Obesity

OBESITYPathophysiology and Management

Fardan QadeerResident, Department of PharmacologyELMC&H

Moderator:Dr. Ali Ahmad

OVERVIEW

EPIDEMIOLOGY

CLASSIFICATION OF OBESITY

MEDICAL COMPLICATIONS OF OBESITY

ETIOLOGY

MANAGEMENT OF OBESITY

PHARMACOTHERAPY

According to the WHO(2014) more than 1.9billion adults, 18 years and older, wereoverweight. Of these over 600 million wereobese.

Overall, about 13% of the world’s adultpopulation (11% of men and 15% of women)were obese in 2014.

WHO defines obesity as “abnormal or excessive fataccumulation.”

The Obesity is classified according to the BMI:

COMPLICATIONS:

ETIOLOGYIt may be simply attributed as the imbalance between energy intake

and energy output however it has a more complex and multifactorial

etiology. Possible factors in the development of obesity include the

following:

Race, sex, and age factors

Ethnic and cultural factors

Metabolic factors

Genetic factors

Psychological factors

Endocrine factors

Dietary habits

Level of inactivity

Psychological factors

THE REGULATION OF BODY WEIGHT

This process is tightly regulated by a homeostatic system thatintegrates inputs from a number of internal sensors andexternal factors.

Important components of the system include the following:

•Hormones that signal the status of fat stores (e.g. leptin).

•Hormones released from the gut during feeding that conveysensations of hunger (e.g. ghrelin), satiety (e.g. CCK) orsatiation (e.g. PYY3-36).

THE REGULATION OF BODY WEIGHT

•This hormonal information together with neural gustatory,olfactory and viscerosensory input is integrated in thehypothalamus.

•Two groups of opposing neurons in the arcuate nucleussense hormonal and other signals. Those secretingPOMC/CART products promote feeding while thosesecreting NPY/AgRP inhibit feeding.

•The net output from this process is relayed to other sitesin the brain stem motor nuclei that control feedingbehaviour.

LEPTIN: ITS ROLE IN OBESITY

Friedman and his colleagues in 1994 identified a protein leptin.

When recombinant leptin was administered in animals it strikinglyreduced food intake and body weight.

It had a similar effect when injected directly into the lateral or the thirdventricle, implying that it acted on the regions of the brain that controlfood intake and energy balance.

LEPTIN ARCUATE NUCLEUS

Glucocorticoids insulin

oestrogens

Beta adrenergic stimulation

+

-

ADIPONECTIN

A peptide hormone made by adipocytes in response to high fat reserves:

Increases FA uptake by myocytes and the rate of FA oxidation.

Slows FA synthesis in the liver.

Slows gluconeogenesis in the liver.

Adiponectin is the only adipose-specific protein known to date that is negatively regulated in obesity

Adiponectin levels are significantly reduced among obese subjects in comparison with lean control subjects

GUT HORMONES

PYY- Peptide YY

1. Secreted from L cells of GI tract

2. Reduces food intake

Ghrelin

1. Mainly secreted from stomach

2. A potent Orexigenic

Cholecystokinin

1. Mainly secreted in duodenum

2. Decreasing meal size and duration both

THE PATHOGENESISLEPTIN DISORDER

Insufficient amounts of this hormone.

resistance to leptin

Defect in leptin carriage, transport into the CNS,

Leptin receptor defect in the hypothalamus (as occurs in db/db mice)

Postreceptor signalling

Mediators other than leptin are certainly implicatedin obesity. TNF-α, and cytokines that can relayinformation from fat tissue to brain, is increased inthe adipose tissue of the obese individuals.

Reduced insulin sensitivity of muscle and fat,

alterations in the function of specific nuclearreceptors, such as PPARα, β and γ, may play a rolein obesity.

Proopiomelanocortin (POMC)

Alpha-MSH

melanocortin

receptor 4

Genetic defects in POMCproduction and mutations in the MC4 gene are described as monogenic causes of obesity in humans

Reduce dietary intakeData suggest that up to 5% of children who are morbidly obese have MC4 or POMC mutations

Most common identifiable genetic defects associated with obesity in humans

Prohormone convertase

Genetic factors are presumed to explain 40-70% of the variance in obesity.

Genome-wide association studies have found a robust number of genetic susceptibility loci associated with

obesity.

THE GENETIC FACTORS

Leptin deficiency

Rare cases of humans with congenital leptin deficiencycaused by mutations in the leptin gene have beenidentified. (The involved band is at 7q31.)

PPAR-gamma

PPAR-gamma is a transcription factor that is involvedin adipocyte differentiation. All humans with mutationsof the receptor (at band 3p25) described so far havehad severe obesity.

DRUG INDUCED OBESITY

DIET AND OBESITY

Various animal models have shown that high fat diet causes obesity.

Similar observations are seen with High carbohydrate diet

Hence, a diet rich in carbohydrate plus fats in

definitely implicated for obesity.

OBESITY IN DISEASE

Obesity is a common feature in various endocrinedisorders:

Hypothyroidism

Cushing’s Syndrome

Pseudohypoparathyroidism

Growth hormone deficiency

TREATMENT OF OBESITY

The first weapons in the fight against obesity are dietand exercise. Unfortunately, these often fail or show only short-term efficacy, leaving only surgical techniques (such as gastric stapling or bypass) or drug therapy as a viable alternative. Surgery is much more effective than currently licensed drugs.

DIETARY MODIFICATION

Ensure low calorie diet for moderate weight loss:

Nutrient Recommended Intake

Calories Approximately 500 to 1,000 kcal/day reduction from usual intake

Total fat 30 percent or less of total calories

Saturated fatty acids 8 to 10 percent of total calories

Monounsaturated fatty acids Up to 15 percent of total calories

Polyunsaturated fatty acids Up to 10 percent of total calories

Carbohydrate 55 percent or more of total calories

Protein Approximately 15 percent of total calories

Fiber 20 to 30 g/day

PHYSICAL ACTIVITY

Physical activity should be an integral part of weight losstherapy and weight maintenance. Initially, moderatelevels of physical activity for 30 to 45 minutes, 3 to 5 daysper week, should be encouraged.

Example

Walking 13/4 miles in 35 minutes (20 min/mile)

Bicycling 5 miles in 30 minutes

Running 11/2 miles in 15 minutes(15 min/mile)

Swimming laps for 20 minutes

PHARMACOTHERAPY

Currently, the 3 major groups of drugs used tomanage obesity are as follows:

Centrally acting medications that impair dietary intake

Medications that act peripherally to impair dietary absorption

Medications that increase energy expenditure

ORLISTAT

Orlistat is a gastrointestinal and pancreatic lipase inhibitor that induces

weight loss by inhibiting dietary fat absorption.

ORLISTAT

Indication: Indicated in patients with pretreatment BMI >30kg/m², or BMI >27 kg/m² in presence of other risk factorsor diseases (eg, HTN, DM, hyperlipidemia)

Dose:120 mg PO q8hr with each fat-containing meal

Side effects:

Oily spotting (5%)

Flatulence, Fatty/oily stool ,Increased defecation, Fecalincontinence, Nausea, Vomiting, Reduced absorption offat soluble vitamins and beta-carotene

Serious interaction: Orlistat decreases levels ofcyclosporine by inhibition of GI absorption

LORCASERIN

It decrease food consumption and promote satiety by selectively activating 5-HT2C receptors on anorexigenic pro-opiomelanocortin neurons located in the hypothalamus.

LORCASERINIndication: Indicated in patients with pretreatment BMI >30 kg/m²,or BMI >27 kg/m² in presence of other risk factors or diseases(eg, HTN, DM, hyperlipidemia)

Dose: 10 mg PO q12h

Side effects:

Interactions:Almotriptan, Amitriptyline, bupropion

>10% Uncommon

Headache (16.8%)Upper respiratory tract infection (13.7%)Nasopharyngitis (13%)

Dizziness (8.5%)Nausea (8.3%)Fatigue (7.2%)Diarrhea (6.5%)Urinary tract infection (6.5%)Back pain (6.3%)Constipation (5.8%)

SYMPATHOMIMETIC AMINE

Phentermine

Diethylpropion

Phendimetrazine

Benzphetamine

Phentermine/topiramate

Sympathomimetic amine increases the release and reuptake of norepinephrine and dopamine.

Its anorexiant effect occurs as a result of satiety-centerstimulation in hypothalamic and limbic areas of the brain.

SYMPATHOMIMETIC AMINE

Side effects:

Dysuria, Excitement, Hair loss, Headache, Hypertension,Tremor, Urticaria, Primary pulmonary hypertension,Psychotic disorder

Serious interaction: Amoxapine, Cabergoline, Citalopram,Clomipramine

Contraindication: Arteriosclerosis, cardiovascular disease,moderate-to-severe hypertension, glaucoma, agitation,hyperthyroidism, history of drug abuse

Not approved for long-term use

BUPROPION AND NALTREXONE

Combination may regulate activity in the dopamine reward system of the brain that helps control food cravings and overeating behaviours

Bupropion Increases dopamine activity in the brain, which appears to lead to a reduction in appetite and increase in energy expenditure by increasing activity of pro-opiomelanocortin (POMC) neurons

Naltrexone Blocks opioid receptors on the POMC neurons, preventing feedback inhibition of these neurons and further increasing POMC activity

LIRAGLUTIDELiraglutide was approved by the FDA on December 23, 2014 for treatment for obesity in adults with some related comorbidity.

Liraglutide (NN2211) is a long-acting glucagon-like peptide-1 receptor agonist.

Thyroid cancer concern:

Liraglutide caused a statistically

significant increase in thyroid

tumors in rats. The clinical

relevance of these findings is

unknown.

DRUGS WITHDRAWN BY FDA

DRUGS UNDER TRIAL

Target Drug CompanyMechanism of

actionStatus

Central neuropeptide signaling

Melanocortinreceptor

MK-0493 Merck

Selective MC4R agonist,

increasing MC3/4R signaling

Phase II completed

RM-493 Rhythm

Selective MC4R agonist,

increasing MC3/4R signaling

Phase II

NPY

MK-0557 MerckY5 receptor antagonist, NPY blocker

Phase II completed

Velneperit (S-2367)

Shionogi USAY5 receptor antagonist, NPY blocker

Phase III

Target Drug CompanyMechanism of

actionStatus

Monoamine neurotransmission

Dopamine / norepinephrine / serotonin

Contrave (bupropion / naltrexone)

Orexigen

Norepinephrine/dopamine

reuptake inhibitor

Phase III completed

NDA submission

Intestinal peptide hormone signaling

GLPByetta®

(exenatide)Amylin

GLP1R agonist, GLP-1 mimicking

Phase III

OXM

Qxyntomodulin (OXY-RPEG)

ProlorGLP1R

agonist, OXM mimicking

Phase I recruiting

TKS1225Thiakis /

Wyeth / Pfizer

GLP1R agonist, OXM Phase I

Target Drug CompanyMechanism of

actionStatus

Pancreatic hormone signaling

PP PP1420Wellcome

Trust

Pancreatic polypeptide

analog

Phase I completed

AmylinDavalintide (AC2307)

AmylinAmylin

mimickingPhase II

Adipose tissue hormone signaling

Leptin MetreleptinAmylin / Takeda

Leptin receptor agonist

Phase III recruiting

Inhibition of lipase

Pancreatic lipase

Cetilistat (ATL-962)

Alizyme / Takeda / Norgine

Pancreatic lipase

inhibitor, inhibiting

intestinal lipid

Phase III completed

SURGICAL MANAGEMENT

Weight loss surgery is an option for weight reduction inpatients with clinically severe obesity, i.e., a BMI ≥40, or aBMI ≥ 35 with comorbid condition(morbid obesity)

THANK YOU

Eat and drink, but be not excessive. Indeed, He does not like those who commit excess.”

[Quran Sûrah al-A`râf: 31]