Pharmacotherapy of obesity

Dr. Sachin R. ChoudhariJR-1, Dept. of pharmacology

SVNGMC, Yavatmal

Scope of presentationWhat is obesity ? Epidemic of obesityProblems related to obesityWhy to treat obesity?Energy homeostasis Treatment options for obesityCurrently available drugs for obesityConclusion

Obesity :

It is defined as abnormal growth of the adipose tissue due to enlargement of fat cell size (hypertrophic obesity) or an increase in fat cell number (hyperplastic obesity) or a

combination of both

EPIDEMICS in obesity :

It is prevalent in both developed and developing countries , and affecting children as well as adults

Obesity is the fifth leading risk of global death

In 2014, more than 1.9 billion adults, 18 years and older, were overweight. Of these over 600 million were obese.

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

In 2014, 39% of adults aged 18 years and over (38% of men and 40% of women) were overweight.

The worldwide prevalence of obesity more than doubled between 1980 and 2014

In 2013, 42 million children under the age of 5 were overweight or obese.

India is 3rd largest country contributing to obesity burden next to United states and China

In India , Tamilnadu, Karnataka, Andhra pradesh , Maharashtra, Kerala contributes more to obesity

WHO classify this obesity according to individual’s BMI :

Why to classify ??? Meaningful comparison of weight status within and in-

between population Identification of individual and group with increased risk of

morbidity / mortality Identification of priorities for intervention at individual and

community levels A firm basis for evaluating interventions

Problems related to obesity :

Why to treat obesity ???Contributes to approximately 300,000 deaths a year,

making it 2nd only to smoking as a cause of deathDisease burden is increasing day by dayContributes or causes to many other health problems

including:

Type 2 Diabetes MellitusCoronary Artery DiseaseDegenerative Joint DiseaseCertain Types of CancerNonalcoholic Steatohepatitis

Available treatment options for obesity :Diet and exercise

Pharmacotherapy

Surgical option

Indications for use of obesity drugs

BMI of 30 kg/m² or more or a BMI of 27 kg/m² or more with comorbid condition

Understand that drug therapy is adjunctive to lifestyle intervention Have realistic expectations about weight loss goals and outcomes

Are unable to lose/maintain weight with lifestyle change alone

Comply with medication use

Have no medical or psychiatric contraindications

Energy Homeostasis :

Pharmacotherapy :

Peripherally acting agents reducing the efficiency of digestion:

Modulation of appetite and energy expenditure :Centrally acting agents affecting the hedonic

control of food intake :Combination approach to obesity treatment :Peripherally acting agents :

Peripherally acting agents reducing the efficiency of digestion:

“ ORLISTAT ”

Stable analogue of lipstatin (a naturally occurring lipase inhibitor produced by streptomyces toxytricini )

Indicated for the treatment of obesity in conjunction with a reduced calorie intake

MOA : Acts locally to potently inhibit pancreatic and gastric lipase and thus hydrolysis of TG

approx. only two third of dietary TG intake is absorbed by small intestine

Dose : 120mg three times daily

FDA Approved on 2007

Effect : It induces weight loss of approx. 2-4 Kg more than diet and exercise alone.

ADRs : 1. Deficiency of fat soluble vitamins 2. Diarrhea, flatulence, bloating, abdominal pain , dyspepsia

Recently it comes with additional warning of possible severe liver injury

It is contraindicated in patients with malabsorption of fats or cholesterol

Centrally acting agents affecting the homeostatic regulation of food intake :

Meal induced hormonal & neuronal signal travels GIT to area postrema and NTS in brainstem

Sensory inputs from there transmitted to others centers (amygdala and nucleus accumbence). Dopaminergic , opioid and endocannabinoid signaling assign reward value to consumed food

Inputs from these pathway integrates with circulating signals of nutritional state i.e. fatty acid and LEPTIN which are detected in Arcuate nucleus

Activates Activates

neurons expressing neuron expressing Pro-opiomelanocortin (POMC) Neuropeptide Y (NPY)

Stimulate release of α MSH Activation of NPY-Y1 and Y5

Activating the melanocortin receptor 4 increase food intake and reduction in energy expenditureReduction in food intake & increasein energy expenditure

Serotonin reuptake inhibitors :SIBUTRAMINE

Approved by FDA in 1997 as 5HT and NE reuptake inhibitor (presynaptic)

Potentiate anorexic effect of these two neurotransmitters in the CNS

Act at hypothalamic site that regulates food intake

Reduces food intake and causes dose dependent weight loss with reduction in visceral fat

In addition , it also decreases plasma TGs , LDL , VLDL but increases HDL

Also, stimulates thermogenesis by activating β3 receptors in adipose tissue

Dose : 10-15 mg once daily

Weight loss is between 5-10%

ADRs : 1. Increase in HR and BP 2. Dry mouth , constipation , insomnia

Contraindicated in cardiovascular diseases

SCOUT trial showed that , there is higher risk of cardiovascular events in patient taking sibutramine as compared to placebo

Based on these findings it has undergone a revision process and was finally withdrawn from European and US market in 2010

TESOFENSINE (NS2330)

Described in clinical trial as an inhibitor of the reuptake of nor adrenaline , dopamine and 5 HT

It initially developed in the treatment of Alzheimer’s and Parkinson’s disease

Reported to cause some weight loss in obese patients being treated for these two conditions

It induced promising weight reduction of 2.1% (0.125mg dose), 8.2 % (0.25mg), 14.1 % (0.5mg), 20.9 % (1mg ) after 14 weeks of therapy

Phase 2 trial cleared

Now in phase 3 trial

Serotonin receptor agonist and antagonist :

LORCASERIN

Selective 5 HT2c receptor agonist

Phase 3 trial successful with avrg. Weight loss of 5.8 kg compared to placebo after 1 year

Recently approved (2013-14 ) as anti obesity drug

No serotonin related valvulopathy / neuropsychiatry issue

ADRs : Headache , nausea, URI

Dose : 10 mg BD

If weight reduction is < 5 % after 12 weeks stop the drug

Contraindicated in renal failure (GFR : < 30ml / min )

Decreases systolic and diastolic BP , HR, total and LDL-c

FENFLURAMINE , DEXFENFLURAMINE

Induce weight loss via formation of active metabolite D- norfenfluramine , a potent 5-HT2C agonist

used in 1980 and 1990s

But soon escape from their effect and landed with rare but serious adverse effect i.e. Pulmonary hypertension

Use declines

PHENTERMINE

Amphetamine like compound which acts by releasing noradrenaline from presynaptic vesicles in lateral hypothalamus

It is used along with dexfenfluramine as combination therapy in 1990s but withdrawn from market in 1997 after dexfenfluramine shown to be associated with valvulopathy and PH

Melanocortin 4 receptor agonist :

MK- 0493

Melanocortin 4 receptor (MC4R) is crucial regulation of appetite

MC4R deficiency is the most common monogenetic cause of obesity in human

its an orally active , selective MC4R agonist

No significant weight reduction results in phase 2 trial

But peptide of MC4R shows promising results in rodents and will soon enter in phase 1 trial

NPY receptor ligands : Neuropeptide NPY is thought to stimulate appetite by activation of the Y1 and Y5

receptors

So antagonist at this level have been produce with the aim of blocking these orexigenic effect

MK- 0557

A 52 week multicenter , double blind RCT showed only 1.6 kg reduction in weight among humans

Various other drugs been developed and under trial :

BMS- 193885 ( only animal study no human trial yet ) PYY3-36 ( phase 2 ) RG7089 ( phase 1 ) Pegylated PYY3-36 plus metformin ( phase 1 )

Nausea if frequent side effect of all these drugs

Glucagon like peptide 1 receptor agonist :

GLP-1 receptor is expressed in paraventricular, arcuate and dorsomedial nuclei in the hypothalamus and NTS , area postrema and parabrachial nucleus in brainstem

It has been shown to inhibit food intake when administered peripherally and centrally

It acts as incretin, increasing glucose stimulated insulin release and inhibit glucagon release and gastric emptying

Chronis subcutaneous infusion of GLP to patients with type 2 DM can induced weight loss and improved glucose homeostasis

EXENATIDE AND LIRAGLUTIDE

Approved for treatment of DM2 but not licensed to treat obesity

Exenatide shows increased risk of benign C cell adenomas

TAPSOGLUTIDE

Another product shows promising results in pre clinical and animal study but stop in phase 3 due to diverse GI events and hypersensitivity issues

OXYNTOMODULIN ( phase 1 )

Endogenous GLP – receptor agonist

It reduces food intake in rats when administered centrally or peripherally but unlikely GLP -1 oxyntomodulin also increases energy expenditure

In humans iv infusion of oxyntomodulin reduces food intake

While repeated sc injections increases energy expenditure and causes weight loss in obese volunteers

Pegyaated form of it named PF- 05212389 also in phase 1 trial

Centrally acting agents affecting the hedonic control of food intake :

Here, target is the brain’s reward pathways

The reward system is activated in response to the intake of high calorie palatable foods and thought to stimulate intake of these foods even in the absence of nutrients deficit and weight loss

Cannabinoid receptor (CB1) antagonists :

Endogenous lipid derived from arachidonic acid , which activates G- protein coupled receptors

Administration of an endocannabinoid into ventromedial hypothalamus ond nucleus accumbens of rats causes increased food intake and effect blocked by receptor antagonist

RIMONABANT

Selective CB1 receptor antagonist

It is thought to control food intake by reinforcing motivation to consume food

First approved product to treat obesity in this class

Weight loss appr. 7% achieved over a 1 year period in patients treated with this drug

Significant decrease in co-morbidities also noted

Never approved in USA but licensed in Europe

Suicidal thoughts and depression are major side effects and for the same it has been banned in Europe 2009 but still used in India

Trials on some other drug such as TARANABANT , OTENABANT terminated rapidly

Combination approaches :PHENTERMINE – TOPIRAMATE ( QNEXA )

Its an combination of two approved drug

Phentermine : Amphetamine derivative Topiramate : Anti convulsant drug

Combination is approved in Dec 2012

They demonstrated biphasic dopaminergic and serotonergic activity

 In combination with a balance diet and exercise lost 10% to 11% of their body weight compared to 1% to 2% for those who received placebo

ADRs : paraesthesia (tingling in fingers/toes), dizziness, dysgeusia (altered taste), insomnia, constipation, and dry mouth

BUPRIPION – NALTREXONE ( CONTRAVE)

Its an combination of centrally active opioid receptor antagonist

Approved in Sept. 2014 as anti obesity drug

Both these stimulates firing of anorexigenic POMC neurons

Naltrexone is hypothesized to block opioid mediated negative feedback that suppresses POMC firing

Weight loss of 4.2% is seen in clinical trials

ADRs : nausea, headache, constipation, dizziness, vomiting, dry mouth, risk of major cardiovascular events in obese patients

BUPRIPION – ZONISAMIDE ( EMPATIC)

Another combination which in phase 2 trial showed significant weight reduction in obese patients with or without depression compared with placebo

Zonisamide induced bodyweight loss has not been fully characterized ; however it has been shown to have dopaminergic and serotoninergic activity and likely to work through these pathways

Weight loss is around 7.2 % as compared to 2.9 % with placebo

ADRs : Increased cardiovascular events , mood disorders

Currently in phase III trial

Peripherally acting agents : Several anorectic peptides are released from gut postprandially and there

has been interest in developing therapeutics to mimic this effect

CB1 antagonist

New antagonist have been designed to antagonize peripherally expressed CB1 receptors but not to penetrate blood brain barrier and thus avoids behavioral effects

They induce weight loss and also have beneficial effect on energy expenditure

Two products are now in clinical trial :

1. TM38837 ( cleared phase 1 trial now in phase 2 ) 2. AM6545 ( in preclinical studies )

Gut related peptide to treat obesity &metabolic syndrome :

Similar to GLP -1R agonist , other new agents , which not only affect weight control but also improve metabolic and cardiovascular disorders

PRAMLINTIDE

An analog of pancreatic hormone amylin

Approved as an adjunct to mealtime insulin in patients with type 1 &2 DM

But it also associated with reduction in appetite and food intake through a delayed gastrointestinal motility

In clinical trial, with the dose 120, 240, 360 μg it shows progressive weight reduction at 12 months i.e. from 6.1 kg to 7.2 kg

Two another amylin analog undergoing development for obesity treatment

1. DAVALINTIDE 2. PRAMLINTIDE – METRELEPTIN ( RECOMBINANT HUMAN LEPTIN )

Hypoglycemia , nausea, vomiting are side effects

AMP activated protein kinase & peroxisome proliferator activated receptor modulator :

Its an key enzyme in the regulation of energy metabolism that has pleiotropic effects in multiple tissue

Experimental study activation of AMPK in the periphery maybe beneficial to obese patients by increasing energy expenditure

In brain, its suppression would be desirable to inhibit appetite

Similar effects are seen with PPAR-y antagonism

Products in clinical trial are :

1. GW0072 2. LG100641

G- protein coupled receptor 119 :

Glucose dependent insulinotropic receptors are predominantly expressed in islets β cells and GI tract

These receptors are attractive target for the treating type 2 DM as they have been shown to play crucial role in glucose homeostasis through modulation of insulin secretion

They also seems to have major beneficial effect on bodyweight

Sodium – glucose transporter 2 inhibitors :

Selective inhibitors of SGLT2 reduce glucose reabsorption

Leads to excessive glucose to be eliminated from urine

Decrease in plasma glucose level

This glucosuria is a/w weight loss and reduce blood pressure

Available drugs : 1. DAPAGLIFLOZIN 2. CANAGLIFLOZIN 3. BL 10733

Currently all drugs are in clinical development

Leptin :

• Naturally occurring hormone that plays a role in satiety and weight maintenance.

• Produced in adipocytes

• Its role in weight regulation is related to its effects on the hypothalamus, where it leads to:

• satiety • decreased food intake• increased energy expenditure in the periphery

Initial human trials with recombinant leptin were modestly successful

Most subjects in the initial trial developed local reactions at the injection site

Weight loss was relatively modest

However, the hormone needs to be given subcutaneously and has a short half-life

Thus a modified recombinant human leptin (m-leptin) was created that has a longer half-life

Efficacy of current anti obesity drugs :DRUG LENGTH OF RCT WT LOSS (KG)

Phen / Topiramate > 1 year - 10.2

Bupropion 24 weeks - 8.0

Diethylpropion 18 weeks - 6.5

Phentermine 13 weeks - 6.4

Bupro / Naltrex > 1 year - 6.1

Lorcaserine > 1 year - 5.8

Orlistat > 1 year - 5.3

Exenatide 24 weeks - 2.9

Liraglutide 24 weeks - 2.8

Metformin 1 year - 2.8

Need of new drugs : Efficacy of available drug is not satisfactory

No sustained weight loss

High side effect profile

Different mechanism of action not fully explore

Current drug increases energy expenditure : no drug yet that alter signals of hunger & satiety

Very few drug options are available currently

Pipeline drugs :

Drug name class status

GT 389-225 Conjugate of pancreatic lipase

inhibitor & fat binding hydrogel polymer

Phase I

BVT 74316,PRX 07034

5 HT-6-R antagonist Phase I

TKS 1225 GLP-1 –R agonist Phase I

Bupropion - zonisamide

FDC suspended

Drug name class Status

Cetilistat Pancreatic lipase inhibitor

Phase III

Beoranib Methionine aminopeptidase II

inhibitor . Decreases hepatic FA &

promotes fat break down

Suspended ( Prader wili )

Phase II

Semaglutide GLP-1-R agonist Phase III(DM)Phase II (obesity)

Remogliflozin etabonate

SGLT -2 inhibitor (increase urinary

secretion of glucose)

Phase II (DM)Phase I (obesity)

Conclusion ???

Obesity – abnormal excessive fat accumulation that harms

WHO cut off points BMI > 25kg/m2 and > 30 kg/m2 for obesity and overweight

Obesity impacts the whole world through its harmful effects and comorbid conditions

Current drugs are not satisfactory as far weight reduction results are concern

Lifestyle management , diet control and exercise precedes drug therapy

Take home message :Think healthy

Behave healthy

Eat healthy

Be happy

References : Katzung BG, Trevor AJ. Basics and clinical pharmacology.

13th ed.McGraw Hill education:2015;p664-5

Bruton Chabner B, Knollman B. Goodman & Gilman’s The Pharmacological basis of therapeutics. 12th ed. McGraw Hill medical: 2011;p881,91

HL sharma, KK sharma. Principles of Pharmacology. 2nd ed.2011;p 901

Rodgers RJ, Tschop MH, Wilding JPH. Antiobesity drugs: past,present and future. Dis model mech. 2012 Sept;5(5):621-626

Fenske W, Parker J, Bloom S. Pharmacotherapy of obesity. Expert Review of endocrinology and metabolism.2011;6(4):563-577

Bray GA. Obesity in adults: Drug therapy. Accessed on 06/12/2015 from URL http://www.uptodate.com/contents/obesity-in-adults-drug- therapy?source=search_result&search=obesity&selectedTitle=~150

For pipeline drug status ( http://adisinsight.springer.com/drugs )

For various trial details ( https://clinicaltrials.gov )