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Evolving Treatment Strategies:The Complexity of Energy Homeostasis
Artificial sweetners lead to weight gain?
Energy Balance and Body Weight:What is Metabolism?
Body WeightEnergy In(Caloric Intake)
Energy Out(Metabolism)
Energy Homeostasis:The Quick Fix?
The Diet StrategyFailure Rate of Diet Alone 90-98%
Weight
Baseline
Counter-Regulation
New Set Point
↓ 5-10%
Weight ManagementCounter-Regulation and the Failure of the “Diet” – HCG Diet
Weight LossCounter-Regulation and the Failure of the “Diet” –
Ideal Protein
295
Ideal Protein Diet↓ 28%
211
308
Fatigue, Depression, Fibromyalgia,Sleep Disorder,
“Must be something hormonal”
Energy Balance and Body Weight:What is Metabolism?
Body WeightEnergy In(Caloric Intake)
Energy Out(Metabolism)
Low MetabolismHow Do I Fix It? – “Get Your Ducks in a Row”
• Sleep Problems – Sleep Apnea
• Vitamin D Deficiency
• Thyroid
• Vitamin B12
• Low Testosterone (male)
• Medications (centrally acting)
Energy Homeostasis:The Miracle Pill?
Energy Homeostasis:The Search for the Magic Pill?
SubstratesGlucose
AminoacidsFree Fatty Acids
Lipids
HormonesInsulinLeptinGhrelin
PYYCCK
Adiponectin
MechanicalGastric Distension
NeuralVagal Afferents
PsychologicalPleasureRewardVisual
OlfactoryTaste
Hypothalmus
Dopamine, CannabanoidsNorepinephrine, NPY
Serotonin, POMC,GABA etc…
SibutramineSibutramine(Meridia)(Meridia)
SibutramineSibutramine(Meridia)(Meridia)
TopiramateTopiramate(Topomax)(Topomax)TopiramateTopiramate(Topomax)(Topomax)
PhenterminePhenterminePhenterminePhentermine
RimonobantRimonobantRimonobantRimonobant
QsymiaQsymia(phentermine + (phentermine +
topiramate)topiramate)
QsymiaQsymia(phentermine + (phentermine +
topiramate)topiramate)
ContraveContrave(bupropion + (bupropion + naltrexone)naltrexone)
ContraveContrave(bupropion + (bupropion + naltrexone)naltrexone)
Energy Balance Center
Weight Loss Pills
EmpaticEmpatic(bupropion + (bupropion + zonisamide)zonisamide)
EmpaticEmpatic(bupropion + (bupropion + zonisamide)zonisamide)
TesofensineTesofensine((NS2330))
TesofensineTesofensine((NS2330)) 4-8% Total body weight loss
Not sustainable20-30% Non-response rate
The Miracle Pill
Making Progress??
Belviq N=8,000 52-104 weeks
Weight Loss: 3-3.7% over placebo
47% loss >5%
Dosing: 10mg BID
Belviq N=8,000 52-104 weeks
Weight Loss: 3-3.7% over placebo
47% loss >5%
Dosing: 10mg BID
Qsymia N=3,700 52-104 weeks
Weight Loss: 6.7-8.9% over placebo
70% loss >5%
Dosing: 3.75/23mg, 7.5/46mg, 11.25/69mg, 15/92mg
Qsymia N=3,700 52-104 weeks
Weight Loss: 6.7-8.9% over placebo
70% loss >5%
Dosing: 3.75/23mg, 7.5/46mg, 11.25/69mg, 15/92mg
The Ominous Octet – Treatment Strategies
Islet -cell
ImpairedImpairedInsulin SecretionInsulin SecretionImpairedImpairedInsulin SecretionInsulin Secretion
NeurotransmitterNeurotransmitterDysfunctionDysfunction
Decreased GlucoseDecreased GlucoseUptakeUptakeDecreased GlucoseDecreased GlucoseUptakeUptake
Islet -cell
IncreasedIncreasedGlucagon SecretionGlucagon SecretionIncreasedIncreasedGlucagon SecretionGlucagon Secretion
IncreasedIncreasedLipolysisLipolysisIncreasedIncreasedLipolysisLipolysis
Increased GlucoseIncreased GlucoseReabsorptionReabsorptionIncreased GlucoseIncreased GlucoseReabsorptionReabsorption
IncreasedIncreasedHGPHGPIncreasedIncreasedHGPHGP
DecreasedDecreasedIncretin EffectIncretin Effect
DecreasedDecreasedIncretin EffectIncretin Effect
Surgery?
ADA Clinical Practice Recommendations 2011:Changing Treatment Paradigms
Energy Homeostasis:A Role for Surgery?
Lap BandRestriction of caloric intake
Gastric Bypass (Roux-En-Y)Restriction of caloric intakeMalabsorption of nutrients
X
Gastric Bypass: Five Operations
CONFIDENTIAL
Gastric Bypass: Five Operations
1. Isolation of gastric cardia
CONFIDENTIAL
Gastric Bypass: Five Operations
2. Exclusion of distal stomach
CONFIDENTIAL
Gastric Bypass: Five Operations
3. Exclusion of duodenum and proximal jejunum
CONFIDENTIAL
Gastric Bypass: Five Operations
4. Exposure of distal jejunum to undigested nutrients
CONFIDENTIAL
Gastric Bypass: Five Operations
5. Partial vagotomy
CONFIDENTIAL
Energy Homeostasis:A Role for Surgery?
Sleeve GastrectomyStomach becomes a “sleeve”Alters signaling mechanismsIndependent glycemic effect
Metabolic Surgery: The STAMPEDE Trial
Type 2 DM, A1c > 7.0%, BMI 27 - 43
N = 150, single center, one surgeon
Intensive Medical Therapy
No Surgery
Sleeve Gastrectomy
Gastric Bypass
Primary Outcome: Proportion with A1c < 6.0% at 12 months
Metabolic Surgery: The STAMPEDE Trial
Metabolic Surgery: The STAMPEDE Trial
THE END