1. 2017년 제13회 분당서울대병원 내과 연수강좌
근거 중심의 비만치료
오 태 정
내분비내과

2. Definition of Obesity
Overweight and obesity are defined as abnormal or excessive fat accumulation that presents a risk to health.
Body mass index (BMI) = weight (kg)/height (m2)
Waist circumference (WC): ≥ 90 cm (men), ≥ 85 cm (women)
Classification
BMI (kg/m2)
Korean
Underweight
<18.50
Normal range
18.50  24.99
18.5022.99
Overweight
≥25.00
23.0024.99
Obese
≥30.00
Class I
30.00  34.99
25.0029.99
Class II
35.00  39.99
Class III
≥40.00

3. Mortality according to BMI
NEJM 1999; 341(15):

4. BMI cut-off points for public health action
Lancet 2004; 363:

5. At least one risk factor for cardiovascular disease
Lancet 2004; 363:

6. Epidemiology of obesity
Men
Steadily increase from 34.4% in 2006 to 40.7% in 2015
Women
Steady state or slightly increase from 23.3% in 2006 to 24.5% in 2015
The percentages and the total number of people over the age of 20 were determined using the National Health Checkup Database from 2006 through to 2015 made by National Health Insurance Service (NHIS).

7. Complications of Obesity
Psychological
Neoplastic
Inflammatory
Structural
Metabolic
Degenerative
Several of these complications exacerbate the underlying
obesity, creating a vicious cycle:
Diabetes Many diabetes drugs cause weight gain
PCOS Insulin resistance
promotes lipogenesis
Sleep apnea Disrupted sleep
can cause weight gain
Arthritis Limit exercise capacity
Back pain
Inflammatory Steroids often cause
disorders weight gain
Depression Eating disorders and
Psychological many psychotropic agents
cause weight gain

8. Therapeutic weight loss for complications of obesity
Obesity complication
Weight loss required for therapeutic benefit (%)
Notes
Diabetes (prevention)
3-10
Maximum benefit at 10%
Hypertension
5 to >15
Blood pressure still decreasing at >15%
Dyslipidemia
3 to >15
Triglycerides still decreasing at >15%
Hyperglycemia (elevated A1c)
A1c still decreasing at >15%
NAFLD 10
Improves steatosis, inflammation, and mild fibrosis
Sleep apnea
Little benefit at 5%
Osteoarthritis
5-10
Improves symptoms and joint stress mechanics
Diabetes Care 2015; 38:

9. Treatment strategies for weight loss
Meal plan
Physical activity
Behavior
Medication

10. Lifestyle modification
2016 AACE/ACE Algorithm for the medical care of patients with obesity

11. FDA requirements for weight management agents
There is a statistically significant difference in weight loss between the intervention and placebo-treated groups (a mean absolute difference of ≥5%).
At least 35% of subjects who experience weight loss of ≥5% received the active drug.
The proportion of patients who experience weight loss in the intervention group is approximately double that in the placebo group.
Am J Health Sys Pharm 2015; 72:

12. Current US-approved anti-obesity therapeutics
Drug name
Brand name
Year approved (FDA)
Body weight loss (%)
Orlistat
Xenical (Roche) and Alli (GlaxoSmithKline)
1999
511
Lorcaserin
Belviq (Arena Pharmaceuticals)
2012
35
Phenteramine-topiramate ER
Qsymia (Vivus)
911
Naltrexone-bupropion XR
Contrave (Takeda Pharmaceuticals) and Mysimba (Orexigen)
2014 5
Liraglutide
Saxenda (Novo Nordisk)
512

13. Targets of anti-obesity drugs
Lancet 2016; 387:

14. 1. Lorcarserin (Belviq) https://www.belviq.com/hcp/about/moa
Belviq 10mg bid
Belviq 10mg qd (당뇨병 환자)

15. BLOOM Study
NEJM 2010; 363:

16. BLOOM-DM Study
Obesity 2012; 20:

17. Adverse reactions of Lorcaserin
Placebo
(n = 3185)
Headache
16.8%
10.1%
Dizziness
8.5%
3.8%
Fatigue
7.2%
3.6%
Nausea
8.3%
5.3%
Dry mouth
2.3%
Constipation
5.8%
3.9%

18. 2. Naltrexone-bupropion (Contrave)
naltrexone 8mg, bupropion 90mg = 1 tablet
첫 주: 오전 1정
둘째 주: 오전 1정, 오후 1정
셋째 주: 오전 2정, 오후 1정
넷째 주: 오전 2정, 오후 2정
Mechanism for naltrexone/bupropion action in the hypothalamicmelanocortin system. The hypothalamus contains cells that produce pro-opiomelanocortin (POMC). In these cells, POMC is cleaved into peptides including -melanocyte stimulating hormone ( -MSH) and -endorphin, which are co-released from POMC cells. -MSH stimulates the melanocortin-4 receptor (MC4R),which leads to decreased food intake, increased energy expenditure and weightloss. -Endorphin binds to the inhibitory -opioid receptor (MOP-R) on POMC cellsand acts like a brake to reduce activity of POMC cells. Bupropion stimulates activityof POMC cells, increasing POMC production and release of -MSH and -endorphin.Naltrexone blocks the MOP-R and prevents the -endorphin-mediated feedbackautoinhibition of POMC cells. Together, the naltrexone/bupropion combinationproduces a greater increase in POMC activity than either drug alone. This increasedPOMC activity is thought to contribute to weight loss in humans.
Pharmacological Research 2014; 84: 1-11

19. Contrave Obesity Study (COR)
Lancet 2010; 376:

20. Contrave Obesity Study (COR)-DM
32mg/360mg
Diabetes Care 2013; 36:

21. Adverse reactions of Naltrexone-bupropion
Contrave
(n = 2545)
Placebo
(n = 1515)
Nausea
32.5%
6.7%
Constipation
19.2%
7.2%
Headache
17.6%
10.4%
Vomiting
10.7%
2.9%
Dizziness
9.9%
3.4%
Insomnia
9.2%
5.9%
Dry mouth
8.1%
2.3%
Diarrhea
7.1%
5.2%
* Special concern: suicidal behavior, risk of seizure, drug-drug interaction

22. Comparison of weight loss and adverse events
JAMA 2016; 315(22):

23. Common adverse effects
Drugs
Mode of action
Common adverse effects
Phentermine (Adipex)
Noradrenergic causing appetite suppression
Insomnia, HR , dry mouth, taste alteration, dizziness, tremors, headache, diarrhea, constipation, vomiting, GI distress, anxiety, and restlessness
Orlistat (Xenical)
Lipase inhibitor causing excretion of approximately 30% of ingested TG in stool
Oily spotting, flatus with discharge, fecal urgency, fatty oily stool, increased defecation, fecal incontinence
Lorcaserin (Belviq)
Highly selective serotonergic 5-HT2C receptor agonist causing appetite suppression
Headache, dizziness, fatigue, nausea, dry mouth, cough, and constipation
Naltrexone-bupropion (Contrave)
Activates POMC neurons by binding to MC4Rs and antagonizeds the opioid system.
Nausea, constipation, Headaceh, seizure, glaucoma, HR 

24. AACE/ACE Algorith for the medical care of patients with obesity

25. Individualization of therapy
Orlistat
Lorcaserin
Naltrexone ER/bupropion ER
Diabetes Prevention
Preferred
Use with caution
Diabetes mellitus
Hypertension
Monitor BP and HR
CIx in uncontrolled HTN
Cardiovascular disease
Monitor for bradycardia
Monitor HR, BP
CKD
Mild
Moderate
Do not exceed 1T bid
Severe
Watch for oxalate nephropathy
Urinary clearance of drug metabolites
Urinary clearance of drug
Hepatic impairment
Mild-moderate
Watch for cholelithiasis
Hepatic metabolism of drug
Do not exceed 1T qd
CIx

26. Long-term therapy 체질량지수 (BMI)와 비만관련 동반질환의 유무에 따라 약물치료 시작여부를 고민
Xenical, Belviq, Contrave  FDA approved
Benefit, price, risk 를 고려하여 처방
3개월 처방 후 기저대비 5% 이상의 체중감소가 없을 시 중단필요.

27. Surgical treatment ??

28. Bariatric surgery, the most powerful anti-obesity treatment
JAMA 2004; 292:

29. Three common procedures
Roux-en-Y Gastric Bypass
RYGB
Vertical Sleeve Gastrectomy
VSG
Adjustable Gastric Banding
AGB

30. Weight change after bariatric surgery
N Engl J Med 2007;357:741-52

31. Indication for bariatric/metabolic surgery
BMI range
Eligible for surgery
Prioritized for surgery
<30 No
3035
Conditional**
3540
YES
>40
* Action points should be lowered by 2.5 BMI levels for Asians
** Conditional: HbA1c >7.5% despite fully optimized conventional therapy,
other weight responsive co-morbidities – HTN, Dyslipidemia, OSA
IDF Taskforce on Epidemiology and Prevention

32. Bariatric surgery in patients with diabetes
DSS-II recommendation, Diabetes Care 2016; 39:

33. Lifelong postoperative care
Immediate tapering of glucose lowering agents
Effective nutrition education
Physical activity
Supplements: Ca/Vit D, iron, folate, Vit B12
Long-term medical f/u strategy
Complication: hypoglycemia, osteoporosis

34. Summary Clinical benefits with 5-10% weight reduction
Lifestyle modification: ~ kcal daily deficit, aerobic exercise >150 mins/week, resistance exercise 2-3 times/week
Drug therapy (long term): Orlistat, Lorcaserin, Naltrexone-bupropion
Bariatric surgery: appropriate candidate