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Obesity & its management
1. Treatment Strategy And Management
Presented by:-
Dr. Rupendra Kumar Bharti
Department of Pharmacology
IGMC, Shimla H.P.
2. The definition
An appropriate definition of obesity
today must include 'excess' adiposity
with 'ectopic' fat deposition in non-
adipose tissue.
3. Normal Mechanism Of Adipocytes
Adipose tissue is the only dedicated storehouse of fat
in our body.
It stores excess calories as triglycerides (TG) in
adipocytes. From an evolutionary perspective, this is
the most efficient form of energy conservation, where
stored triglyceride is released during periods of fasting
or calorie deprivation.
The major fat depots in the body are the subcutaneous
adipocytes. Subcutaneous adipose tissue (SAT),
accounts for 80% of the total body fat.
Another 10% is stored in the body cavities as visceral
adipose tissue (VAT), as omental, mesenteric and
retroperitoneal fat.
4. Remaining 10% fat is distributed at non-adipose
tissues, such as skeletal muscles, nervous system,
liver, pancreas, heart, blood vessels and bone-
marrow, whereas very small amount of lipids are
required for their structural support, normal cellular
functions, membrane integrity and fluidity, neural
signal transmission, thermo-regulation and
cushioning of the organs.
These sites are never designed for fat storage.
Therefore, they have no capacity to store excess
fat without causing harm.
5. More than half of the world's 671 million obese
individuals living in just ten countries— the USA
(more than 13 per cent), China and India (15
per cent combined), Russia, Brazil, Mexico,
Egypt, Germany, Pakistan, and Indonesia.
In developed countries having highest rates of
obesity prevalence then developing countries.
The Epidemiology
9. In India
A study conducted in 15 to 25-year-old Asian
Indian adolescents and young adults reported an
average total fat intake of 29- 84 g/d in males and
21-72 g/d in females, nearly 4 times the
recommended dietary allowance for Asian Indians
(20-25 g/d).
17. BMI (by WHO) WORLDWIDE
BMI SOUTH ASIAN
Under weight
Normal range
Pre obese
Obese
BMI
≤18.5
18.5 - 22.99
23-27.5
≥27.5
Risk of comorbidities
Low (but risk of clinical problem
increase due to underweight)
Average
Increase
Very increase
Classification
1.
18. 2. Waist circumference
3. Waist-to-hip ratio:- its used to compare the fat distribution b/w
abdomen and gluteal region.
Normal Male:- <1
Female :- <0.8
Its useful predictor of diabetes and cardiovascular disease risk in
adults.
19. 4. Skin fold thickness (Harpenden calliper instrument)
:-
Normal – Male :- 61-80 mm
Female:- 71-90 mm
5. Bioelectrical impedance (BIA):- It is a easy and
non invasive technique. Technique was based on the
fact, that lean tissue is a good conductor of electricity
then fat. It’s used for the measurement for LBM, TBW
and water distribution in the various compartment of
body.
If the total body weight is increase, the impedance
was reduced.
6. CT, MRI, USG for anatomical distribution of fat.
7. Palmitic acid Extended overfeeding challenge test
for partition of nutrient storage
21. Prevention
1. Increase physical activity:- as we already known
that sedentary life style is increase the risk of
obesity.
2. Maintain diet: low energy-dense foods (including
wholegrain, cereals, fruits, vegetables and salads)
probably protect against weight gain, overweight,
and obesity.
high energy-dense foods (including foods
containing animal fats, other high fat foods,
confectionery and sugary drinks) are probably a
cause of weight gain, overweight, and obesity,
particularly when large portion sizes are consumed
regularly. sugary drinks probably cause weight
gain, overweight, and obesity.
‘fast foods’ probably cause weight gain,
overweight, and obesity.
22. 3. Avoid medicines which is associated with obesity,
like
i. Atypical antipsychotics, including clozapine
ii. Beta adrenergic blockers, particularly propranolol
iii. Lithium
iv. Sodium valproate
v. Sulphonylureas, including chlorpropamide,
glibenclamide, glimepiride and glipizide
vi. Thiazolidinediones, including pioglitazone
vii. Tricyclic antidepressants, including amitriptyline
23. Treatment strategy
• Primary Prevention Of Obesity In Children,
Young People And Adults
• ƒƒTreatment Of Overweight/Obesity By Diet And
Lifestyle Interventions
• ƒƒTreatment Of Obesity By Pharmacological
Therapy And Bariatric Surgery
• ƒPrevention Of Weight Regain Following
Treatment.
26. • Are indicated for use in patients with a BMI >30 or BMI
>27 with obesity related comorbidities. When used
under the medical supervision of a physician and
dietician, VLEDs are able to induce rapid weight loss
and have been shown to achieve an average weight
loss of 18–20% with better sustained weight reduction.
• It also improve glycaemic control in patients with type
2diabetes, improve blood pressure and reduce total
cholesterol.
• This high protein-low carbohydrate diets induce fat
burning and mild ketosis, which results in suppression
of hunger and promotion of satiety.
• Treatment duration with a VLED is generally 8–12
weeks.
Non pharmacological treatment
Very low energy diets (VLEDs)
(<800 kcal/day or <3350 kJ/day)
27. • Pregnant or lactating women, infants, children,
adolescents (under 18 years).
• Elderly (over 65 years), patients with a history of
Psychological disturbances, alcohol misuse or
drug abuse, in the presence of porphyria, recent
myocardial infarction or unstable angina.
Monitoring and support of patients on VLEDs
is required for success.
VLEDs Contraindicated
30. Phentermine, Amphetamine
MOA:- Appetite suppressant. Its stimulates the anorexic
signaling in hypothalamus or dopamine receptor in the
hippocampus. It’s also having sympathomimetic action
similar to norepinephrine with CNS stimulatory activity.
Phentermine
Weight loss ≥ 3.6 kg then
placebo.
ADR:- Appetite suppression
and weight loss, including
dry mouth, dizziness,
sleeplessness, N/V/D with
withdrawal symptoms.
Approved by FDA in 1959
Amphetamine
Effect:- Weight loss ≥ 1kg
then placebo.
ADR:- with withdrawal
symptoms, patient may
will developed headache,
fear anxiety, raise BP and
HR.
Its approved for ADHD
with weight lowering drug
31. Lorcaserin, Desvenlafaxine,
Sibutramine
MOA:- It is a serotonin, dopamine,
norepinephrine reuptake inhibitor that
potentiates the neurotransmitter activity in
the CNS.
Lorcaserin 5HT2C agonist
Effect:- mean body weight
loss 5.8±0.2 kg
ADR:- limited weight loss
efficacy and possible
increase cancer
risk(breast cancer), while
m/c ADR is headache,
followed by sinusitis
nausea depression
anxiety
Approved by USFDA in
Desvenlafaxine
Effect:- mean body
weight loss 2.2 ±1.41 kg
ADR:- nausea,
headache, dizziness,
Xerostomia,
hyperhidrosis, diarrhea,
Insomnia, Constipation,
Fatigue, High blood
pressure.
Approved Antidepressant
in February 2008 with
Sibutramine
Until 2010 it was
marketed and prescribed
as an adjunct in the
treatment of exogenous
obesity along with diet
and exercise.
It has been associated
with increased
cardiovascular events
and strokes and has been
32. Bupropion
MOA: - its inhibits neuronal uptake of dopamine,
norepinephrine and serotonin.
is a drug primarily used as an antidepressant and
smoking cessation.
its seems that bupropion decrease body weight then
placebo.
Effect:- Bupropion SR 400 mg/day reduces weight
5.1% and in 300mg /day reduced 2.2%
ADR:- Insomnia, Headache, pyrexia, Asthenia,
Dizziness, Agitation, Alopecia, Tremor, N/V/C,
Pruritus, Urticaria due to hypersensitivity
Approved for Anti depression By USFDA in 30
December 1985.
33. Orlistat (Tetrahydrolipstatin)
Its primary function is preventing the absorption of fats from the
human diet by acting as a intestinal lipase inhibitor, thereby
reducing caloric intake. It is intended for use in conjunction
with a healthcare provider-supervised reduced-calorie diet.
Orlistat is the saturated derivative of lipstatin, a potent natural
inhibitor of pancreatic lipases.
Effect:- Mean body weight loss ≥ 4.2 kg
ADR:- Weight loss, increase of bowel movement and potential
changes in the bowel function (steatorrhea), Long term used
may lead to Breast carcinoma.
Approved in 1999 by USFDA.
34. Topiramate
Is an anticonvulsant (anti epilepsy) drug. In late 2012,
topiramate was approved by the USFDA in combination
with phentermine for weight loss.
MOA :- Its enhancing GABA signaling to promote
anorexigenic signaling, with inhibition of voltage gated
channels and AMPA(α- amino-3-hydroxy-s- methyl-4-
isoxazole propionate) receptor in the orexigenic
neurons.
Effect:- weight loss is greater then placebo was 6.5kg.
ADR:- Dizziness, Weight loss, Paraesthesia, Somnolence,
Nausea, Diarrhea, Fatigue, Nasopharyngitis,
Depression, acute myopia, secondary angle closure
glaucoma.
35. GLP 1 receptor agonist
GLP-1 secretion by ileal L cells is dependent on the
presence of nutrients in the lumen of the small intestine.
It is a secretogogus analog, which increase the secretion of
insulin and delayed gastric empty time.
Once in the circulation, GLP-1 has a half-life of less than 2
minutes, due to rapid degradation by the enzyme dipeptidyl
peptidase-4, which is inhibited by sitagliptin.
Exenatide
Effect:- mean body weight loss
with extentide (2.49± 0.66 𝑘𝑔)
and with placebo (0.43± 0.63 kg)
ADR:- Decrease blood glucose
and body weight along with GIT
symptoms, pancreatitis, dizziness
and headache. It might increase
sulfonylurea-induced
hypoglycemia and thyroid cancer.
Approved by USFDA for Diabetes
Liraglutide
Effect:- Weight loss greater
then placebo was 4.4kg
ADR:- Maintained normal
blood glucose and body
weight, with increase risk of
C-cell carcinoma and thyroid
C- cell focal hyperplasia were
observed in rat and mice.
Approved by USFDA for
Diabetes
36. Amylin analog
Amylin, or Islet Amyloid Polypeptide (IAPP), is a
37-residue peptide hormone. It is co secreted with
insulin from the pancreatic β-cells in the ratio of
approximately 100:1. Amylin plays a role in
glycaemic regulation by slowing gastric emptying
and promoting satiety, hereby preventing post-
prandial spikes in blood glucose levels.
37. Cocktail drug…
The combination of Phenteramine (PHEN) and
Topiramate (TPM)
Effect:- weight loss from baseline was
placebo-2.2% (PHEN 7.5mg/ TPM
46mg) control release 9.3%, (PHEN
15mg/ TPM 92mg) control release –
10.7%
38. BIGUANIDE
METFORMIN
MOA: Its nonsecretogogus drug, which do not enhance
insulin but by inhibiting hepatic genolysis by inhibiting
enzyme AMP kinase, decreasing renal neoglucogenesis,
decrease intestinal absorption and increase exhibits
glucose to muscles and adipose tissue, its enhance
insulin metabolism and maintain body glucose level.
Effect:- it may lead to infertility in pregnant women, without
diabetes treated with atypical anti psychotics, reduces
weight 4.8% following 12-14 weeks treatment.
ADR:- Most frequent S/E is Nausea. Other are
megaloblastic anemia, hepatitis.
39. Rimonabant
It is a arachidonic acid derivative known as
endocannabinoids, were identified as endogenous substance
that activate cannabinoid receptor(CB1, CB2, CB3).
It’s regulate energy regulator hormones and neuropeptide.
This receptor were overactive in the case of overweight and
obesity.
Rimonabant which is CB1 antagonist, is present more in brain
and peripheral tissue (liver, GIT, adipocyte, cardiac muscles).
It’s inhibits excess food intake and maintain nutrient
metabolism.
USFDA Approved in 2007.
40. Off- label medicines not approved by
USFDA
A. “Fen-Phen” (fenfluramine+ phenteramine) causing
hyperthyroidism and major CVS disease
B. Dinitrophenol (cataracts and neuropathy)
C. Rainbow diet pill (mixture of digitalis and diuretics)
arrhythmias and electrolyte imbalance
D. Aminorex is a 2-amino-5-aryl oxazoline class drug (pulmonary
hypertension)
E. Phenylpropanolamine (MI and Stroke)
F. Axokine (ciliary neurotropic factor) Increase obesity due to
inhibition of anorexigenic signaling receptors. (DM2)
G. SSRI (Fluoxetine)
H. Methylephenidate
I. Zonisamide
J. Octreotide
K. Ephedrine
41. i. Chromium
ii. Ephedral Alkaloids
iii. St. John’s Wort
iv. Pyruvate
v. Hoodia
vi. White Willow Bark
vii. Guarana and Tea
extract
viii. Chitosan
Alternative
therapy for lowering body weight
43. Criteria….
Patient should have a BMI of 40 kg/m2 or
more, or between 35 kg/m2 and 40 kg/m2 and
other significant disease (for example, type 2
diabetes or high blood pressure) that could be
improved if they lost weight.
All appropriate non-surgical measures have
been tried but have failed to achieve or
maintain adequate, clinically beneficial weight
loss for at least 6 months.
44. The Three Most Commonly
Performed Procedures
Laparoscopic Adjustable Gastric Banding
(LAGB)
54% weight loss at 3–5 yr.
Gradual Pattern of weight loss
4-6% Morbidity at 1 year
Advantage
i. Effective, with good
long term weight
maintenance.
ii. Ability to adjust the
iii. degree of restriction.
Reversible.
iv. Maintains gastric.
v. integrity
Disadvantage
i. Gastric pouch dilatation.
ii. Erosion of band into the
stomach.
iii. leaks to the LAGB system.
iv. Weight regain.
v. Iron vitamin B12 and folate
45. Roux-en-Y gastric bypass (RYGB)
60% weight loss at 3–5 years
Rapid, maximal weight loss in 1–2 years
14.9% Morbidity at 1 year
Advantage
i. Very effective with
ii. good long term
weight
iii. maintenance
iv. Few failures
Disadvantage
i. Abdominal pain, staple
line leak, stomach ulcer,
ii. Intestinal obstruction,
iii. Gallstones
iv. Nutritional deficiency
v. Weight regain
vi. Deficiencies in iron,
vitamin B12, folate,
calcium, vitamin D,
copper, zinc
46. Sleeve gastrostomy (SG)
50- 60% weight loss at 3–5 years
Rapid, maximal weight loss in 1–2 years
10.8% Morbidity at 1 year
Advantage
i. Allows for rapid weight
loss.
ii. No dumping syndrome
as pyloric portion of the
stomach is intact
iii. Provides fixed restriction
and does not require
adjustment
Disadvantage
i. Staple line leak
ii. Gastroesophageal reflux
disease,
iii. Dilatation of the gastric
remnant,
iv. Weight regain
v. Deficiencies in iron,
vitamin B12, folate,
calcium, vitamin D, copper,
zinc, thiamine
48. TRIALS
PHASE I
Intestinal Peptide Hormone
Signaling
GLP1R agonist with OXM gut
hormone mimicking
A. Oxyntomodulin
B. TKS 1225
PHASE II
Melanocortin receptor
agonist (MC4R agonist)
a. MK-0493
b. RM- 493
Neuropeptide Y (NPY
blocker)
a. MK-0557
Amylin agonist
a. Duvalintide
49. PHASE III TRAILS..
Neuropeptide Y (NPY Blocker (Y5 #) )
a. Velneperit (S-2367)
Dopamine, serotonin, norepinephrine reuptake inhibitor
a. Contrave (III completed NDA submission)
GLP 1 agonist
a. Liraglutide (III completed NDA submission)
b. Byetta
Adipose tissue hormone signaling (LEPTIN agonist)
a. Metreleptin(Phase III recruiting)
Inhibitor of lipase (Pancreatic lipase inhibitor)
Its inhibits intestinal lipid absorption
a. Cetilistat ATL-962 (Phase III completed)
