Download Orlistat

대한비만학회 연수강좌
비만 치료약물
을지대학교 서울을지병원
가정의학과 김정환
Obesity : result of energy balance
Energy Intake
Energy Output
Only FOOD !
100%
Basal Energy
Expenduture
60-70%
Exercise
15-20%
Thermogenesis
10-15%
Etc 5%
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
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)
Now using drugs
• Long-term use medication
: Orlistat (Xenical®)
• Short-term drugs (within 3months)
: Phentermine, phendimetrazine, Diethlpropion,
benzphetamine, mazidol etc.
Orlistat
• 1997 approved by US FDA/ 2001 in Korea
• Lipoprotein lipase inhibitor
Orlistat
• 1yr effect : 2.9Kg body weight loss (than placebo)
• 4yr effect (+LSM) : 6.7Kg loss
Torgerson JS et al. Diabetes Care 2004;27(1):155-61
Orlistat
Paolo M. Suter et al., Atherosclerosis 2005; 180(1):127-35
Orlistat
Dose-Response Curve
% fecal fat excretion
60
50
40
30
20
10
0
30 60
120
240
400
Orlistat dose (mg) tid
Zhi J et al. Clin Pharmacol Ther 1994; 56: 82–85
Orlistat
Pooled Rossner and Hauptman Studies
Anderson Study
0
Placebo
-2
60 mg tid
-4
-6
120 mg tid
-8
% change from baseline
% change from baseline
0
Placebo
-2
-4
60 mg tid
-6
-8
-10
-10
0
4
8
12
16
Study Week
20
24
0
4
8
12
16
20
24
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
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?
Orlistat
• 임상진료 현장에서
• 식단 확인
– 기름진 식사 많이 하는 사람에게 우선 투여
– 기름진 식사 할 때만 먹도록
– 1일 3회?
• 지방변
– 충분한 주의
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
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
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: 876–882, 2010.
Phentermine
• 임상 진료 현장에서
• 식단 확인
– 최근 식사량 증가
– 식욕(식탐) 조절 어려움
• 심혈관계 질환자 : 조심스럽게 접근
– BP, HR monitoring
• 저녁에는 복용하지 않도록 : 불면증 유발
• 단기 처방이 원칙
Phendimetrazine
•
•
•
•
Amphetamine like action
Norepinephrine-Dopamine releasing Agent (NDRA)
1976, FDA approved as short-term
1960’s 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 7;87:29-31
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)
New Medicine (FDA Approval)
• Lorcaserin : 5-HT2C agonist
• Qnexa : Topiramate/Phentermine
Qnexa
• Qnexa : Phentermine + Topiramate
• Appetite suppressant
• 2012. 7 FDA approval (Qsmya® by Vivus)
Qnexa
Controlled release phentermine topiramate in severely obese adults_ a randomized controlled trial_ EQUIP. David B.
Allison etc., Obesity (2011) 20, 330–342.
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: 1341–52
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: 1341–52
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 2012;95:297–308.
Qnexa
•
•
•
•
Dosage and administration
Start dosage : low dose (3.75/23) – 14days (2wks)
Increasing dosage : mid dose (7.5/46) – 12 wks
3~5% 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.
Lorcaserin
• Lorcaserin : 5-HT2C agonist
• Appetite suppressor
• 2012. 6. FDA approval (Belviq® by Arena)
• 2013. 6. Market in US
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)
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: 3067–3077, 2011
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
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®)
Metformin
A. Lee, Obesity Research 6(1);47-53, 1998
Erin S. LeBlanc, et al. Ann Intern Med. 2011;155:434-447.
Mechanism
of DPP-IV inhibitor & GLP-1 agonist
DPP-VI inhibitor
DPP-VI inhibitor
Δ in bodyweight
Sitagliptin
-0.4 to +0.6
Vildagliptin
WMD: 0.56 (95% CI: 0.27–0.84)
Saxagliptin
-0.4
Linagliptin
Not associated with weight
-> 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), 481–492 (2012).
•Neumiller JJ, Setter SM. Review of linagliptin for the treatment of Type 2 diabetes mellitus. Clin. Ther.34(5), 993–
1005 (2012).
GLP-1 agonist
Exenatide
JULIO ROSENSTOCK et al.,
Diabetes Care 33:1173–1175, 2010
Liraglutide
M. Nauck et al., Diabetes, Obesity and Metabolism
15: 204–212, 2013.
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 31:1816–1823, 2008
SGLT 2 inhibitor
• Mechanism
Edward C. Chao & Robert R. Henry Nature Reviews Drug Discovery 9, 551-559
• Side Effect
– UTI, Cancer?
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. 2012;156(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 2010;12 (6):510-516.
Trying to approve
• Contrave
• CKD 732
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: 595–605
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: 595–605
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: 595–605
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 May;21(5):935-43
CKD 732
Assessment of the anti-obesity effects of the TNP-470 analog, CKD-732. Kim YM, J Mol Endocrinol. 2007 Apr;38(4):455-65.
Discussion and conclusion
• Anti-obesity drug
– Daring use vs. careful use
– Mainstream of anti-obesity strategy?
• Hopeful future of obesity drugs
Thank you for attention