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from Debate to Confidence - Rosiglitazone stories 2008. 5. 9. KDA Satellite Symposium Kim, Sungrae MD,PhD The Catholic university of Korea

from Debate to Confidence - Diabetes · 2014-06-27 · Larochellière MD, Cezar S. Staniloae MD, Kreton Mavromatis MD, Jacqueline Saw MD, Bo Hu PhD, A. Michael Lincoff MD, and E

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Page 1: from Debate to Confidence - Diabetes · 2014-06-27 · Larochellière MD, Cezar S. Staniloae MD, Kreton Mavromatis MD, Jacqueline Saw MD, Bo Hu PhD, A. Michael Lincoff MD, and E

from Debate to Confidence- Rosiglitazone stories

2008. 5. 9.KDA Satellite Symposium

Kim, Sungrae MD,PhDThe Catholic university of Korea

Page 2: from Debate to Confidence - Diabetes · 2014-06-27 · Larochellière MD, Cezar S. Staniloae MD, Kreton Mavromatis MD, Jacqueline Saw MD, Bo Hu PhD, A. Michael Lincoff MD, and E

Rosiglitazone

최근 주요 임상 연구

• Diabetes Prevention -

• Delay Progression

-

Page 3: from Debate to Confidence - Diabetes · 2014-06-27 · Larochellière MD, Cezar S. Staniloae MD, Kreton Mavromatis MD, Jacqueline Saw MD, Bo Hu PhD, A. Michael Lincoff MD, and E

Placebo Metformin Troglitazone Lifestyle intervention

0

4

8

12

16

Inci

denc

e (c

ases

/100

per

s-yr

)Diabetes Prevention Program (DPP)

Overall p<0.001

TROG v. PLAC

P<0.001

TROG v. MET

P=0.02

TROG v. LSI

P=0.18

Diabetes 54:1150-1156, 2005

6.7

12.0

3.0

5.1

Page 4: from Debate to Confidence - Diabetes · 2014-06-27 · Larochellière MD, Cezar S. Staniloae MD, Kreton Mavromatis MD, Jacqueline Saw MD, Bo Hu PhD, A. Michael Lincoff MD, and E

Diabetes REduction Assessment with ramipril and rosiglitazone Medication

Page 5: from Debate to Confidence - Diabetes · 2014-06-27 · Larochellière MD, Cezar S. Staniloae MD, Kreton Mavromatis MD, Jacqueline Saw MD, Bo Hu PhD, A. Michael Lincoff MD, and E

Glucose or Primary Outcome Status in 94% at study end Vital Status in 98%

Screening & Randomization

Aims: Does ramipril 15 mg/d prevent diabetes?Does rosiglitazone 8 mg/d prevent diabetes?

Design: 2 X 2 factorial, double-blind RCTSample: Age 30+; IGT (FPG < 126 & 2 hr 140-199) &/or IFG (FPG 110-125)

Pts: 5269 in 191 sites, 21 countries, & F/U 3 yrs Outcome: Incident DM (confirmed FPG > 7 or

2 hr > 11.1; or MD diagnosis) or death*

Screened24592

Screened24592

Randomized5269

Randomized5269

Run-in5808

Run-in5808

Excluded: 539Excluded: 539

Excluded: 18784Excluded: 18784

Page 6: from Debate to Confidence - Diabetes · 2014-06-27 · Larochellière MD, Cezar S. Staniloae MD, Kreton Mavromatis MD, Jacqueline Saw MD, Bo Hu PhD, A. Michael Lincoff MD, and E

Primary Outcome: Rosiglitazone

HR = 0.40 (0.35-0.46); P<0.0001

Rosiglitazone

Placebo

0 Year

Cum

ulat

ive

Haz

ard

0.0

0.1

0.2

0.3

0.4

0.5

0.6

1 2 3 4

2634 2470 2150 1148 1772635 2538 2414 1310 217

Placebo Rosiglitazone

60%

Page 7: from Debate to Confidence - Diabetes · 2014-06-27 · Larochellière MD, Cezar S. Staniloae MD, Kreton Mavromatis MD, Jacqueline Saw MD, Bo Hu PhD, A. Michael Lincoff MD, and E

Summary & Conclusions: Rosiglitazone

• IGT 또는 IFG 대상으로 8 mg/day의 rosiglitazone을 투여 시

새로운 당뇨병 발생을 60% 이상 예방

• 공복 혈당과 식후 2시간 혈당은 70% 이상에서 정상화

• 전세계 모든 지역에서 같은 현상

• 3% 까지 체중증가는 있으나, waist/hip ratio에는 악영향 없음.

• ALT 수치의 감소

Page 8: from Debate to Confidence - Diabetes · 2014-06-27 · Larochellière MD, Cezar S. Staniloae MD, Kreton Mavromatis MD, Jacqueline Saw MD, Bo Hu PhD, A. Michael Lincoff MD, and E

Rosiglitazone is effective in improvingtraditional CVD risk factors

RSG

Fat Fat redifferentiationredifferentiation

   ↓ BPBP

   ↓ Microalbuminuriaicroalbuminuria

↑ HDL and ↓ small dense LDL

↓ Insulin Insulin resistanceresistance

   ↓ Atherosclerosis therosclerosis ↓ CVDCVD

   ↓ HyperglycemiaHyperglycemia

Festa A et al. Circulation 2000; 102: 42–7; Reaven GM. Annu Rev Med 1993; 44: 121–31.

Page 9: from Debate to Confidence - Diabetes · 2014-06-27 · Larochellière MD, Cezar S. Staniloae MD, Kreton Mavromatis MD, Jacqueline Saw MD, Bo Hu PhD, A. Michael Lincoff MD, and E

A Diabetes Outcome Progression Trial

Page 10: from Debate to Confidence - Diabetes · 2014-06-27 · Larochellière MD, Cezar S. Staniloae MD, Kreton Mavromatis MD, Jacqueline Saw MD, Bo Hu PhD, A. Michael Lincoff MD, and E

ADOPT Objective

Compare the durability of glycaemic control using rosiglitazone versus metformin or glyburide as initial monotherapy in patients with recently diagnosed type 2 diabetes mellitus

Page 11: from Debate to Confidence - Diabetes · 2014-06-27 · Larochellière MD, Cezar S. Staniloae MD, Kreton Mavromatis MD, Jacqueline Saw MD, Bo Hu PhD, A. Michael Lincoff MD, and E

ADOPT Design

Diet/exercisereinforcement

Run-In4 weeks

Randomisation Study end

Treatment Period4 to 6 years

Metformin (N = 1454)

Glyburide (N = 1441)

Rosiglitazone (N =1456)

Clinic visits every 2 months for 1 yr,then every 3 months

• Type 2 diabetes mellitus ≤3 years• Drug naïve• Male and female• Aged 30−75 yr inclusive• Fasting plasma glucose

126−180 mg/dl (7−10 mmol/l) after 4-week run-in and prior to randomisation

Page 12: from Debate to Confidence - Diabetes · 2014-06-27 · Larochellière MD, Cezar S. Staniloae MD, Kreton Mavromatis MD, Jacqueline Saw MD, Bo Hu PhD, A. Michael Lincoff MD, and E

Cumulative Incidence of Monotherapy Failure (FPG >180 mg/dl)

10781076958

120712051114

139313971337

957950781

844818617

324311218

Patients at RiskRosiglitazone

MetforminGlyburide

Time (years)0 1 2 3 4 5

Perc

ent

0

10

20

30

40

Glyburide

Metformin

Rosiglitazone

Rosiglitazone vs Metformin32% risk reduction, P<0.001

Rosiglitazone vs Glyburide63% risk reduction, P<0.001

63%

32%

Page 13: from Debate to Confidence - Diabetes · 2014-06-27 · Larochellière MD, Cezar S. Staniloae MD, Kreton Mavromatis MD, Jacqueline Saw MD, Bo Hu PhD, A. Michael Lincoff MD, and E

Fasting Plasma Glucose Over Time

Rosiglitazone vs Metformin−9.8 (−12.7 to −7.0), P<0.001Rosiglitazone vs Glyburide−17.4 (−20.4 to −14.5), P<0.001

mg/

dl

0

120

160

140

130

150Glyburide

Metformin

Rosiglitazone

0 1 2 3 4 5

Time (years)

Page 14: from Debate to Confidence - Diabetes · 2014-06-27 · Larochellière MD, Cezar S. Staniloae MD, Kreton Mavromatis MD, Jacqueline Saw MD, Bo Hu PhD, A. Michael Lincoff MD, and E

HbA1C Over Time

0 1 2 3 4 5

Time (years)

%

0

6.0

8.0

7.0

6.5

7.5

Rosiglitazone

Glyburide

Metformin

Rosiglitazone vs Metformin−0.13 (−0.22 to −0.05), P=0.002Rosiglitazone vs Glyburide−0.42 (−0.50 to −0.33), P<0.001

Page 15: from Debate to Confidence - Diabetes · 2014-06-27 · Larochellière MD, Cezar S. Staniloae MD, Kreton Mavromatis MD, Jacqueline Saw MD, Bo Hu PhD, A. Michael Lincoff MD, and E

단독 요법으로 혈당 조절이 유지되는 기간Time to Mean HbA1C >7%

Rosiglitazone

0 20 40 60

Metformin

Glyburide

Months

57 mo

33 mo

45 mo

Page 16: from Debate to Confidence - Diabetes · 2014-06-27 · Larochellière MD, Cezar S. Staniloae MD, Kreton Mavromatis MD, Jacqueline Saw MD, Bo Hu PhD, A. Michael Lincoff MD, and E

Clinical Implications

• 제2형 당뇨병에서 고혈당의 진행을 늦출 수 있음.

• Rosiglitazone 이 insulin sensitivity and beta-cell function에 대한 긍정적인 효과로 인해 가장 효과적이었다.

• 제2형 당뇨병의 초기에 Rosiglitazone을 사용하는 것이

SU제제인 glyburide 나 metformin을 사용하는 것보다

바람직하다.

Page 17: from Debate to Confidence - Diabetes · 2014-06-27 · Larochellière MD, Cezar S. Staniloae MD, Kreton Mavromatis MD, Jacqueline Saw MD, Bo Hu PhD, A. Michael Lincoff MD, and E

Adverse Events, Hospitalizations and Deaths

Hospitalizationfrom any cause

Patients, n (%)Events, n

Death from any cause, n (%)

Rosiglitazone(N = 1456)

1338 (92%)

Metformin(N = 1454)

1341 (92%)

Glyburide(N = 1441)

1321 (92%)

169 (12%)251

172 (12%)267

150 (10%)203

Patients with event(s), n (%)

34 (2.3%) 31 (2.1%) 31 (2.2%)

Page 18: from Debate to Confidence - Diabetes · 2014-06-27 · Larochellière MD, Cezar S. Staniloae MD, Kreton Mavromatis MD, Jacqueline Saw MD, Bo Hu PhD, A. Michael Lincoff MD, and E
Page 19: from Debate to Confidence - Diabetes · 2014-06-27 · Larochellière MD, Cezar S. Staniloae MD, Kreton Mavromatis MD, Jacqueline Saw MD, Bo Hu PhD, A. Michael Lincoff MD, and E
Page 20: from Debate to Confidence - Diabetes · 2014-06-27 · Larochellière MD, Cezar S. Staniloae MD, Kreton Mavromatis MD, Jacqueline Saw MD, Bo Hu PhD, A. Michael Lincoff MD, and E

*연구 방법 ; meta-analysis*연구 대상 ; 발표된 논문, FDA web site, GSK의 clinical registry*포함 data ; 116 연구 중 포함 기준에 적합한 42 연구*결과; OR for MI, 1.43 (95% CI 1.03-1.98; p=0.03), OR for death from CV causes, 1.64 (95% CI 0.98-2.74; p=0.06)

Page 21: from Debate to Confidence - Diabetes · 2014-06-27 · Larochellière MD, Cezar S. Staniloae MD, Kreton Mavromatis MD, Jacqueline Saw MD, Bo Hu PhD, A. Michael Lincoff MD, and E

* 환자를 대상으로 한 것이 아니고 발표된 data를 대상으로 한 연구였다.* 각 논문마다 MI의 기준이 통일되어 있지 않고, 여기서 보고된 작은 수의events를 가지고 위험율을 산정하는 것은 정확하지 않을 수 있다.

* 인용된 연구들은 모두 심혈관 결과를 보기 위한 것을 목적으로 한연구가 아니었다.

* 각 연구 마다 Protocol이 다르다. * 연구들은 대부분 규모가 작고 단기간의 관찰이다.

* 투약 기간과 MI, 심혈관 원인에 의한 사망 사이의 기간이 매우다양하고, 발표된 연구의 events summary만을 보고 분석하였으므로투약과 events 사이의 분석이 취약하다.

연구의 대상;

연구 대상이 된 논문의 내용;

연구 대상이 된 논문의 분석;

Page 22: from Debate to Confidence - Diabetes · 2014-06-27 · Larochellière MD, Cezar S. Staniloae MD, Kreton Mavromatis MD, Jacqueline Saw MD, Bo Hu PhD, A. Michael Lincoff MD, and E

통계 방법의 선택?Rosiglitazone arm (n) Comparator arm (n)

15,560 12,283

GSK Data on fileEradburn MJ, et al. Stat Med 2007;26:53

Page 23: from Debate to Confidence - Diabetes · 2014-06-27 · Larochellière MD, Cezar S. Staniloae MD, Kreton Mavromatis MD, Jacqueline Saw MD, Bo Hu PhD, A. Michael Lincoff MD, and E

Selection bias?

Event 가 없었던 연구를 포함하여 분석한 경우MI 1.43 1.26 (0.93 - 1.72)

Death 1.64 1.14 (0.74 - 1.74)

N Engl J Med 2007;357:937

Page 24: from Debate to Confidence - Diabetes · 2014-06-27 · Larochellière MD, Cezar S. Staniloae MD, Kreton Mavromatis MD, Jacqueline Saw MD, Bo Hu PhD, A. Michael Lincoff MD, and E

Differences Between Rosiglitazone and Pioglitazone Clinical Trials Pools: Implications

for Overall Risk Estimates

RSG:• Appr 85% pbo-

controlled (where higher risk difference seen)

• Appr 15% head-to-head against SU (where less risk seen)

PIO:• Appr 20% pbo-

controlled

• Appr 62% head-to-head against SU

Page 25: from Debate to Confidence - Diabetes · 2014-06-27 · Larochellière MD, Cezar S. Staniloae MD, Kreton Mavromatis MD, Jacqueline Saw MD, Bo Hu PhD, A. Michael Lincoff MD, and E

Risk of Cardiovascular Events in ADOPT

Endpoint Treatment # of patientswith event

Event rate per 100 PY

Hazard ratio (95% CI)

AVANDIA, n = 1456 35 0.71

MET, n = 1454 36 0.73 1.00 (0.63–1.59)MACE – adjudicated†

SU, n = 1441 28 0.66 1.11 (0.67–1.82)AVANDIA 6 0.12

MET 8 0.16 0.79 (0.27–2.27)All CV death –adjudicated†

SU 12 0.28 0.46 (0.17–1.23)

†Post-study ad-hoc analysis.Data on file, GlaxoSmithKline.

AVANDIA 106 2.14

MET 111 2.26 0.99 (0.76–1.30)

Myocardial Ischemia AEs – Non-adjudicated

SU 82 1.93 1.18 (0.88–1.57)AVANDIA 20 0.4

MET 17 0.35 1.21 (0.64, 2.32)Myocardial Infarction-adjudicated†

SU 15 0.35 1.2 (0.62, 2.35)AVANDIA 13 0.26

MET 17 0.35 0.77 (0.38–1.59)Stroke – Non-adjudicated†

SU 12 0.28 0.94 (0.43–2.07)

Page 26: from Debate to Confidence - Diabetes · 2014-06-27 · Larochellière MD, Cezar S. Staniloae MD, Kreton Mavromatis MD, Jacqueline Saw MD, Bo Hu PhD, A. Michael Lincoff MD, and E

RECORD (Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of glycaemia in Diabetes)

Europe, New Zealand, Australia의 300개 centers

4,447 명

평균 추적기간: 3.75년

2000년에 시작, 2008년 후반기에 종료될 예정, 결과는 2009년 5월에 발표될 예정.

Page 27: from Debate to Confidence - Diabetes · 2014-06-27 · Larochellière MD, Cezar S. Staniloae MD, Kreton Mavromatis MD, Jacqueline Saw MD, Bo Hu PhD, A. Michael Lincoff MD, and E

RECORD study design

Run-in phase

Metformin

Previoustherapy

Screening

Sulfonylurea

† ≥ 8.5% on two consecutive tests > 1 month apart* ± metformin or sulfonylurea according to local clinical practice

Insulin therapy

If HbA1c remains≥ 8.5 %†

Insulin*

Insulin*

Triple therapyor insulin

+Sulfonylurea

If HbA1c ≥ 8.5 % †

+Metformin

Insulin*

Insulin*

+ Rosiglitazone

+ Sulfonylurea

+ Metformin

+ Rosiglitazone

CV outcomes assessment

Add-on study therapy; dose adjustment

Randomized treatment phase (treat to target)

Randomization

Home PD, et al. Diabetologia 2005; 48:1726–1735.

Page 28: from Debate to Confidence - Diabetes · 2014-06-27 · Larochellière MD, Cezar S. Staniloae MD, Kreton Mavromatis MD, Jacqueline Saw MD, Bo Hu PhD, A. Michael Lincoff MD, and E

RECORD의 특징

RECORD는 양 군에서 혈당조절 정도를 일치시키도록설계되었다.

이는 조절되지 않는 혈당 자체가 심혈관계 질환의

위험과 관련된 변수로서 영향을 제거하기 위해서이다.

아반디아 safetyRECORD

아반디아 efficacyADOPT

Page 29: from Debate to Confidence - Diabetes · 2014-06-27 · Larochellière MD, Cezar S. Staniloae MD, Kreton Mavromatis MD, Jacqueline Saw MD, Bo Hu PhD, A. Michael Lincoff MD, and E

RECORD Interim

Independent data safety monitoring board confirmed that the trial should continue.

NEJM 이슈로 환자들에게 혼란을 초래하였기 때문에RECORD Steering Committee는 환자의 안전을 최선으로생각하여 중간 분석 결과를 발표하는 것이 중요하다고 판단하였다.

이 결과는 RECORD 연구의 최종 결론이 아닌 중간 보고이다.

모든 중간분석은 최종 결론을 제공하지는 못하지만, 이번중간분석 결과는 이 논쟁에 대해서 현재까지 가장 믿을만한 결과를 제시한다.

이 정보가 의사 및 환자들에게 즉각적이고 적절하게 알려짐으로써 치료 선택이 전반적인 과학적 증거에 근거해서이루어지기를 바라기 때문이다.

Page 30: from Debate to Confidence - Diabetes · 2014-06-27 · Larochellière MD, Cezar S. Staniloae MD, Kreton Mavromatis MD, Jacqueline Saw MD, Bo Hu PhD, A. Michael Lincoff MD, and E

Kaplan–Meier Analysis of the Primary End Point of Hospitalisation or Death from Cardiovascular Causes

Home P. et al. N Engl J Med. 2007 Published online 10.1056/NEJMoa073394

일차 평가변수인 CV 관련 입원 또는 사망에있어 아반디아 군과

대조군 사이에 통계적유의한 차이가 없었다.

Page 31: from Debate to Confidence - Diabetes · 2014-06-27 · Larochellière MD, Cezar S. Staniloae MD, Kreton Mavromatis MD, Jacqueline Saw MD, Bo Hu PhD, A. Michael Lincoff MD, and E

Death from any cause; Cardiovascular deaths; CV Death; MI and Stroke; Acute MI (all adjudicated events)

Home P. et al. N Engl J Med. 2007 Published online 10.1056/NEJMoa073394

사망률(CV 관련 사망 또는 모든 원인의 사망), MACE, MI 등 여러 2차평가변수에서도 아반디아군과 대조군 사이 유의한 차이가 없었다.

Page 32: from Debate to Confidence - Diabetes · 2014-06-27 · Larochellière MD, Cezar S. Staniloae MD, Kreton Mavromatis MD, Jacqueline Saw MD, Bo Hu PhD, A. Michael Lincoff MD, and E

Hospitalisation or Death from Cardiovascular causes

Home P. et al. N Engl J Med. 2007 Published online 10.1056/NEJMoa073394

Page 33: from Debate to Confidence - Diabetes · 2014-06-27 · Larochellière MD, Cezar S. Staniloae MD, Kreton Mavromatis MD, Jacqueline Saw MD, Bo Hu PhD, A. Michael Lincoff MD, and E

RECORD Interim Analysis 요약

Cardiovascular events로 인한 입원 및 사망에

차이가 없었다.

Cardiovascular deaths또는 기타 원인으로 인한

deaths의 차이가 없었다.

Heart attack을 포함한 기타 이차 평가 변수에 차이가 없었다.

2차 평가변수 중 CHF는 두 군간 유의한 차이가 있었다.

• 이는 TZD계열과 체액저류의 관련성으로 설명된다.

CHF의 증가에도 불구하고 주 평가변수인 CV 관련 입원 및사망에서 차이가 없었다는 점이다.

Home P. et al. N Engl J Med. 2007 Published online 10.1056/NEJMoa073394

Page 34: from Debate to Confidence - Diabetes · 2014-06-27 · Larochellière MD, Cezar S. Staniloae MD, Kreton Mavromatis MD, Jacqueline Saw MD, Bo Hu PhD, A. Michael Lincoff MD, and E

Summary and suggestion

현재까지의 연구결과에 의하면 rosiglitazone 이

심혈관계 질환을 악화시킨다고 볼 수 없다.

Rosiglitazone 사용시 심부전이 있는 환자의 경우는 주의를 요하며 이에 대한 추가 연구가 필요하다.

체액증가가 심할 경우 소량의 이뇨제를 병용해 볼 수있다.

Page 35: from Debate to Confidence - Diabetes · 2014-06-27 · Larochellière MD, Cezar S. Staniloae MD, Kreton Mavromatis MD, Jacqueline Saw MD, Bo Hu PhD, A. Michael Lincoff MD, and E

Nat Clin Pract Cardiovasc Med. 2007 Jul;4(7):345.

Page 36: from Debate to Confidence - Diabetes · 2014-06-27 · Larochellière MD, Cezar S. Staniloae MD, Kreton Mavromatis MD, Jacqueline Saw MD, Bo Hu PhD, A. Michael Lincoff MD, and E

Nat Clin Pract Cardiovasc Med. 2007 Jul;4(7):345.

NEJM에 발표된 논문은 아반디아가 심근 경색 혹은심혈관-관련 사망을 증가 시키는가 ? 에 대한

대답을 주지 못하고 있다.

자세한 내용을 모르는 환자 입장에서는 의사가처방한 약이 위험한 것이라고 만 생각함으로써

의사와 환자 사이의 신뢰만 떨어뜨리는 결과가 된다.

NEJM 논문에서 보듯이 완전하지도 않은 논문을 무조건빨리 발표하면 이번 경우와 같이 대중에게 커다란

영향을 주어 혼란을 일으키게 된다.

Page 37: from Debate to Confidence - Diabetes · 2014-06-27 · Larochellière MD, Cezar S. Staniloae MD, Kreton Mavromatis MD, Jacqueline Saw MD, Bo Hu PhD, A. Michael Lincoff MD, and E

Nat Clin Pract Cardiovasc Med. 2007 Jul;4(7):345.

약의 안전성이나메타 분석은대규모의

RECO

처방의 변경에 대한 연구를 하는데 있어표준 방법이 아니며 ADOPT나 RECORD같은

무작위 관리 시험 (RCT)을 통해서만 가능하다.

RD 연구의 결과를 보면 아반디아는 심혈관-관련사망을 17% 낮추었다.

이는 메타 분석과는 반대되는 결과이다.

Page 38: from Debate to Confidence - Diabetes · 2014-06-27 · Larochellière MD, Cezar S. Staniloae MD, Kreton Mavromatis MD, Jacqueline Saw MD, Bo Hu PhD, A. Michael Lincoff MD, and E

Without the statistical complex and fundamentally limitedmeta-analysis, the actual net events suggest a relative 0.021 %

lower MI risk associated with rosiglitazone.

86/14,376 (0.598) 72/11,635 (0.619) -0.021 %

McGuire DK, Diab Vasc Dis Res. 2007 Jun;4(2):77-79

Page 39: from Debate to Confidence - Diabetes · 2014-06-27 · Larochellière MD, Cezar S. Staniloae MD, Kreton Mavromatis MD, Jacqueline Saw MD, Bo Hu PhD, A. Michael Lincoff MD, and E

미국 FDA에서는 여러 전문가의 의견을 수렴하고 FDA 자체의 조사를 종합하여2007년 11월 공식 입장을 발표하였다. 그 내용을 정리하면 다음과 같다.

“현재로서 FDA의 결론은 심장 질환이나 사망의 위험에 있어 아반디아와 다른경구 당뇨병 치료제 사이에 차이가 있다는 충분한 증거가 없다.

따라서 FDA는 아반디아가 대조군에 비하여 심혈관 위험을 실제 증가시키는 가를판단하기 위하여 GSK로 하여금 새로운 장기간의 연구를 하도록 요청하였다.

이에 GSK도 동의하였고 FDA는 곧 연구가 착수되도록 할 것이다.”

추가 경고문; “ 42개의 임상 연구 (평균 기간 6 개월; 환자 14237 명)를 대상으로 한메타 분석에서 아반디아가 위약 군에 비하여 협심증이나 심근 경색증과 같은

심근 허혈 질환 위험의 증가와 연관되어 있다는 것을 보여주었다. 다른 3 개의 연구 (평균 기간 41 개월; 환자 14067 명)에서는, 아반디아와 경구

당뇨병 치료제 혹은 아반디아와 위약 군의 비교에서 이와 같은 위험이 확인되지도않았고 배제되지도 않았다. 결과적으로, 현재까지의 모든 데이터를 종합해 볼 때

심근 허혈증과 이반디아의 관계에 대해서는 결론을 내릴 수 없다.”

어떤 경구 당뇨병 치료제도 심혈관 위험을 줄일 수 있다는 증거가 없으므로 모든허가된 당뇨병 치료제에 이러한 사실을 명기할 것을 요구한다.

Page 40: from Debate to Confidence - Diabetes · 2014-06-27 · Larochellière MD, Cezar S. Staniloae MD, Kreton Mavromatis MD, Jacqueline Saw MD, Bo Hu PhD, A. Michael Lincoff MD, and E

PERISCOPEComparison of Pioglitazone vs. Glimepiride on Progression of Coronary Atherosclerosis

in Patients with Type 2 Diabetes

PERISCOPEComparison of Pioglitazone vs. Glimepiride on Progression of Coronary Atherosclerosis

in Patients with Type 2 Diabetes

Stephen J. Nicholls MBBS PhD, Kathy Wolski MPH, Richard Nesto MD,

Stuart Kupfer MD, Alfonso Perez MD, Horacio Jure MD, Robert De

Larochellière MD, Cezar S. Staniloae MD, Kreton Mavromatis MD, Jacqueline

Saw MD, Bo Hu PhD, A. Michael Lincoff MD,

and E. Murat Tuzcu MD for the PERISCOPE Investigators*

Stephen J. Nicholls MBBS PhD, Kathy Wolski MPH, Richard Nesto MD,

Stuart Kupfer MD, Alfonso Perez MD, Horacio Jure MD, Robert De

Larochellière MD, Cezar S. Staniloae MD, Kreton Mavromatis MD, Jacqueline

Saw MD, Bo Hu PhD, A. Michael Lincoff MD,

and E. Murat Tuzcu MD for the PERISCOPE Investigators*

Steven E. Nissen MDSteven E. Nissen MD

Page 41: from Debate to Confidence - Diabetes · 2014-06-27 · Larochellière MD, Cezar S. Staniloae MD, Kreton Mavromatis MD, Jacqueline Saw MD, Bo Hu PhD, A. Michael Lincoff MD, and E

Baseline Patient Characteristics (n=543)Baseline Patient Characteristics (n=543)Glimepiride

(n=273)Pioglitazone

(n=270)

Age (years) 59.7 60.0

Male gender 65.9% 68.9%

White 80.6% 83.3%

DM duration (years) 5.9 5.8

Weight (kg) 92.8 94.2

BMI 32.0 32.1

Hypertension 91.6%* 83.3%*

Current Smoker 19.4%† 11.5%†

*P = 0.002*P = 0.002 †P = 0.01†P = 0.01

Page 42: from Debate to Confidence - Diabetes · 2014-06-27 · Larochellière MD, Cezar S. Staniloae MD, Kreton Mavromatis MD, Jacqueline Saw MD, Bo Hu PhD, A. Michael Lincoff MD, and E

Baseline Laboratory Values & Blood Pressure*Baseline Laboratory Values & Blood Pressure*

Glimepiride (n=181)

Pioglitazone (n=179)

HbA1c (%) 7.4 7.4

LDL-cholesterol (mg/dL) 94.4 93.5

HDL-cholesterol (mg/dL) 43.4† 40.8

Triglycerides (mg/dL) 145 139

hsCRP (mg/L) 3.0 2.6

Systolic BP (mmHg) 128.6 127.8

Diastolic BP (mmHg) 75.2 75.7†P = 0.05†P = 0.05*N=360 (patients with both baseline and final IVUS)*N=360 (patients with both baseline and final IVUS)

Page 43: from Debate to Confidence - Diabetes · 2014-06-27 · Larochellière MD, Cezar S. Staniloae MD, Kreton Mavromatis MD, Jacqueline Saw MD, Bo Hu PhD, A. Michael Lincoff MD, and E

Change in Percent Atheroma Volume (%)Change in Percent Atheroma Volume (%)

P < 0.001P < 0.001

P = 0.44P = 0.44

P = 0.002P = 0.002

Glimepiride Pioglitazone

Primary Efficacy ParameterPrimary Efficacy Parameter

Page 44: from Debate to Confidence - Diabetes · 2014-06-27 · Larochellière MD, Cezar S. Staniloae MD, Kreton Mavromatis MD, Jacqueline Saw MD, Bo Hu PhD, A. Michael Lincoff MD, and E

Results of a Multicenter Randomized Double-blind Placebo-Controlled Study to Assess

the Benefit and Safety of Rosiglitazone in Preventing Atherosclerosis Progression After

Coronary Artery Bypass Surgery in Patients with Type 2 Diabetes

Results of a Multicenter Randomized Double-blind Placebo-Controlled Study to Assess

the Benefit and Safety of Rosiglitazone in Preventing Atherosclerosis Progression After

Coronary Artery Bypass Surgery in Patients with Type 2 Diabetes

Olivier F. Bertrand, MD, PhDOlivier F. Bertrand, MD, PhDPaul Poirier, MD, PhDPaul Poirier, MD, PhD

JeanJean--Pierre DesprPierre Despréés, PhDs, PhDon behalf of VICTORY Investigatorson behalf of VICTORY Investigators

VICTORY: A Cardiometabolic TrialVICTORY: A Cardiometabolic Trial

Page 45: from Debate to Confidence - Diabetes · 2014-06-27 · Larochellière MD, Cezar S. Staniloae MD, Kreton Mavromatis MD, Jacqueline Saw MD, Bo Hu PhD, A. Michael Lincoff MD, and E

Study Population (n = 193)

Placebo (n = 95)

Rosiglitazone (n = 98)

Age 65 ± 7 64 ± 7

Males 92% 92%

Previous MI 60% 55%

Stroke 5% 8%

Hypertension 84% 84%

Current Smoking 8% 12%

DM with diet/oral Rx 13%/87% 13%/87%

DM duration (yrs) 8.4 ± 6.9 7.8 ± 6.4

Time since CABG (yrs) 3.7 ± 2.5 3.9 ± 2.5

Results:Results:

Page 46: from Debate to Confidence - Diabetes · 2014-06-27 · Larochellière MD, Cezar S. Staniloae MD, Kreton Mavromatis MD, Jacqueline Saw MD, Bo Hu PhD, A. Michael Lincoff MD, and E

Study Population

Variables Placebo (n = 95)

Rosiglitazone (n = 98)

Weight (kg) 84 ± 15 86 ± 14

BMI 29.5 ± 4.6 30.2 ± 4.2

Systolic Pressure (mmHg) 129 ± 14 129 ± 13

Diastolic Pressure (mmHg) 73 ± 9 71 ± 9

Cholesterol (mg/dl) 151 ± 28 153 ± 31

LDL-Cholesterol (mg/dl) 88 ± 24 87 ± 26

HDL-Cholesterol (mg/dl) 41 ± 8 41 ± 9

TG (mg/dl) 142 ± 74 163 ± 81

Fasting Glucose (md/dl) 135 ± 30 139 ± 35

HbA1c (%) 6.91 ± 0.78 6.92 ± 1.2

CRP (mg/L) 2.54 ± 3.79 3.31 ± 7.11

Results:Results:

Page 47: from Debate to Confidence - Diabetes · 2014-06-27 · Larochellière MD, Cezar S. Staniloae MD, Kreton Mavromatis MD, Jacqueline Saw MD, Bo Hu PhD, A. Michael Lincoff MD, and E

4

5

6

7

8

9

Baseline 2 4 6 8 10 12 mo

Glu

cose

(m

mol/

L)

Placebo Rosiglitazone

5

6

7

8

Baseline 2 4 6 12 mo

HbA1c

(%)

Placebo Rosiglitazone

P<0.0001 interaction P<0.0001 interaction

Fasting Glucose HbA1c

Glycaemic ControlResults:Results:

134 mg/dl

116 mg/dl

P = 0.94 P < 0.0001 P < 0.0001P = 0.32 P < 0.0001 P < 0.0001

Page 48: from Debate to Confidence - Diabetes · 2014-06-27 · Larochellière MD, Cezar S. Staniloae MD, Kreton Mavromatis MD, Jacqueline Saw MD, Bo Hu PhD, A. Michael Lincoff MD, and E

0

5

10

15

20

Baseline Follow-up (6 mo) Follow-up (12 mo)

Adip

onec

tin (

ug/m

L)Placebo Rosiglitazone

P<0.0001 interaction

AdiponectinResults:Results:

P = 0.46 P < 0.0001 P < 0.0001

Page 49: from Debate to Confidence - Diabetes · 2014-06-27 · Larochellière MD, Cezar S. Staniloae MD, Kreton Mavromatis MD, Jacqueline Saw MD, Bo Hu PhD, A. Michael Lincoff MD, and E

1.0

1.5

2.0

2.5

3.0

Baseline Follow-up (6 mo) Follow-up (12 mo)

LDL-

chole

ster

ol (m

mol/

L)

Placebo Rosiglitazone

10

20

30

40

50

60

Baseline Follow-up (6 mo) Follow-up (12 mo)

Sm

all LD

L par

ticl

es (

%)

Placebo Rosiglitazone

P=0.18 interaction P<0.0001 interaction

LDL-Cholesterol % Small LDL

Lipid ParametersResults:Results:

84 mg/dl

86 mg/dl

P = 0.50

P = 0.65 P = 0.0001 P = 0.001

Page 50: from Debate to Confidence - Diabetes · 2014-06-27 · Larochellière MD, Cezar S. Staniloae MD, Kreton Mavromatis MD, Jacqueline Saw MD, Bo Hu PhD, A. Michael Lincoff MD, and E

200

250

300

350

400

450

Baseline Follow-up

SVG

pla

que

volu

me

(mm

3)

Placebo Rosiglitazone

P=0.25 ANOVAP=0.22 LSM

SVG Plaque VolumeResults:Results:

Page 51: from Debate to Confidence - Diabetes · 2014-06-27 · Larochellière MD, Cezar S. Staniloae MD, Kreton Mavromatis MD, Jacqueline Saw MD, Bo Hu PhD, A. Michael Lincoff MD, and E

20

30

40

50

60

70

80

90

Baseline Follow-up (6 mo) Follow-up (12 mo)

E-s

elec

tin (

ng/m

L)

Placebo Rosiglitazone

P=0.0037 interaction

E-Selectin

Results:Results:Thrombosis

P = 0.53 P = 0.03 P = 0.23

Page 52: from Debate to Confidence - Diabetes · 2014-06-27 · Larochellière MD, Cezar S. Staniloae MD, Kreton Mavromatis MD, Jacqueline Saw MD, Bo Hu PhD, A. Michael Lincoff MD, and E

What can we learnfrom past experience in

type 2 diabetes?

Page 53: from Debate to Confidence - Diabetes · 2014-06-27 · Larochellière MD, Cezar S. Staniloae MD, Kreton Mavromatis MD, Jacqueline Saw MD, Bo Hu PhD, A. Michael Lincoff MD, and E

Analysis includes only patients continuing on monotherapy

Rosiglitazone vs metformin−9.8 (−12.6 to −7.0) mg/dl, P < 0.001

Rosiglitazone vs glyburide−17.4 (−20.4 to −14.5) mg/dl, P < 0.001

FPG (mg/dl)

Glibenclamide

Metformin

Rosiglitazone

0 1 2 3 4 5Time (years)

0

120

160

140

130

150

4-year prespecified time point for analysis

Adapted from Kahn SE, et al. N Engl J Med 2006; 355:2427–2443. http://www.adopt-study.org/slides.php (accessed 23.11.07).

Do short-term results reflect long-term outcomes?

ADOPT

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Adapted from Dormandy JA, et al. Lancet 2005; 366:1279–1289.

0.25

0.20

0.15

0.10

0.05

0.0

0 6 12 18 24 30 36

5,238 5,018 4,786 4,519 4,433 4,268 693N at risk:

Pioglitazone (N events: 514/2,605)Placebo (N events: 572/2,633)

3-year estimate:23.5%21.0%

Kap

lan-

Mei

er e

vent

rate

Time from randomization (months)

Pioglitazone vs placebo: HR 0.90 (95% CI 0.80, 1.02), P = 0.095

Do short-term results reflect long-term outcomes?

PROactive

Page 55: from Debate to Confidence - Diabetes · 2014-06-27 · Larochellière MD, Cezar S. Staniloae MD, Kreton Mavromatis MD, Jacqueline Saw MD, Bo Hu PhD, A. Michael Lincoff MD, and E

*Median trial duration: 5 months (range 3–24 months). Did not include UKPDSRR = relative risk

Short-term studies: metformin has less benefit than comparators

Study METn/N

Comparisonn/N

RR (fixed)95% CI

Weight(%)

RR (fixed)95% CI

All-cause mortalityDeFronzo 1995 1/210 0/209 49.6 2.99 [0.12, 72.88]

Horton 2000 1/178 0/172 50.4 2.90 [0.12, 70.69]Subtotal (95% CI) 388 381 100.0 2.94 [0.31, 28.16]

Ischaemic heart diseaseDeFronzo 1995 1/210 0/209 25.2 2.99 [0.12, 72.88]Hallsten 2002 1/13 0/14 24.2 3.21 [0.14, 72.55]Horton 2000 1/178 0/172 25.5 2.90 [0.12, 70.69]Teupe 1991 1/50 0/50 25.1 3.00 [0.13, 71.92]

Subtotal (95% CI) 451 445 100.0 3.02 [0.62, 14.75]

Saenz A, et al. Cochrane Database of Systematic Reviews 2005, Issue 3.

0.01 0.1 1 10 100Favours metformin Favours comparison

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UKPDS: metformin has greater benefit than comparators

UKPDS METn/N

Conventional n/N

RR (fixed)95% CI

Weight(%)

RR (fixed)95% CI

Any diabetes-related outcomes

98/342 160/411 100.0 0.74 [0.60, 0.90]

Diabetes-related death

28/342 55/411 100.0 0.61 [0.40, 0.94]

All-cause mortality 50/342 89/411 100.0 0.68 [0.49, 0.93]

Myocardial infarction 39/342 73/411 100.0 0.64 [0.45, 0.92]

Stroke 12/342 23/411 100.0 0.63 [0.32, 1.24]Peripheral vascular disease

6/342 9/411 100.0 0.80 [0.29, 2.23]

Microvascular 24/342 38/411 100.0 0.76 [0.46, 1.24]

Saenz A, et al. Cochrane Database of Systematic Reviews 2005, Issue 3.

0.2 0.5 1 2 5

RR = relative risk

Favours metformin Favours comparison

Page 57: from Debate to Confidence - Diabetes · 2014-06-27 · Larochellière MD, Cezar S. Staniloae MD, Kreton Mavromatis MD, Jacqueline Saw MD, Bo Hu PhD, A. Michael Lincoff MD, and E

Meta-analysis * Summary of relevant study results

* Quality depend on each study

Original study (RCT)* Summary of individual

patient data * Design and conduct for

specific primary objective

Meta-analysis generates hypothesis,RCT provides the answer.

Page 58: from Debate to Confidence - Diabetes · 2014-06-27 · Larochellière MD, Cezar S. Staniloae MD, Kreton Mavromatis MD, Jacqueline Saw MD, Bo Hu PhD, A. Michael Lincoff MD, and E

What is the CV profile of rosiglitazone?Signal of

increased risk

Meta-analysesGSK ICT analysis1

Nissen, et al.2

Singh, et al.3

Ongoing CV studies

Randomized controlled trials

ACCORDAPPROACH

BARI 2DRECORD

VADTVICTORY

No increased risk

Randomized controlled trialsRECORD Interim Analysis4

ADOPT5

Meta-analysesLago, et al.6

Epidemiological studies7

Rosen, et al.8

McAfee, et al.9

“… we believe that only prospective clinical trials designed for the specific purpose of establishing the cardiovascular benefit or risk of rosiglitazone will resolve the

controversy about its safety”10 (Diamond 2007)1http://ctr.gsk.co.uk/Summary/Rosiglitazone/III_CVmodeling.pdf (accessed 23.02.08). 2Nissen SE et al. N Engl J Med 2007; 356:2457–2471.

3Singh S et al. JAMA 2007; 298:1189–1195. 4Home PD. N Engl J Med 2007; 357:28–38. 5Krall RL. Lancet 2007; 369:1995–1996. 6Lago RM et al. Lancet 2007; 370:1129–1136. 7GSK Briefing Document 2007. http://www.fda.gov/ohrms/dockets/ac/07/briefing/2007-4308b1-02-gsk-backgrounder.pdf (accessed 23.02.08). 8Rosen CJ. N Engl J Med 2007; 357:844–846. 9McAfee AT et al. Pharmacoepidemiol Drug Saf 2007; 16:711–

725. 10Diamond GA et al. Ann Intern Med 2007; 147:578–581.

Page 59: from Debate to Confidence - Diabetes · 2014-06-27 · Larochellière MD, Cezar S. Staniloae MD, Kreton Mavromatis MD, Jacqueline Saw MD, Bo Hu PhD, A. Michael Lincoff MD, and E

Between Cloud , 2007

Page 60: from Debate to Confidence - Diabetes · 2014-06-27 · Larochellière MD, Cezar S. Staniloae MD, Kreton Mavromatis MD, Jacqueline Saw MD, Bo Hu PhD, A. Michael Lincoff MD, and E

Sunset of Great Ocean Road , 2007

Thank you for your attention !!