, not late evening
Dry mouth

18. Naltrexone and Bupropion SR (Contrave) Adverse Events and Other Effects
Recommend slow titration to start due to nausea
Monitor BP Regularly
Do not give to patient on chronic opioids
Ticlopidine and Clopidogrel (Plavix)
Decrease dose to 1 BID
Seizure risk with bupropion:
Do not give to patients with a seizure history or bulimia
Taper off (do not stop abruptly)

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

20. Liraglutide 3.0 Adverse Events and Other Effects
Nausea %
Titrate slowly
Vomiting %
Elevated pancreatic enzymes
Pancreatitis 0.2% vs. Placebo 0.0%
Diarrhea – 20.9%
Constipation – 20.0%
Acceptable to use in patients with cardiovascular disease
Do not use:
Personal history of pancreatitis
Personal or family history of medullary thyroid cancer (MEN)

21. 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:
Patient is a non-responder
Side effect(s) emerge
Avoid use of phentermine, phentermine/topiramate ER, and buproprion/naltrexone SR in patients with:
Active CAD/CHF
Untreated HTN
Untreated hyperthyroidism
MAO inhibitors

22. Obesity (as a disease) Management: Timeline
Pre-modern
Modern
Ave. Weight Loss
Lifestyle: ~ 4%
Pharmacology: ~6-10%
Bariatric surgery: ~25-30%
Ave. Weight Loss
“Eat less < 5%
Move More”
1994