비만학회 연수강좌
소아청소년 비만약물처방
어떻게 할 것인가?
2015.03.22
인제의대 일산백병원 소아청소년과
김재현
목차
1
4
소아 청소년 비만
2
소아 청소년 비만의 치료
3
소아청소년 비만의 약물 치료
요약
소아청소년비만
• Obesity (in children & adolescents)
• BMI: >95th percentile (for same age & sex)
• Weight for height: >120% (for ideal body weight)
• Obesity (in adults)
• BMI
Organization
Definition of Obesity
World Health Organization
Overweight ≥25 kg/m2
Obesity ≥30 kg/m2
대한비만학회, 일본
Obesity ≥25 kg/m2
중국
Obesity ≥28 kg/m2
35
35
30
30
BMI (kg/m2)
BMI (kg/m2)
BMI curve (KOREA)
25
20
25
20
15
15
10
10
2 3 4 5 6 7 8 9 1011121314151617181920
남아 나이(세)
2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20
여아 나이(세)
한국소아청소년 성장도표, 2007
소아청소년 비만의 유병률 변화
비만+과체중
우리나라 학생검진결과 (2006-2013)
비만+과체중
비만
비만
Lancet 2014;384:766
Age-standardised prevalence of obesity,
ages 2–19 years, boys, 2013
Lancet 2014;384:766
Age-standardised prevalence of obesity,
ages 2–19 years, girls, 2013
Lancet 2014;384:766
소아청소년 비만의 문제점
• 성인기
• 성인 비만의 가능성 높음
• 대사 및 심혈관 질환의 가능성 높음
• 단기 합병증
• 이상지질혈증, 고혈압, 당뇨병, 골/관절 문제, 수면 무호흡증, 심
혈관 질환
• 정신, 사회적 문제 생길 가능성 높음
• 가능한 장기 합병증
• 심혈관 질환, 당뇨병, 뇌졸중, 암, 골관절염
Use of an estimate of $19,000 as the incremental lifetime
medical cost of an obese child relative to a normal weight
child who maintains normal weight throughout adulthood.
Pediatrics 2014;133:854
소아청소년 비만의 치료
• 원칙: 포괄적인 다면적 접근
• 1단계: 예방적 접근 (Prevention plus)
• 2단계: 구조화된 체중 조절 (Structured weight
management)
• 3단계: 포괄적 다면적 처치 (Comprehensive
multidisciplinary interventions)
• 4단계: 삼차적 처지 (Tertiary care intervention)
약물
치료
고려
JCEM 2008;93:4600
소아청소년 비만의 치료
• 생활 습관 개선 (Lifestyle modification)
• 식사 치료
• 운동 치료
• 행동 치료
• 약물 치료 (Pharmacotherapy)
• 수술적 치료 (Bariatric surgery)
JCEM 2008;93:4600
Intensive
lifestyle
modification
Lifestyle interventions
often fail as a result of
lack of family support
or weight regain.
Pharmacotherapy
Bariatric
surgery
Bariatric surgery is
reserved for adolescents
with BMI >50 kg/m2 or
BMI >40 kg/m2 with severe
comorbidities who failed
lifestyle modifications
and/or pharmacotherapy.
Timeline of anti-obesity drugs
Hyperthyroidism
CV event
Overheating
Death
CV event
Addiction (abuse)
Pulmonary
hypertension
CV event
(withdrawn in
2010)
Increased anxiety
Depression
Trends in Neuroscience 2013;36:133
Pharmacotherapy recommendations
• We suggest that pharmacotherapy (in combination with lifestyle
modification) be considered if a formal program of intensive
lifestyle modification has failed to limit weight gain or to
mollify comorbidities
in obese children.
Overweight
비만: 생활습관개선이
실패했을
때 children
should not be treated with pharmacotherapeutic agents unless
과체중:severe
합병증
있고 생활습관개선
실패했을
때
significant,
comorbidities
persist despite
intensive
lifestyle modification. In these children, a strong family history
↓
of T2DM or cardiovascular risk factors strengthens the case for
pharmacotherapy 경험 많은 의사가 처방
• We suggest that pharmacotherapy be offered only by clinicians
who are experienced in the use of antiobesity agents and are
aware of the potential for adverse reactions.
Prevention and treatment of Pediatric obesity
JCEM 2008;93:4576
비만치료제의 종류
• Drugs that reduce food intake (food suppressants)
• Noradrenergic (NOR) drugs, serotonergic (5HT) drugs,
serotonergic and adrenergic drugs (agonist)
• Drugs binding to the γ-aminobutyric acid (GABA) receptors
• Drugs binding to the endo-cannabinoid receptors (CB)
(antagonist)
• Some peptides that reduce appetite or elicit a feeling of
satiety
• Drugs that interfere with fat absorption
• Orlistat (pancreatic lipase inhibitor)
• Drugs that increase energy expenditure and thermogenesis
• Thyroid hormone
• Ephedrine and caffeine
Best Pract Res Clin Gastroenterol 2014; 28: 665
The mesolimbic dopamine system
Hindbrain neural circuits (within
the orange circle), including DVC,
NTS, AP, and PBN, control
satiation.
Hypothalamus
Green arrows (PVN: NPY/AgRP)
: stimulate feeding
Red arrows (ARC: POMC/CART)
: inhibit feeding
Leptin
Ghrelin
GLP-1
PYY3-36
Trends in Neuroscience 2013;36:133
성인비만 치료 약제
JAMA 2014;311:74
Orlistat (Xenical®)
• An inhibitor of pancreatic lipase reducing dietary fat absorption
• The compound is a partially hydrated derivative of an
endogenous lipstatin produced by Streptomyces toxytricini.
Orlistat (Xenical®)
• Orlistat binds irreversibly to the active sites of lipase through
covalent binding. Approximately 30% of triglyceride intakes
does not undergo digestion and is not absorbed by small
intestine, crossing the GI tract and being eliminated.
• Because of low systemic absorption and first-pass metabolism,
the bioavailability of orlistat is <1%; most of the drug being
excreted remains unchanged with stools.
Orlistat – Clinical studies
사용 허가는 12세 이상
Ann Pharmacother 2015;49:220
JCEM 2008;93:4600
Orlistat – Adverse events
• Transient and gastrointestinal in nature, resolving within 6
weeks
• increased fat excretion and included increased defecation
(14-100%), fatty/oily stools (50-90%), soft stools (15-85%),
oily spotting (29-83%), liquid stools (25-65%), abdominal pain
(13-65%), increased flatus (6-55%), flatus with discharge (2047%), fecal urgency (13-44%), fecal incontinence (6-40%), and
oily evacuation (20-23%).
• Study withdrawal caused by adverse effects varied greatly (2%33%) ; related to noncompliance before high fat meals to avoid
adverse effects.
Ann Pharmacother 2015;49:220
Orlistat – Adverse events
• Long-term fat-soluble vitamin deficiencies (Vitamin A,D,E,
and K) are potentially concerning and result from decreased
absorption. No significant decreases in vitamins A, E, or K
occurred with supplementation. However, decreases in serum
vitamin D levels were reported.
• One incidence of symptomatic cholelithiasis requiring
cholecystectomy potentially related to orlistat therapy has
occurred. In the same study, 6 additional orlistat-treated patients
were found to have asymptomatic gallstones not seen at
baseline, and 5 of them experienced substantial weight loss.
Ann Pharmacother 2015;49:220
Sibutramine
• A centrally acting monoamine reuptake inhibitor that mainly
acts to increase satiety
• Its most important mechanism of action is to block
norepinephrine and 5-HT re-uptake, but it also stimulates
thermogenesis that plays a minor role in weight reduction.
• 용량: 5-15 mg PO daily
• 허가: 16세 이상
Sibutramine – Clinical studies
Ann Pharmacother 2015;49:220
JCEM 2008;93:4600
Sibutramine – Adverse events
• The most common adverse effects found in adolescents taking
sibutramine was tachycardia.
• Other common side effects include insomnia, elevation of blood
pressure, headache, dizziness, dry mouth, and constipation.
• FDA safety announcement
• [10-8-2010] The U.S. Food and Drug Administration (FDA) is recommending
against continued prescribing and use of Meridia (sibutramine) because this drug
may pose unnecessary cardiovascular risks to patients. FDA has requested that
Abbott Laboratories—the manufacturer of Meridia—voluntarily withdraw this drug
product from the United States market. Abbott has agreed to voluntarily stop
marketing of Meridia in the United States.
• FDA’s recommendation is based on new data from the Sibutramine Cardiovascular
Outcomes (SCOUT) trial, which demonstrated a 16% increase in risk of major
adverse cardiovascular events (a composite of non-fatal heart attack, non-fatal
stroke, resuscitation after cardiac arrest and cardiovascular death) in patients
treated with Meridia compared to patients taking a placebo.
Metformin
Mechanism of metformin action on hepatic and muscle
glucose metabolism
Horm Res Paediatr 2013;80:78
JAMA Pediatrics 2014;168:178
Ann Pharmacother 2015;49:220
• 10세 이상에서 처방 가능
• 비만 치료에 효과는 있으나, 크지는 않음 (평균 BMI 감소 5% 미만)
• 장기간 치료에 BMI 가 약간 감소하는 것이 과연 효과적인지 의문점
• 이전에 lifestyle intervention에서 효과를 보였고, BMI >35 인 12세 이하의
소아에서 더 효과적인 것으로 보임
JAMA Pediatrics 2014;168:178
Ann Pharmacother 2015;49:220
Metformin – Adverse events
• Lactic acidosis is cited as a major problem. It is a potentially fatal
metabolic condition that can occur whenever substantial tissue
hypoperfusion and hypoxia exist.
• Metformin is at present contraindicated in patients with cardiovascular,
renal, hepatic, pulmonary, peripheral vascular disease, and sepsis, as these
conditions may increase the risk of tissue anoxia and therefore the
development of lactic acidosis.
Pediatric Diabetes 2011;12:580
Future anti-obesity drugs for children
• Phentermine
• Lorcaserin
• Topiramate
• Naltrexone SR/bupropion SR
• Anti-diabetic drugs – Liraglutide, Pramiltide
Phentermine
• A sympathomimetic amine
• FDA approved for short-term use.
• Phentermine is associated with CV adverse effects.
• Because of these effects and the potential need for chronic obesity
management
• Controlled-release phentermine and topiramate in combination
has yielded decreases in weight of 8.1 to 10.9 kg (6.7-14.4% of
bodyweight) and improvements in BP, glucose, TG, TC, LDL, HDL,
and CRP after 1 to 2 years of treatment in adults (FDA-approved
in 2012).
• Adverse events, including paresthesia (0.7-21%), dry mouth (0.7-21%),
constipation (4.1-21%), dysgeusia (0.7-13.2%), insomnia (3.7-10%),
depression (3-4.7%), irritability (1.7-4.5%), alopecia (2.1-4.3%), anxiety (2-4%),
attention disturbances (0.4-4%), sinusitis (7-13.2%), URI (12-18.6%), and
hypoesthesia (0.8-3.3%) may limit use in adolescents.
Lorcaserin
• A serotonin 5HT2c receptor agonist
• Lorcaserin reduced weight and BMI over 1 to 2 years in
obese adults with CV risk factors (decreased FBS, insulin,
HbA1c, BP, and CRP) (FDA-approved in 2012).
• Adverse events
• headache (14.5-18%), nasopharyngitis (11.3-16.4%), URI
(12.7-14.8%), back pain (5.9-11.7%), nausea (3.5-9.4%),
dizziness (7.0-8.7%), fatigue (2.6-8.4%)
• A single-dose, pharmacokinetic study has been
completed in obese adolescents 12 to 17 years old;
however, results are unavailable.
Topiramate
• FDA-approved anti-epileptic drug (AED)
• Monotherapy or adjunctive therapy for patients ≥2 years old with
partial onset or primary generalized tonic-clonic Sz and LennoxGastaut Synd.
• Patients ≥12 years old for migraine prophylaxis
• The mechanism of action of topiramate in weight loss
• Increase in serum adiponectin and reduction in leptin to adiponectin
ratio, possibly centrally or peripherally acting energy expenditure
• Dysgeusia; dose-related taste perversion or loss, potentially reducing
caloric intake while receiving topiramate
• Adverse CNS-related events
• Cognitive dysfunction (memory, language comprehension, and
attention)
• Dose-related events (esp. >3.3mg/kg/day)
Summary
• 아직까지는 소아비만의 일차 치료는 lifestyle
interventions
• 약물 치료는 제한적으로 사용해 볼 수 있음
• 반드시 생활습관 개선과 병행해야 효과 기대해 볼 수
있음
Summary
• 치료약제의 종류가 제한적
• 현재 사용 가능한 약제는 orlistat, metformin 정도
• 적용할 수 있는 환자가 제한적
• 장기간의 치료효과는 불분명
• 성인에서 승인된 약제(Lorcaserin, Qsymia)를 소아에
서 적용해 보는 것 필요
• 소아청소년 연령에서의 임상연구 필요
• 현재로서는 off-label use
Thank you for your attention !
Drugs with US FDA-approved indication
for obesity
Shortterm
Longterm
Generic drugs
Mechanism of Action
1-y Weight Change
Relative
to Placebo, Mean
(95% CI), kg
Common Adverse Effects
Phentermine
Noradrenergic causing
appetite suppression
Not included
Insomnia, elevation in heart rate, dry
mouth, taste alterations, dizziness,
tremors, headache, diarrhea,
constipation, vomiting, gastrointestinal
distress, anxiety, and restlessness
Diethylpropion
Noradrenergic causing
appetite suppression
Not included
Same as phentermine
Phendimetrazine
Noradrenergic causing
appetite suppression
Not included
Same as phentermine
Benzphetamine
Noradrenergic causing
appetite suppression
Not included
Same as phentermine
Orlistat
Lipase inhibitor causing
excretion of approximately
30% of ingested triglycerides
in stool
60 mg, −2.5 kg
(−1.5 to −3.5)
120 mg, −3.4 kg
(−3.2 to −3.6)
Oily spotting, flatus with discharge,
fecal urgency, fatty oily stool, increased
defecation, fecal Incontinence
Lorcaserin
Highly selective serotonergic
5-HT2C receptor agonist
causing appetite suppression
−3.2 kg (−2.7 to −3.8)
Headache, dizziness, fatigue, nausea, dry
mouth, cough, and constipation; and in
patients with type 2 diabetes, back pain,
cough, and hypoglycemia
Phentermine plus
topiramateER
Noradrenergic + GABAreceptor
activator, kainite/AMPA
glutamate receptor inhibitor
causing appetite suppression
7.5 mg/46 mg,
−6.7 kg (−5.9 to −7.5)
15 mg/92 mg,
−8.9 kg (−8.3 to −9.4)
Paresthesias dizziness, taste alterations,
insomnia, constipation, dry mouth,
elevation in heart rate, memory or
cognitive Changes
비만치료약제 작용 기전
성인비만 치료 약제
Best Pract Res Clin Gastroenterol. 2014;28:665