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