EASD Xenical Symposia

1
????S?????
???S??S ???????T?G????? - ?????OS??S
T?????????? ???????O??S? ????S
F?O????S ???????????G?S
2

????S????? ?????? ?????????? ??S???

• ? ?a???sµ??? ???a??sµ?? ??e?a? a?a??????e? t??
  pa??sa???a sa? µ?a pa???sµ?a ep?d?µ?a ?a? ??
  s?ßa?? p??ß??µa ??a t? ??µ?s?a ??e?a
• ?? pa??sa???? as?e?e?? ????? a???µ??? ???d???
  p?????? ???s?µ?t?ta? (WHO)
• ?a 2/3 t?? as?e??? µe ?p??tas? e??a? ?p??ßa??? ?
  pa??sa???? (WHO)
• ? s????t?ta t?? Sa??a??d? ??aß?t? t?p?? 2 ??e?
  t??p?as?aste? ta te?e?ta?a 30 ?????a ???? t??
  a???s?? t?? pa??sa???a? (Nurses study)
• ? ?a???sµ??? O??a??sµ?? ??e?a? a?a??????e? t??
  pa??sa???a sa? t? ??s? t?? 21?? a???a

3
? ??????? ??? ??????????S

• ??t?µet?p????µe µ?a µe???? ep?d?µ?a µe
  ?atast??f???? s???pe?e?. ?? p?s?st? t??
  pa??sa???a? d?p?as???eta? ?a?e 5 ?????a sta
  pe??ss?te?a ???t? t?? ??sµ?? ?aµß????ta?
  d?ast?se?? pa??????a??? ??µat?? ??a ??a ta
  s?st?µata ??e?a?.
• Professor Philip James
• Chairman of the WHO International Obesity Task
  Force

4
.?a??? t? p??ß??µa d??????eta? ??????a st?
pa?d??? ?????a.
5
(No Transcript)
6
???S???
????S????? ? ?pe?ß????? s?ss??e?s? ??p???
(??p?d?? ?st??) µ?sa st? s?µa
?????????? ????S ??e??asµa s?µat???? ß?????
se s??s? µe t? ????
7
G??a??e?

• ??s?st? ??p?d??? ?st?? gt 30 S? ????S?????

??d?e?

• ??s?st? ??p?d??? ?st?? gt 25 S? ????S?????

8
?e??t?? ???a? S?µat?? (???)
S?µat??? ?????
BMI
????2
????G???? ??? ???????S
???e?p?ßa??? lt18.5
????µ???? F?s????????? ?????? 18.5 - 25
?aµ???? ?p??ßa??? 25
- 30 ??t???? ?a??sa???? 30
- 40 ????µ???? S?ßa?? pa??sa????
gt40 ???? ????µ????
World Health Organization, 1998
9
? ?e??µet??? ??s?? e??a? ?e??t?? ?pa????
?????a??? ??p???
G??a??e?
??d?e?
gt88 cm ????µ???? ???d???? ??a µetaß????? ??s?µa
gt102 cm ????µ???? ???d???? ??a µetaß????? ??s?µa
10
????S ????? ?? ?????S ??S ????S?????S ?

• ????pa?a???t???? p????e?s?? µa?? µe t?? ep?d?as?
  t?? ?e?et???? ?a? t?? pe??ßa????t???? pa?????ta
• 60 ?e?et??? p??d???es? 40 pe??ßa????t???
• ? s??????? ?e?ape?a pa??sa???a? ßas??eta? st?
  ep?d?as? t?? pe??ßa????t???? pa?????ta
• 1 p???a?e?ta? ap? sp???a ?e?et??? s??d??µa ?a?
  e?d????????? d?ata?a???

11
???????????T???S ????S?????

• S. Cushing (a???µ??? ???t????? pa??sa???a,
  ?p??tas?, S.?. t?p?? 2, ?ste?p???s?)
• S??d??µ? ??????st???? O?????? (d?ata?a???
  pe???d??, ?pe?t????s? - ?pe?a?d?????a?µ?a,
  pa??sa???a st? 50)
• ?p????e?e?d?sµ?? (µe??s? BMR)
• ?µµ???pa?s? (???e??? ??st???????)
• Ge?et??? ??s?µata - pa?d??? ?????a
• (S. Prader Willi t? p?? s???? 1/10000 15000)

12
??????S? ????????????S

• ??a?ta (?pe??ata????s? t??f??)
• ????µ??? ?ata????s? a?????
• S??e?e?? ap?pe??e? ad??at?sµat?? (yo-yo)

13
Ge????ta ?a? ?atast?se?? pa??sa???a

• ??a??p? ?ap??sµat??
• ??t??? ????????? ???
• ?e??µ??? f?s??? d?ast????t?ta
• ?a??st??? ???
• ??t??e? s??a?s??µat???? ?atast?se?? ( stress,
  a??a, ?at??????, µ??a??? )

14
?????????S ??? ?????????? ?? S???????? ??S
????S?????S

• ?????? ? pa??sa???a a????eta? µe t?? ?????a
  (gt65 et??)
• F??? ? pa??sa???a e??a? p?? s???? st?? ???a??e?
• F??? ? pa??sa???a e??a? p?? s???? st?? µa??e? se
  s??s? µe t?? ?e???? ?µe???a??de?
• ???? ? pa??sa???a e??a? p?? s???? st?? ?aµ????
  ?????????? ta?e?? t?? a?apt??µ???? ??sµ??
• ?????? ? a???s? t?? pa??sa???a? st?? ?ap???a
  ?fe??eta? st?? d?t???? ep?d??se?? t?? ?ap??????
  d?a?ta?

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S????t?ta ?a??sa???a? st?? ??? From Years 1991,
1993, 1995, and 1998
(Reprinted with permission from Mokdad AH, et al.
JAMA. 1999)
16
S????t?ta ?a??sa???a? st?? ????p?
Ireland 31 8
Finland33 10
Sweden33 7
Netherlands29 10
U.K.3012
Denmark31 8
Belgium 31 9
Germany35 11
Luxembourg 27 9
Austria32 10
France24 7
Greece 3511
Portugal 33 9
Italy30 7
Spain33 11
Italics Overweight
Martinez JA, Public Health Nutr 1999
2(1A)125-33.
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HIGH PREVALENCE OF OVERWEIGHT AND OBESITY IN
GREECE
AGE GROUP MEN MEN WOMEN WOMEN
AGE GROUP Overweight Obese Overweight Obese
20-30 30,5 11,4 16,9 7,4
31-40 38,8 27,9 29,1 15,0
41-50 43,3 26,9 32,8 20,8
51-60 42,3 29,8 36,2 33,9
61-70 40,0 28,0 32,5 44,7
Total 41,1 26,0 29,9 18,2
Data from 1st Panhellenic Epidemiological Study
by H.M.A.Obesity
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?p?pt?se?? t?? pa??sa???a?
S??d??µ? ?p????? ?p???a?
???e?a?? ???efa???? epe?s?d??
?p??tas? ??s??p?da?µ?a
?a?d??p??e?e?
????????as?
S. ?. t?p?? 2
?ste?a????t?da
??µ?????? d?ata?a???
?a??????
?????? a????t?da
19
S???????? () ??T?S?O? ??? S?????????? ?? ??
????S?????

• S? t?p?? 2
• ?p??tas?
• Stefa??a?a ??s??
• ????????as?
• ?ste?a????t?da
• ?a?????? µast??
• ?a?????? e?d?µ?t????
• ?a?????? pa???? e?t????

57 17 17 30 14 11 11 11
Wolf et al. Obes Res. 1998697-106.
20
????S????? ??? T??S???????
2.5
??d?e?G??a??e?
?
2.0
?
T??s?µ?t?ta
1.5
1.0
???? ??????
?????aµ????
?pe?ß???????????
?et????
?aµ????
??????
0
20
25
30
35
40
??S (kg/m2)
Adapted from Gray DS. Med Clin North Am. 1989
73(1) 113.
21
S?S????S? ????S?????S ??? S???S???????S
?pe?tas? Stefa??a?a ??s??
S? t?p?? 2 ????????as?
G??a??e?
??d?e?
6
6
5
5
4
4
S?et???? ???d????
3
3
2
2
1
1
0
0
??S (kg/m2)
??S (kg/m2)
Willett WC, et al. N Engl J Med. 1999 341
427434.
22
????S????? ??? ??????GG????? ??S?S
S?et???? ???d???? ?? Ta?at?f???? ?a? Ta?at?f????
?. ????a?d??? se s??s? µe t? ??S st?? G??a??e?
4
3
S?et???? ???d????
2
1
0
lt21
21-22.9
23-24.9
25-28.9
gt29
BMI
MI myocardial infarction CHD coronary heart
disease.
Adapted from Willett et al. JAMA.
1995273461-465.
23
ATP III ?etaß????? S??d??µ?

• ?e?t???? ?a??sa???a (?e??µet??? ??s??)
• ??d?e? gt102 cm
• G??a??e? gt88 cm
• ????µ??a ???????e??d?a (gt 150 mg/dL)
• ?aµ??? ?p?peda ?DL ????ste?????
• ??d?e? lt40 mg/dL
• G??a??e? lt50 mg/dL
• ????µ??? ??t???a?? ??es? (gt130/gt85 mmHg)
• ????µ??? G?????? ??ste?a? (gt110 mg/dL)

Adult Treatment Panel III guideline for
cholesterol management ,NCEP, Circulation 2002
24
? ??O???? ?????S S?????????? ??? S????????
?????OS? S???S ????G????S ???????? ???
??????????? S????????
????S?????
??S??????????
??????S?
S.???????S ?????2
25
-58 µe??s? st?? eµf???s? S.??aß?t? t?p?? 2
Tuomilehto J, N Engl J Med 20013441343-50

Knowler WC, N Engl J Med 2002346393-403
26
???OS? T??S???????S S? ?ST????S ??? ???S?? 1-10 KG
??e? a?t?e?
?a??????
0
-10
-9
-20
-20
-30
-40
-37
-44
-50
-53
-60
Am J Epidem 141 1128 (1995)
27
G???? ????? ??S???? ? ??O???? ?????S ???
????????? ? ???????S? ??S ??O????S ?????S?

• F?s????????? ?a?????te?
• ?e??s? st?? ?ata????s? e????e?a? (p??sa?µ?st???
  µe??s? ßas???? µetaß???sµ??)
• ????s? ap????e?s?? ??p???
• ????µ??? e????e?a µe t? d?a?ta
• ?p?t??esµa a???µ??? p??a??t?ta epa???t?s??
  ß????? (?? 90 t?? pa??s????? se 2 ?????a)
• ???????????
• ? pe?????sµ?? t?? ?e?µ?d?? de? e??a? e?????st?
  ?e?????
• ?d??e? se a???est? ep???µ?a ??a fa??t?
• ???e??? a?t?pep???s??

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????G????? ?S???????
???s???? t??f??
?ata?a??s? e?e??e?a?
????s? ?a????
???s???? t??f??
?ata?a??s? e?e??e?a?
???s???? t??f??
?ata?a??s? e?e??e?a?
?p??e?a ?a????
???s???? t??f??
?ata?a??s? e?e??e?a?
29
?p?t???? a?t?µet?p?s? t?? pa??sa???a?
????? s?µat?? (kg)
F?s??? e?????? a???s?? ß?????
?????? ?????
1? F?s? ?p??e?a ??????
Increasing success
2? F?s? ??at???s? ?p??e?a? ??????
????S
??????
?????S
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???????O??S? ????S?????S
??????? a???s?? ß?????
???sp??e?a d?at???s?? ß?????
??t?µet?p?s? ??s???t?ta? t?? pa??sa???a?
???sp??e?a ap??e?a? ß?????
Adapted from WHO Technical Report Series 894
31
T?????????? ???????O??S? ????S?????S
?p??e?µ?d??? ??a?ta
???a?? S?µpe??f????/ ???p?? ???? ??????????
?p?st?????
?s??s?
?at???? ?p?st????? (Fa?µa?e?t??? ?e?ape?a /
?e????????? a?t?µet?p?s?)
32
??????F?
33
?OS ?????G?????? ? ??????????? ????G??? S? ???
?????S?? ???T???????? ????????G?? ?

• ?p?????? e?d???? p??a?e? ?p?????sµ?? t?? ßas????
  µetaß???sµ?? µe ß?s? t?? ?????a, t? ???? ?a? t?
  s?µat??? ß????
• ???s??t??µe 30 e?? 70 t?? ??R µe ß?s? t? f?s???
  d?ast????t?ta t?? at?µ??
• ?p? t? pa?ap??? ?????sµa ?e?µ?d?? afa????µe 500
  e?? 1000 ?e?µ?de? ?a? d????µe e?a d?a?t??????
  ap??e?a? ß????? µe ???µ? ap??e?a? 0,5 e?? 1 ?g
  t?? eßd?µ?da

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???????? ???G?? ??????F?S ?????G?S??S 50 CHO,
30 ????S, 20 ??O?????S
Fats, oils sweets Use sparingly
Milk, yogurt cheese group 2-3 servings
Meat, poultry, fish, dry beans, eggs nuts
group 2-3 servings
Vegetable group 3-5 servings
Fruit group 2-4 servings
Bread, cereal, rice pasta group 6-11 servings
35
??????F???S S???????S
36
SO?????? ???S?????????
37
? ??T??????? F?S??? ???S????????? ????? ????
S???????? S??? ??O???? ??????? S?? ???????S? ??S
??O????S ?????S
38
???G??S SO??????S ???S?????????S

• 3 e?? 5 ?µ??e? eßd?µad?a??? (?da???? se
  ?a??µe???? ß?s?)
• ??????? µet???? ßa?µ?? s?µat??? d?ast????t?ta 30
  45 min
• ?p?? pe?p?t?µa, p?d??at?, ????µp?, ????a??
  e??as?a ??p??????
• G?a pa??s?????? ????? d?ast????t?ta, a??????
  s???st?ta? ?p??? ßa?µ?? s?µat??? d?ast????t?ta

?et???? ßa?µ?? ?s??s? a?t?st???e? se 150
?e?µ?de? e?e??e?a?? ?ata????s? t?? ?µ??a
1. NIH/NHLBI The Practical Guide
Identification, Evaluation and Treatment of
overweight and obesity in adults, Oct. 2000 2.
WHO Technical Report 916 Diet, Nutrition and
Prevention of Chronic Diseases, 2003
39
????G? S??????F???S/ ?????? ?O?S ??????G???
???S??????
40
?????????S? S??????F???S / ????G? ?????? ?O?S

• ?p? t? p?e??? t?? ?e??p??ta st?? ep?s???e??
  ??e???eta?
• ??µ??????a f?????? s??s?? / ?ea??st???? st???? /
  S???? epaf?
• S?µß????? p??? t?? as?e?? ??a a??a?? s?µpe??f????
• ??t???e???? ?ata??af? d?a?t???????, ?s??s??
  ?a? ß?????
• ??taµ??ß? a?a?????s? t?? p??sp??e?a?
• ??e???? ap?f??? pe??asµ?? / ?a t??µe se ??a
  µ????
• ?p????t??s? se s?µa?t??? µ???µata p?? ?????
  s?µas?a

NIH/NHLBI The Practical Guide Identification,
Evaluation and Treatment of Overweight and
Obesity in Adults, October 2000.
41
??????G??? ???S??????

• ? ??e???? (µe??s?) t?? s?µ. ß????? µe???e? t?
  ?at?????? ?a? a????e? t?? a?t?e?t?µ?s?, e?? ?
  epa???t?s? t?? s?µ. ß????? s???de?eta? µe
  a?t??eta ap?te??sµata
• ?? s??d??µ? t?? epe?s?d?a??? ?pe?fa??a? (Binge
  Eating Disorder) s???de?eta? ap? a???µ??a p?s?st?
  pa??sa???a? ?a? ?at??????? (Telch et al, 1988
  Marcus et al, 1988)

42
???G?OS???? ???????? ????S??????S ????F?G??S
(Binge Eating Disorder)

• ?pa?aµßa??µe?a epe?s?d?a ?pe?fa??a?
  (ts?µp?????µa)
• ??t???pt? ap? t?? as?e?? ? ap??e?a e?????? ?at?
  t? d????e?a t?? ?e?µat??
• S????t?ta epe?s?d??? ?pe?fa??a? t??????st?? 2 a??
  eßd?µ?da ??a 6 µ??e?
• ? epe?s?d?a?? ?pe?fa??a p?? de? eµfa???eta?
  ap???e?st??? ?at? t? d????e?a ?????e???? ß????µ?a?

43
??????? ???S?????? (F??????????? T???????)
44
???????G?S? F???????????S ???????O??S?S
????S?????S

• ???? ? a??a?? t??p?? ???? de? e??a?
  ap?te?esµat??? (?p?t??p? sta 2 ?????a gt90)
• ? fa?µa?e?t??? ?e?ape?a ??e? ap?de??e? t??
  ap?te?esµat???t?ta t?? st?? a???s? t?? ap??e?a?
  ß????? ?a? st?? µa????????a d?at???s? t??
  ap??e?a? s?µat???? ß?????

45
??????? F???????????S T???????S

• ??S ? 30
• ??S ? 27 ?a? s???d? µetaß????? ??s?µa (?p??, S?
  t?p?? 2 ?/?a? d?s??p?da?µ?a ?/?a? e?e???µe??
  ?p??tas?)
• S????S T???????S
• ? µ?t??a ap??e?a ß????? (gt5 gt10) ?a? ?
  µa????????a d?at???s? t?? ap??e?a?, d??t? ??e?
  ap?de???e? ?t? p???a?e? s?µa?t??? ße?t??s? st???
  µetaß??????? pa?????te? ???d????, ?p?? S? t?p??
  2, d?s??p?da?µ?a ?a? ?p??tas?

46

F?????? ???? ??S ????S?????S ??????S??S ???S?S
???SOS? ????G?????S ?S???????S
????s? ?ata????s?? e????e?a?
?e??s? p??s????? e????e?a?
?e??a ???esµ?? - Sibutramine ?p????f?s? t??f??
Orlistat
???µ?? ?as???? ?etaß???sµ?? Sibutramine
National Task Force on the Prevention and
Treatment of Obesity. JAMA. 19962761907-1915.
47

• absorption of fat
• Orlistat
• Xenical

CNS acting Sibutramine Reductil
48
??????S??S ???S?S ????S????S

• ??s? a?ast???? t?? ?ast?e?te????? ??pas??
  p???a?e? µe??s? ap????f?s?? t?? ??p??? t??
  t??f?? ( t? 1/3) 2
• ?? µ? ap????f??µe?? ??p?? ap?ß???eta? sta
  ??p?a?a 2

1. Zhi et al. J Clin Pharmacol. 1995351103-1108
2. Zhi et al. Clin Pharmacol Ther. 19945682-85
3. Yanovski and Yanovski. N Eng J Med. Feb
   2002346591-602.

49
????S???? ???????S??????????(????-?????S? 1
year studies)

• ?p??e?a ß????? 9 vs 5.8 (orlistat vs placebo)
• ?pa???t?s? ß????? sta 2 ?????a 35.2 vs 62.4
  (orlistat vs placebo d?af??? 2.5 kg)
• ?s?e?e?? µe S? t?p?? 2 6.2 kg vs 4.3 kg (- 1.9
  kg)
• ??t??a ße?t??s? µetaß?????? pa?a???t?? ???d????
• ??p?da?µ??? ????a?µ??? ??e???
• ??t??a s?µµ??f?s? st? ?e?ape?a

S. Yanovski, J. Yanovski, N Engl J Med 2002, Vol
348, No 8 560-574
50
??????? ?????? XENDOS S?????S??S (4 ?????a,
3305 as?e?e??)
Orlistat 120 mg t.i.d lifestyle
Se s??d?asµ? µe a??a?? t??p?? ???? (?p??e?µ?d???
d?a?ta 800 Kcal/day ?a? µ?t??a ?s??s?)
Baselineexaminations
Screening
Placebo t.i.d lifestyle
Double-blind treatment
Day -21
Day -14
Day 1
Week 208
Torgerson SJ et al. Diabetes Care 2004, Vol
27(1) 155-161
51
XENDOS ??O???? ?????S
Change in weight (kg)
Placebo lifestyle
Xenical lifestyle
0
-3
-4.1 kg
-6
-6.9 kg
-9
plt0.001 vs placebo
-12
0
52
104
156
208
Week
Torgerson SJ et al. Diabetes Care 2004, Vol
27(1) 155-161
52
XENDOS ?????OS? S? ????? 2
Incidence of T2D ()
Placebo lifestyle
Xenical lifestyle
10
9.0
RR37
8
p0.0032
6.2
6
4
Hazard ratio reduction vs placebo plus lifestyle
2
0
0
26
52
78
104
130
156
182
208
Week
Torgerson SJ et al. Diabetes Care 2004, Vol
27(1) 155-161
53
Studies in the prevention of type 2 diabetes -
baseline patient characteristics

• OGTT ( pts)
• Age BMI IGT Normal
• DPS1 55 31 100 0
• DPP2 51 34 100 0
• STOP-NIDDM3 55 31 100 0
• XENDOS4 43 37 21 79

1. Tuomilehto J et al. N Engl J Med 2001 344
1343-50 2. DPP N Engl J Med. 2002 346
393-403 3. Chiasson J-L et al. Lancet 2002 359
2072-77 4. Torgerson SJ et al. Diabetes Care
2004, Vol 27(1) 155-161
54
S???????????? ??????S??S ???S?S

• ??ast???a? ?pa?ap??s?????
• Se??t?????? ?a? ???ad?e?a????? (SNRI)

?e? p???a?e? ape?e?????s? ?e???µetaß?ßast?? ?e?
??e? ep?d?as? st? ???
Yanovski and Yanovski. N Eng J Med. Feb
2002346591-602
55
?????????????S?
???-s??apt??? ???? ?e????a
S??apt??? ??sµa
?eta-s??apt??? ???? ?e????a
56
Releasing Agents
57
??ast??? epa?ap??s????? ( )
58
??????S??S ???S?S ???????OS ??O??O? F?????O? G??
????S?????
??????T??OS? ?????????????S?O?
???S?????S ????????S????S
???S???? ??S??
5-HT
NA
DA
5-HT
NA
DA
?????F???????
?
?
F??????????
?
?
F??F?????????
?
???F??F?????????
?
F??????????
?
S????????????
?
?
59
S???????????? (REDUCTIL)

• ?e? p???a?e? ape?e?????s? ?e???µetaß?ßast??
• ?e? ??e? d??s? st? ?t?paµ???
• ?e? e??a? a???e???????
• ?e? p???a?e? e???t?s?
• ?e? p???a?e? ßa?ß?d?p??e?e? ??te p?e?µ?????
  ?p??tas?
• ??t? ep?ßeßa???eta? se ???????? µe??te? (12.000
  as?e?e??) a??? ?a? ap? t?? µ???? t??a eµpe???a
  µet? t?? ?????f???a t?? p?????t??
• Cole et al, J Clin Phychopharmac 1998
• Schuh et al, Psychopharmac 2000

60
?? REDUCTIL EXEI ????? ???S?
??????? ??? ???????OS? ????G???S (100
?cal/µ??a)
??????? ?? ??ST??? ??? ????S???
???O??? ??? ???S???? ???F?S(-356 ?cal/µ??a)
S?G?????? ??? ??OS? ??? ??S???? ????????S???
61
??????S? ??? REDUCTIL S?? ???S???? ???F?S µet?
ap? 14 ?µ??e? ??????s??
Placebo
2000
1500
????G????? ???S???? (kcal)
1000
500
0
??S????????
??O???
??????
S?????
plt0.05
Rolls BJ, Obes Res 198861-11
62
??????S? ??S S????????????S S?? ??ST??? ???
????S???
????OS ???????S
10
8
6
Visual analogue scale (cm)
4
2
O??S (hrs)
0
8
10
12
14
16
18
24
22
20
??T???? ???????S
Adapted from Hansen DL, Int J Obes Relat Metab
Disord 1999231016-24
63
??OS? ??? ??S???? ????????S??? ???? ??? ??O????
?????S (28 studies)
0
-10
???????? BMR ()
-20
-30
-40
??O???? ?????S ()
Prentice et al, 1991
64
Sibutramine ep?d?as? st? ?e?µ?????es?5,5h µet?
t? ??????s? ,?p?????sµ?? µe ?µµes? ?e?µ?d?µet??a
Hansen et al. Am J Clin Nutr, 1998 68
1180-1186 Randomized,double blind placebo study
in 11 healthy vol..
65
S???????????????????S??????????

• ?p?d?as? t?? S?µp??t?aµ???? st? e?e??e?a??
  ?s??????
• ???s? st??? ?e???µetaß?ßast??
• ?p?te?esµat???t?ta st?? ap??e?a ß?????
• ???a??? p??ß?e?? t?? a?tap????s?? st? ?e?ape?a

66
STORM STUDY 8 ?????? S??? ???O??Sibutramine
Trial in Obesity Reduction and Maintenance
Arne Astrup (Copenhagen) Jannik Hilsted (Hvidœvre)
Philip James (Principal Investigator) (Aberdeen)
Nick Finer (Luton)
Stephan Rössner (Stockholm)
Peter Kopelman(London)
Wim Saris (Maastricht)
Luc Van Gaal (Antwerp)
67
STORM STUDY, Lancet 2000
605 as?e?e??sibutramine 10 mg
352 as?e?e?? sibutramine
SV
BL
1
2
3
4
5
6
????S
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
????S
Follow-
115 as?e?e?? placebo
Up
??????????S? ??? ?????G????? gt5 ??O???? ?????S
S??? ?????? F?S?
???? ?? ?ST????S ????? ??S ????S ??????????S
???G??S
James et al, Lancet 2000
68
??????????? ???????S? ??S ??O????S ?????S 54
?O? ?ST??O? ???S? gt10 ??? ??????? SO?. ?????S
94 ?O? ?ST??O? ???S? gt 5 ??? ??????? SO?.
?????S
Placebod?a?ta?s??s?
Sibutramine d?a?ta?s??s?
104
43 t?? as?e??? µe S?µp??t?aµ??? d?at???sa? t??
a????? ap??e?a ß????? st? d??st?µa t?? 18 µ????
n605
102
100
98
S?µat??? ß???? (Kg)
96
94
92
90
-12????
M??e?
88
0
2
4
6
8
10
12
14
16
18
20
22
24
James WPT et al, Lancet 20003562119-25
69
? T??????? ?? S???????????? ???O??? ??? ????????
????S?????
STORM ???????? S??? ????????? ??S?S S??
???????? ?O? 24 ???O? mean (/- se)
109
Adapted from James et al, Lancet 2000
107
105
?????????S ??S?S (cm)
103
101
????S
70
???????S ??????S ?? SIBUTRAMINE
?????? 1 Se ep?ped? p??t?ß??µ?a? pe???a????
?????? 2???es? d?s?????a?
?????? 3 ?et? ap? d?a?ta p??? ?aµ???? ?e?µ?d??
71
?????? 1?p??e?a ß????? se ep?ped? p??t?ß??µ?a?
pe???a????
Sibutramine 10 mg(n 154)
Placebo(n 157)
Sibutramine 15 mg (n 153)
0
-2
-4

??s? ap??e?a ßa????
-6

-8
???e? ?e?ape?a?
-10
0
2
4
6
8
10
12
??a?t?t???? ?d???e? µ?s? f???ad???
p lt 0.001 vs placebo
Smith IG, J Fam Pract 200150505-12
72
EOS 5 F???S ????SS?????? ?ST????S ?????G??????
S???????? ??O???? ?????S ?? ?O REDUCTIL S?
S?G???S? ?? ?? PLACEBO

gt5 ap??e?a
gt10 ap??e?a



15 mg
10 mg
PLACEBO
PLACEBO
10 mg
15 mg
p lt 0.001 compared to placebo p lt 0.01
compared to placebo Smith IG, Goulder M J Fam
Pract. 2001 Jun50(6)505-12
73
?????? 2 ???es? d?s???????? s??µat??
Placebo (n84)
Sibutramine 10mg
Sibutramine
0
1 mg od (n92)
-5
5 mg od (n103)

-10
Mean Weight Change (lb)
10 mg od (n95)

-15
15 mg od (n94)

20 mg od (n89)

30 mg od (n96)

-20
?d?µ?de? ?e?ape?a?
plt0.05
Bray GA, Obes Res 19997189-98
74
?????? 3 ?et? ap? V.L.C.D.
Placebo (n78)
Sibutramine (n81)
VLCD
0
1
2
3
4
5
6
7
8
9
10
11
12
0
???a? ?e?ape?a?
-4
(-6.9)
?p??e?a ß????? (kg)
-8
-12

(-12.9)








-16

p lt 0.001, comparison vs placeboMean SEM
Apfelbaum M, Am J Med 1999106179-84
75
STORM µetaß??? st??? µetaß??????? pa?????te?
???d???? st??? 24 µ??e?
Placebo(n103)
???? ?? as?e?e?? Sibutramine (n323)
gt5 ap??e?a (n235)
gt10 ap??e?a (n131)
25
15
5
?etaß???
T??????e??d?a
VLDL
HDL
-5
-15
-25
Abbott Laboratories data on file unpublished from
STORM study
76
21 ????S? HDL 2-3 F???S ??G??????? ????S? ???
??? ?????????? MOMO ??? ??? ??O???? ?????S
STORM ??S? ???????? T?S HDL S???S 24 M???S
James et al, Lancet 2000
77
(No Transcript)
78
G???????? ?????? ?????????T?S (n6360)

• ?????S 1623 (25)
• G??????S 4619 (75)
• ?????? 46.9 11.9
• BMI 34.7 5.4
• Waist (cm) 108.3 17.7

• 59 ?st????? µ???? 5 ap?t???µ??e? p??sp??e?e?
  ap??e?a? ß?????
• ??????S? 2067 (33)
• se ?e?ape?a 1676 (81)
• ??S?????????? 1394 (22)
• ???????S 725 (11)
• se ?e?ape?a 424 (58)

J. Scholze, Berlin Medical University Polyclinic,
Dtsch. Med. Wochenschr. 2002
79
J. Scholze, Berlin Medical University Polyclinic,
Dtsch. Med. Wochenschr. 2002
80
G???????? ?????? ?????????T?S ?etaß???? S?? ?a?
??? se s??s? µe t?? a?????? t?µ?? se as?e?e??
?p? a???? µe S?µp??t?aµ???
S?st????? (mmHg)
??ast????? (mmHg)
AV
AV
?ßd?µ?de?
?ßd?µ?de?
AV Admission Visit
WHO/ISH ?at?ta?? µe ß?s? t?? a?????? ??µ?? ?.?.
?pe?tas? Stad??? 2 (n378) 160-179/100-109mmHg
?p??tas? Stad??? 1 (n1237) 140-159/90-99mmHg
???µ?tas???? (n1644) lt140/90mmHg
Scholze J, DMW 2002 127 605-610
81
G???????? ?????? ?????????T?S (n6360)???S??
?????

• 10 t?? as?e??? d?a??p? ???? ??st??? ?a?
  a?ap?te?esµat???t?ta?
• ???? 1.8 t?? as?e??? a?af??? ?.?.
• ????st?µ?a (n23)
• ??s??????t?ta (n22)
• ??p??a (n17)
• ?a???a?d?a (n20)

J. Scholze, Berlin Medical University Polyclinic,
Dtsch. Med. Wochenschr. 2002
82
? ?????? ??O???? ?????S ?????????? ?? ???????????
?????????S? S?? T???????
1
6
9
12
3
0
-6
5-10 ?????????S?
-12
??O???? ?????S(kg)
10-15
-18
15-20
-24
gt20
-30
Finer N, Int J Obes Relat Metab Disord 200125
(Suppl 4)S12-S15
83
? ap??e?a ß????? se ?p??ßa???? d?aß?t?????
as?e?e?? t?p?? 2 e??a? p?? d?s????
?? d?aß?t???? as?e?e??
??aß?t???? as?e?e??
0
plt0.02
-4
plt0.02
plt0.01
plt0.02
-8
-12
?etaß??? ß?????
-16
-20
eßd?µ?de?
5
10
15
20
Adapted from Wing RR, Diabetes Care 198710563-6
84
G???? S???S ??????????S ?ST????S ???????????? ???
??S???? ??O???? ?????S ?

• ?e?a??te?? ?????a
• S???p?????se? pa??se?? (p.?. ?at??????)
• ????fa?µa??a
• ???????µe?e? p??sp??e?e? ap??e?a? ß?????
• S???f????????e? ?a? ??s?????? p??????? t?? a???s?
  ß?????

85
? ???OS? 1 ??S HbA1c ???G?? S?
???OS? ??? S??????? ???????? ????

• 21 RR ???? t?? d?aß?t???? ep?p?????
• 25 RR ???t?t?ta? s?et???µe?? µe t?? d?aß?t?
• 17 RR ???s?µ?t?ta? ap? ??e? t?? a?t?e?
  
• 18 RR ??a ??? ?µf?a?µa µ???a?d???
• 35 RR ??a µ????a??e??p??e?a

Based on UKPDS data RRS??????S ???????S
86
???????S ??????S ?? S???????????? S? ?ST????S ??
S.?. ????? 2
Control
Sibutramine 15 mg
0
(n122)

• ?p? d?a?ta
• (Rissanen et al, 12 µ??e?)

plt0.001
(n114)
-8
0
(n65)
?p??e?a ß????? ()
?p? s???f????????a (Serrano-Rios et al, 6
µ??e?)
(n60)
plt0.001
-8
0
(n68)
?p? µetf??µ??? McNulty et al Diabetes Care 2003,
12 µ??e?
(n62)
plt0.001
-8
12
8
0
4
M??e?
2
6
10
87
? S???????????? ???O??? S???????? ?? HBA1C ???
?????O??? ?? G????????? ???G?? ?s?e?e?? ?p?
a???? µe s???f????????a (n134)
placebo
????
10
?p??e?a ß?????
0.0
-0.5
?etaß??? t?? HbA1c ()
-1.0
-1.5
p lt0.01

-2.0
Serrano Rios et al Role of Sib in the treatment
of obese type 2 diabetic patients receiving
sulphonylurea therapy Diabetes Medicine
2002,19,119-124,
88
? S???????????? ???O??? S???????? ?? HBA1C ???
?????O??? ?? G????????? ???G?? ?s?e?e?? ?p?
a???? µe µetf??µ??? (n195)
placebo
????
10
?p??e?a ß?????
0.0
-0.5
?etaß??? t?? HbA1c ()
-1.0

-1.5
p lt0.01
-2.0
MC NULTY JS, et al, Sibutramine with
metformin in type 2 diabetes, Diabetes Care, Vol
26 (1), Jan 2003
89
??????S? S????????????S S??? ????S??????
????F?G?? (Binge Eating Disorder)(Randomized,
double-blind, placebo-controlled study, n 60)

• ?e??s? s?µat???? ß?????
• (Sibutramine 15mg vs Placebo 7.4 Kg vs 1.4
  Kg)
• S?µa?t??? µe??s? t?? ?µe??? µe epe?s?d?a
  ?pe?fa??a? ß?se? e??t?µat??????? (Binge Eating
  Scale- BES) ?a? ße?t??s? t?? s?µpt?µ?t?? p??
  s?et????ta? µe ?at?????? ß?se? e??t?µat???????
  (Beck Depression Inventory- BDI)

J.C. Appolinario et al. Arch Gen Psychiatry 2003
60 1109-1116
90
S?G??????? ?????? F???????????S T???????S S??
????S?????(Sibutramine vs Orlistat vs
Combination)

• 89 pa??sa??e? ???a??e? (?.?.S. gt30) µe µ?t??a
  s?µat??? ?s??s? (????a??)
• ??????s? ?p?a? ?p??e?µ?d???? d?a?ta? (NHBI)
• ???a??p???s? se 3 ?µ?de?, µet? t? 1? µ??a
• ?µ?da 1 ????st?t? ??a?ta
• ?µ?da 2 S?µp??t?aµ??? ??a?ta
• ?µ?da 3 S??d?asµ?? ??a?ta
• ?a?a???????s? ??a 6µ??e?

R Sari et al. Endocr. Res. 2004 May 30 (2)
159-67
91
???????S???? S?G???????S ??????S ??s?st? as?e???
µe s?µa?t??? ap??e?a ß?????
R Sari et al. Endocr. Res. 2004 May 30 (2)
159-67
92
S???????????? ??? ??????S? S?? ??????GG?????

• Ep?d?as? st?? a?t???a?? p?es? ?a? st?? ?a?d?a??
  s????t?ta
• ?s?e?e?? ????? ?p??tas?
• ?pe?tas????
• ??ep???µ?te? e????e?e? ?a? asf??e?a
• ??????? eµpe???a

93
??S??????O???? ??????S? S??? ????????? ???S?
(S.?.?.)
20 mg n1126
30 mg n128
15 mg n1924
10 mg n1318
Placebo n1944
10
Sibutramine
8
6
3.8
?etaß??? st? S.?.?. (mmHg)
4
2.6
1.0
2
-0.1
-0.1
0
-1
Adapted from Sharma AM, Int J Obes Relat Metab
Disord 200124 (Suppl 4) S20-S23
plt0.05 compared to placebo
94
???????? S??? ?.?. S? ????S?????S ?ST????S ?O??S
??????S? (n1102)
Placebo(n201)
??a?e??µ??? ??????s? Sibutramine(n 395)
S??e??? ??????s? Sibutramine (n 405)
S?st????? ?.?.
150
130
110
eßd?µ?de?
??ast????? ?.?.
90
70
0
4
8
12
16
20
24
28
32
36
40
44
48
Wirth A, JAMA 2001 2861331-9
95
???????? ??S S.?.?. S? ?ST????S ?? ???G??????
??????S? (12 eßd?µ?de?, n127)
Sibutramine 10mg
Placebo
6
-2.3
-4.7
4
?p??e?a ß?????
2
mmHg
0
-2
-4
NS
-6
Hazenberg Cardiology 2000 94 152-158
96
?p?s??s? as?e??? ???? a.e. st?? e?e???µe?e?
µe??te? µe????? d????e?a? µe S?µp??t?aµ???
COSTART
?e??te? µe????? d????e?a?
Placebo(n770)
Sibutramine (n1741)
plt
??????S?
0.6
1.1
0.21
??ST??? ????O?
0.0
0.2
0.22
T?????????
0.0
0.6
0.048
?GG??????S????
0.0
0.1
0.48
S???????
8.7
9.0
Adapted from Sharma AM, Int J Obes Relat Metab
Disord 200125 (Suppl 4)S20-S23 Narkiewicz K,
Int J Obes Relat Metab Disord 200226 (Suppl
4)S38-S41.

97
????????S S??? S.?.?. ?????G? ?? ??? ??O????
?????S Placebo vs S?µp??t?aµ??? (1-30mg)
Sibutramine (n4,636)
Placebo (n2,255)
lt5 ap??e?a ? ????s? ß?????
4
2
gt5ap??e?a ß?????
gt10ap??e?a ß?????
0
?etaß??? st?? S.?.?.(mmHg)
-2
-4
-6
Sharma AM, Int J Obes Relat Metab Disord 200125
(Suppl 4)S20-S23
98
S??????S????

• ? S?µp??t?aµ??? p???a?e? s?µa?t??? ap??e?a ß?????
  se as?e?e?? µe s???p?????se? pa??se??
• ? ap??e?a ß????? µe S?µp??t?aµ??? ?d??e? se
  s?µa?t??? ße?t??s? t?? µetaß?????? pa?a???t??
  ???d???? t?? ?etaß?????? S??d??µ??
• ? Sp?a?????? ??p???
• ? T??????e??d?a
• ? HDL ????ste????
• ? HbA1c
• ? ?????? ???

99
? S???????????? ????? ?SF???S

• ?e??ss?te??? ap? 14 e?at?µ???a ???ste?
• gt 12000 as?e?e?? se ???????? µe??te?
• G??st? p??f?? a?ep???µ?t?? e?e??e??? (????st?µ?a,
  d?s??????t?ta, a?p??a)
• ?a?? a????
• ?? p?s?st? t?? as?e??? st?? ???????? µe??te? p??
  d?a??pte? t? ?e?ape?a ???? a.e e??a? pa??µ??? µe
  a?t? t?? placebo

100
??S???G??? S????

• 1 ??????a t?? 10 mg ,µ?a f??? t?? ?µ??a (s??????
  p???,???????? µe ??a p?t??? ?e??)
• Se as?e?e?? µe µ? ??a??p???t??? a?tap????s? (d??
  lt2 kg se 4 eßd?µ?de?) ? d?s? µp??e? ?a a????e? se
  1 ?a????? 15mg,?p? t?? p??p??es? ?t? t? Reductil
  10mg ?p???e ?a?? a?e?t?
• ?p?s?? µp??e? ? d?s? ?a a????e? se15mg ?a? se
  as?e?e?? µe ?a?? a?tap????s? ?p? t?? p??p??es?
  ?t? t? Reductil 10mg ?p???e ?a?? a?e?t?

Sibutramine Summary of Product Characteristics
(SmPC)
101
??? ??????????? ? ????G?S? S? ?ST????S

• ????at???? ??s?? / ta?t?????? ???s? ? ???s? t??
  te?e?ta?e? 2 ßd?µ?de? a?ast????? ??? ? ?????
  ?e?t????? d???t?? fa?µ???? ??a t?? a?t?µet?p?s?
  ??????? d?ata?a??? (a?t??ata???pt????,
  a?t?????s????) ? t??pt?f????(??a d?ata?a???
  ?p???)
• ?st????? Stefa????a? ??s??,s?µf???t???? ?a?d?a???
  a?ep???e?a?,ta???a?d?a?, pe??fe?????
  a?t???a???? ap?f?a?t???? ??s??,app??µ?a? ?
  e??efa??a??e?a??? ??s??

• ??epa???? e?e???µe?? ?p??tas?(gt145/90mmHg)
• ?pe????e?e?d?sµ??/ Fa?????µ???tt?µa
• ???s?,?a?????a ??p

Sibutramine Summary of Product Characteristics
(SmPC)
102
???????? T???????S

• 1 ?????? µe ß?s? t?? pa???sa ?????s? (FDA 2
  ?????a)
• ? ?e?ape?a ?a d?a??pteta? se
• ap??e?a lt5 t?? a?????? ß????? st? t??µ???
• Se as?e?e?? p?? ?a?apa?????? gt3 kg µet? t??
  a????? ap??e?a

Sibutramine Summary of Product Characteristics
(SmPC)
103
??????? ???S?????? (?e????????? a?t?µet?p?s?)
104
??????? ???????G???S ???????O??S?S ??S gt40 ?
??S gt35 µe ep?p?????

105
?e??t? SOS Swedish Obese Subjects ??O???? ?????S

Agren G, et al., IJO (2002) 26184-192.
106
S??????S????
107
?? f??t?? e??? pa??sa????

• ??????? ???????
• ???
• ?p???a ?p???
• ??s?fa??t?da
• Stefa??a?a ??s??
• ?p??tas?
• S? t?p?? 2
• ?ste?a????t?da
• ?????? a????t?da

• ???SO???? ???????
• ????????? ap?µ???s?
• ?e??s? epa??e?µat???? p??sd?????
• ???e??? a?t?e?t?µ?s??
• ?f?d??se??
• ??sp???a
• ???a??t?
• ?a?? p???t?ta ????

108
S??????S????

• ? pa??sa???a ??e???eta? µa????????a ?e?ape?a ?a?
  a?t?µet?p?s?, ?p?? ? S.?. t?p?? 2 ?a? ? ?p??tas?1
• ??t??a ap??e?a ß????? (5 µe 10) p??sf??e?
  s?µa?t??? ??????? ?f???
• ??e???eta? µ?a pe??a???µ??? ?e?ape?a ?ata t?
  d????e?a ???? t?? ????
• ?????????S? S??????F???S /????G? ?????? ?O?S
• 1. Atkinson. Ann Intern Med. 1993119(7 pt
  2)677-680. 2. Bray. Ann Intern Med. 1993119(7
  pt 2)707-713.

109
S??????S????

• ?.?.?. a?t?µet?p?s? µe s??d?asµ? ?at???????
  d?a?t???????, ?s??s?? ?a? fa?µa?e?t???? ?e?ape?a?
  ?ta? ????eta? apa?a?t?t?

110
? ????S????? ?????? ?? ????? ? T??????????S
S????S ??? ??????????? S????????
Després JP et al. BMJ 2001322716
111
?? ????T???S ???S?????S ?ST??O? ??? ????O?
Reference Ziegler O, Meyer L, Guerci B et al.
112
?? ?F????? S????? ??S?S ???S FASHION MODEL vs
??S?S ???S G?????O?
AverageFashion Model
AverageWoman
???S ????S BMI
5' 4" 142 lb 24.3
5' 9" 110 lb 16.3
BMI body mass index - ?e??t?? ???a? S?µat??.
113
SOS?? ???????O??S? (Mechanism)
Medicalise the problem
Motivate
Establish individual responsibility
Focus
Set individual long-term targets
Reinforce
Provide means
Measure
Use individualised objective measures
114
(No Transcript)
115
??OG??? G??
?? ??S????