Obesity : result of energy balance

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Obesity result of energy balance
Energy Intake Only FOOD ! 100
Energy Output Basal Energy Expenduture 60-70
Exercise 15-20
Thermogenesis 10-15
Etc 5
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Anti-obesity drugs

• Targeting for less energy intake
• Control of appetite
• Phentermine, Phendimetrazine etc
• Inhibition of uptake
• Orlistat
• Targeting for more energy expenditure
• Caffeine, ephedrine etc. (not effective so
  far)
• New DM drugs
• Glucose uptake inhibition/long satiety time

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Effect of anti-Obesity drug

• Mean weight loss of at least 5 compared with
  placebo
• At least 35 of subjects in the active arm of the
  study, and at least double the percentage in the
  placebo group, must show at least 5 loss of
  baseline body weight
• (FDA efficacy benchmarks for anti-obesity agents)

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Now using drugs

• Long-term use medication
• Orlistat (Xenical)
• Short-term drugs (within 3months)
• Phentermine, phendimetrazine, Diethlpropion,
  benzphetamine, mazidol etc.

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Orlistat

• 1997 approved by US FDA/ 2001 in Korea
• Lipoprotein lipase inhibitor

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Orlistat

• 1yr effect 2.9Kg body weight loss (than
  placebo)
• 4yr effect (LSM) 6.7Kg loss

Torgerson JS et al. Diabetes Care
200427(1)155-61
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Orlistat
Paolo M. Suter et al., Atherosclerosis 2005
180(1)127-35
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Orlistat
Dose-Response Curve
60
50
40
fecal fat excretion
30
20 10 0
30
120
240
400
60
Orlistat dose (mg) tid
Zhi J et al. Clin Pharmacol Ther 1994 56 8285
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Orlistat
Pooled Rossner and Hauptman Studies
Anderson Study
0
0
Placebo
Placebo
-2
-2
60 mg tid
-4
-4
change from baseline
change from baseline
60 mg tid
-6
-6
120 mg tid
-8
-8
-10
-10
0
4
8
12
16
20
24
0
4
8
12
16
20
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Study Week
Study Week
Rossner S, Sjostrom L, Noack R, et al. Obesity
Research 2000 1 49-61 Hauptman J, Lucas C,
Boldrin M, et al. Arch Fam Med 2000 9
160-167 Anderson J, Schwartz S, Hauptman J, et
al. Ann Pharmacother 2006 40 1717-23
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Orlistat

• 2007, low dose agents(60mg) approved as OTC drug
• (NOT OTC in Korea)
• Side Effect
• Steatorrhea
• Vitamin K absorption inhibition
• liver damage ?/ Colon caner?

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Orlistat

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Phentermine

• Phenyl-tertiary-butylamine
• Amphetamine mimetic action
• Work on hypothalamus to stimulate adrenal gland
• (NE releasing)
• Reduced hunger sense, fat tissue breakage
• 1959, first received approval from FDA as
  appetite suppressing drug
• After Fen-phen issues, prescription rate
  decreased
• Controlled substance DEA Schedule IV
• Schedule IV phentermine, diethylpropion,
  sibutramine
• Schedule III benzphetamine, phendimetrazine
• Schedule II amphetamine and its derivatives

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Phentermine
Effects on Weight Reduction and Safety of
Short-Term Phentermine Administration in Korean
Obese People, Kyoung Kon Kim etc. Yonsei Medical
Journal Vol. 47, No. 5, pp. 614 - 625, 2006
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Phentermine
Randomized controlled trial to invetigate the
effects of a newly developed formulation of
phentermine diffuse controlled release for
obesity, J. G. Kang etc. Diabetes, Obesity and
Metabolism 12 876882, 2010.
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Phentermine

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• BP, HR monitoring
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Phendimetrazine

• Amphetamine like action
• Norepinephrine-Dopamine releasing Agent (NDRA)
• 1976, FDA approved as short-term
• 1960s clinical trial..
• Lack of recent study

Study of phendimetrazine bitartrate as an
appetite suppressant in relation to dosage,
weight loss and side effects_Cannadian medical
association journal 1962 Jul 78729-31
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Off-labeled drugs

• Anti-depressants
• Fluoxetine (Prozac)
• Sertraline (Zoloft)
• Bupropion
• Anti-convulsants (serotonin reuptake inhibition)
• Topiramate
• Zonisamide
• Anti-diabetes drugs
• Metformin,
• (DPP-VI inhibitor, GLP-1 agonist)

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New Medicine (FDA Approval)

• Lorcaserin 5-HT2C agonist
• Qnexa Topiramate/Phentermine

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Qnexa

• Qnexa Phentermine Topiramate
• Appetite suppressant
• 2012. 7 FDA approval (Qsmya by Vivus)

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Qnexa
Controlled release phentermine topiramate in
severely obese adults_ a randomized controlled
trial_ EQUIP. David B. Allison etc., Obesity
(2011) 20, 330342.
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Qnexa
Effects of low dose controlled release
phentermine plus topiramate combination on weight
and associated comorbidities in overweight and
obese adults _CONQUER_ a randomised placebo
controlled phase 3 trial. Kishore M Gadde, Lancet
2011 377 134152
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Qnexa
Effects of low dose controlled release
phentermine plus topiramate combination on weight
and associated comorbidities in overweight and
obese adults _CONQUER_ a randomised placebo
controlled phase 3 trial. Kishore M Gadde, Lancet
2011 377 134152
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Qnexa
Two year sustained weight loss and metabolic
benefits with controlled release
phentermine_topiramate in obese and overweight
adults _ SEQUEL _ a randomized placebo
controlled_ phase 3 extension study W Timothy
Garvey etc., Am J Clin Nutr 201295297308.
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Qnexa

• Dosage and administration
• Start dosage low dose (3.75/23) 14days (2wks)
  
• Increasing dosage mid dose (7.5/46) 12 wks
  
• 35 weight loss High dose (15/92)
• Caution and S/E
• Gradually discontinuation (high dose)
• Do NOT use high dose in renal/hepatic impairment
• Do NOT use to pregnant woman (Cleft)
• Increasing heart rate, suicidal idea, cognitive
  dysfunction, Acute myopia/Secondary glaucoma etc.

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Lorcaserin

• Lorcaserin 5-HT2C agonist
• Appetite suppressor
• 2012. 6. FDA approval (Belviq by Arena)
• 2013. 6. Market in US

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Lorcaserin
Multicenter, Placebo-Controlled Trial of
Lorcaserin for Weight Management. Smith, S R. New
England Journal Of Medicine olume 363 Issue 3
(2010-07-15) p. 245-256. (BLOOM study)
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Lorcaserin
A One-Year Randomized Trial of Lorcaserin for
Weight Loss in Obese and Overweight Adults_ The
BLOSSOM Trial. Meredith C. Fidler etc., J Clin
Endocrinol Metab 96 30673077, 2011
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Lorcaserin

• Side-effect
• Headache
• Valvular heart disease?
• Serotonin syndrome?
• Dosage and administration
• One tablet of 10 mg twice daily
• Discontinue if 5 weight loss is not achieved by
  week 12

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Anti-hyperglycemic agent for obesity

• Metformin
• DPP-VI inhibitor
• Sitagliptin (Januvia)
• Vildagliptin (Galvus)
• Saxagliptin (Onglyza)
• Linagliptin (Tradjenta)
• GLP-1 agonist
• Exenatide (Byetta)
• Liraglutide (Victoza)
• SGLT2 inhibitor
• Dapagliflozin (Forxiga)

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Metformin
A. Lee, Obesity Research 6(1)47-53, 1998
Erin S. LeBlanc, et al. Ann Intern Med.
2011155434-447.
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Mechanism of DPP-IV inhibitor GLP-1 agonist
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DPP-VI inhibitor
DPP-VI inhibitor ? in bodyweight
Sitagliptin -0.4 to 0.6
Vildagliptin WMD 0.56 (95 CI 0.270.84)
Saxagliptin -0.4
Linagliptin Not associated with weight
-gt Neutral effect on weight

• Richter B, Bandeira-Echtler E, Bergerhoff K,
  Lerch CL. Dipeptidyl peptidase-4 (DPP-4)
  inhibitors for Type 2 diabetes mellitus. Cochrane
  Database Syst. Rev.2, CD006739 (2008).
• Gerrald KR, Van Scoyoc E, Wines RC, Runge T,
  Jonas DE. Saxagliptin and sitagliptin in adult
  patients with Type 2 diabetes a systematic
  review and meta-analysis. Diabetes. Obes.
  Metab.14(6), 481492 (2012).
• Neumiller JJ, Setter SM. Review of linagliptin
  for the treatment of Type 2 diabetes mellitus.
  Clin. Ther.34(5), 9931005 (2012).

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GLP-1 agonist
Exenatide
JULIO ROSENSTOCK et al., Diabetes Care
3311731175, 2010
Liraglutide
M. Nauck et al., Diabetes, Obesity and Metabolism
15 204212, 2013.
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Pramlintide

• Synthetic analogue of amylin
• Amylin
• co-secreted with insulin from beta cell
• Suppression of glucagon (postprandial)
• Gastric emptying time increased satiety
  induction

Sustained weight loss following 12month
pramlintide treatment as an adjunct to lifestyle
intervention in obesity. STEVE R. SMITH etc.,
Diabetes Care 3118161823, 2008
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SGLT 2 inhibitor

• Mechanism
• Side Effect
• UTI, Cancer?

Edward C. Chao Robert R. Henry Nature Reviews
Drug Discovery 9, 551-559
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Dapagliflozin

1. Long-Term Efficacy of Dapagliflozin in Patients
   With Type 2 Diabetes Mellitus Receiving High
   Doses of Insulin. John et al. Ann Intern Med.
   2012156(6)405-415
2. Dapagliflozin treatment in patients with
   different stages of type 2 diabetes mellitus
   effects on glycaemic control and body weight.
   Zhang. Diabetes, Obesity Metabolism 201012
   (6)510-516.

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Trying to approve

• Contrave
• CKD 732

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Contrave
Effect of naltrexone plus bupropion on weight
loss in overweight and obese adults (COR-I) a
multicentre, randomised, double-blind,
placebo-controlled, phase 3 trial Frank L
Greenway etc., Lancet 2010 376 595605
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Contrave
Effect of naltrexone plus bupropion on weight
loss in overweight and obese adults (COR-I) a
multicentre, randomised, double-blind,
placebo-controlled, phase 3 trial Frank L
Greenway etc., Lancet 2010 376 595605
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Contrave

• 2011. 6. FDA not approved as obesity drug

Effect of naltrexone plus bupropion on weight
loss in overweight and obese adults (COR-I) a
multicentre, randomised, double-blind,
placebo-controlled, phase 3 trial Frank L
Greenway etc., Lancet 2010 376 595605
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COR-II
A randomized, phase 3 trial of naltrexone
SR/bupropion SR on weight and obesity-related
risk factors (COR-II) Caroline M. Apovian et al,
Obesity (Silver Spring). 2013 May21(5)935-43
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CKD 732
Assessment of the anti-obesity effects of the
TNP-470 analog, CKD-732. Kim YM, J Mol
Endocrinol. 2007 Apr38(4)455-65.
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Discussion and conclusion

• Anti-obesity drug
• Daring use vs. careful use
• Mainstream of anti-obesity strategy?
• Hopeful future of obesity drugs

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Thank you for attention