ACTOS® Therapeutic Interventions:

Micro / Macrovascular Complications of DM

台灣武田
DM in Taiwan
• Type 2 DM– 估計約 90-100 萬 (>4%)
• 45 歲以上 , 盛行率 11%
• Since 1988- 高居 10 大死因前 5 位
(cancer,accident,CVA,heart disease)
• 死亡率增加幅度最大， 2003 年竄升到第四名
• 醫療照顧成本 DM : non-DM = 4.3:1
• 超過 60% 死亡率來自於心臟血管病變
Natural History of T2DM
 Pathophysiology of Type 2 Diabetes
The Tip of the Iceberg

Type 2 Diabetes
Diabetes

0
Impaired Macroangiopathy Microangiopathy
Plasma Glucose
Glucose tolerance

Insulin secretory deficiency

10
Normal
Glucose- Microalbuminur. Dyslipidemia
Insulin
tolerance
Visc. obesity Resistance Hypertension

Genes Environment 20
[years]
Matthaei et al., Endocrine Reviews 21:585-618 (2000)
Complications of Insulin Resistance

微血管
及心血管疾病 冠狀動脈疾病

高血糖
( 第 2 型糖尿病 ) 血脂異常
FPG ≧ 110 mg/dl TG ≧ 150 mg/dl
HbA1c ＞ 7% LDL ≧ 100 mg/dl
HDL ≦ 40 mg/dl 男性
HDL ≦ 50 mg/dl 女性

肥胖
( 中廣型 ) 高血壓
BMI ≧ 25 Kg/m 2

SBP ≧ 130 mmHg

DBP ≧ 80 mmHg
心血管疾病 冠狀動脈疾病

1.ADA. Diabetes Care 2003

2.DeFronzo RA. Neth J Med. 1997
 胰 島 素 阻 抗 性

Insulin Resistance Atherosclerosis Sensitivity Study (IRAS) : N=479 Type 2 Diabetes

Haffner SM, et al. Diabetes Care. 1999

 Structures of Thiazolidinediones

Thiazolidine-2-4-dione
S
O

Pioglitazone HCl NH
O O
N

S
Me O

N N NH
Rosiglitazone Maleate O
O

S
O
Troglitazone O NH
O O

PDR 55 edition 2001

 How TZDs work?
• Pioglitazone exertans insulin-
sensitizing effect by binding
to PPARs, leading to
activation of 2nd messengers
and a resultant reduction
levels of TNF-α & FFA.
• Glucose transport,
particularly via GLUT4
protein, is the rate controlling
step for insulin-stimulated
muscle glycogen synthesis in
DM p’t.
• GLUT4 protein accepts
glucose and transports it into
the cell’s interior.
Pioglitazone Monotherapy

*
*

* *

PDR 55 edition 2001

Aronoff et al., Diabetes Care 2000
Study 012, TPA
Pioglitazone Monotherapy – Escalation Dose

* * * *
*
*
* * *
* * * * * *
*
* *
* * *
* *
*
*
* * *

PDR 55 edition 2001

Data on file. Study 012. TPA
 Monotherapy – Unique lipid effects

Pioglitazone QD
increased HDL 19%
* * *
*
*
* * Pioglitazone QD reduced
* * * * TG 28% and FFA 38%
*
* *
* *
* *
*
*
*
Pioglitazone
QD reduced
LDL, total-C

PDR 55 edition 2001

Diabetes Care 2002
Diabetes Mellitus: A Fundamental and Clinical Text. 2000
 Pioglitazone vs Rosiglitazone
Head-to-Head-Comparison
25

20
Pioglitazone 15 mg
15 * + Glimepiride
*
+17,9 *
10 +16,5
** Rosiglitazone 4 mg
Change at 12 months (%)

5 +15 + Glimepiride

0 +2,4
*
-5 * p < 0,05 (vs Baseline)
**
-10 -12,0 ** p < 0,05 (vs
rosiglitazone)
*
-15
**
-20 -22,4 n=87
-25
Triglycerides HDL-C LDL-C

Derosa G et al, Clin Ther 2004; 26(5):744-754

 PPAR-γ and –α as
Therapeutic Target in Disease
•PPAR-γ
主要分布在 adipose tissue 負責 glucose
metabolism 及少部分的 lipid metabolism

•PPAR-α
主要分布在 liver and muscle 負責 lipid
metabolism 。 PPAR-α 對於 lipoprotein metabolism
的調控，是一個 重要的轉錄因子 (transcription
factor) 。

•在 治療濃度 (therapeutic concentration) 下：

•Actos 可以活化 PPAR-γ 及 PPAR-α
•Rosiglitazone 則僅可以活化 PPAR-γ
 Glitazone PPAR Activation
Transient Transactivation Assay
Pioglitazone Rosiglitazone
4 8 4 8

fold induction (PPARγ)

fold induction (PPARγ)

fold induction (PPARα)

fold induction (PPARα)

PPARγ PPARγ
PPARα PPARα
3 6 3 6

2 4 2 4

1 2 1 2

0 0 0 0
-11 -10 -9 -8 -7 -6 -5 -4 -11 -10 -9 -8 -7 -6 -5 -4
log[conc.(M)] log[conc.(M)]

Full-length hPPARγ1 and hRXRα or hPPARα and hRXRα expression plasmids were
cotransfected into COS-1 cells with reporter plasmid contained PPRE, and cells were
cultured in the presence of pioglitazone or rosiglitazone for 48 hours. The cell extracts
were assayed for luciferase activity.
The dotted lines indicate plasma Cmax in the clinical trial at 45 mg of pioglitazone or 8 mg
of rosiglitazone, respectively.
Sakamoto J, et al. BBRC 2000; 278: 704-11
“DM management is not
PG control only.”
UKPDS: Risk Reduction in Diabetes-Related
Complications for 1% Decline in HbA1C
0
Risk Reduction (%)

-10
-12%*
-14%*
-20 -16%*

-30

-40 -37%**

Micro- MI Stroke CHF

vascular
Stratton IM. UKPDS 35. BMJ. 2000;321:405-12.
UKPDS - impact on microvascular and
macrovascular complications
• Over 10 years drug and/or insulin treatment
significantly improved glucose control
compared to diet and exercise
• intensive glucose control significantly reduced
microvascular complications
• no overall impact on MACROvascular disease
• multiple therapies required as disease
progresses
UK Prospective Diabetes Study (UKPDS) Group. Lancet 1998;352:837–853
Ideal Oral Anti-DM Agent

• Corrects hyperglycemia and

prevents microvascular
complications
• Improves known CVRFs and
prevents macrovascular
complications
The 1st TZD Outcome
Study on Macrovascular
Disease: PROactive

PROspective PioglitAzone Clinical

Trial In MacroVascular Events
PROspective PioglitAzone Clinical Trial In
MacroVascular Events: PROACTIVE
●Objective
– Assess the effect of pioglitazone on the secondary prevention of
macrovascular events in high risk patients with Type 2 diabetes and
objective evidence of atherosclerotic disease

●Study Design
– Multicenter, randomized, placebo-controlled, parallel group in 19
countries
– 5,238 patients randomized to either pioglitazone or placebo on top
of their current therapeutic regimen
Add pioglitazone (15-45 mg) to
– 2.5 year follow-up existing therapy
Existing therapy
e.g. diet, SU, metformin,
Insulin + OAD
Add placebo to existing therapy
Chabonnel, Diabetologia 45(suppl 2):A107, 2002
proactive-results.com
 -16%*

proactive-results.com
 -53%*

proactive-results.com
-28%*
-37%*
-47%*
 ACTOS Clinical Trials

Primary Objectives Patient / Treatment

Location Duration
Investigating the potential
CHICAGO for reduction of 1,000 18 months
atherosclerosis USA 25 sites From 2003.4

Evaluating the effect on

PERISCOPE coronary artery disease 1,000 18 months
USA 80 sites From 2003.4
 CHICAGO
A Study Evaluating Carotid Intima-Media
Thickness in Atherosclerosis Using
Pioglitazone
 Background

• Patients with type 2 diabetes mellitus (T2DM) are at a 2-4 times

increased risk for cardiovascular (CV) disease

• The prognosis following a CV event is worse for patients with

T2DM compared to patients without T2DM

• Pioglitazone (PIO) demonstrates several effects that predict

protection from atherosclerosis
• Atheroprotective pattern of gene expression
• Reduction of systemic inflammation
• Improvement in lipids and lipoproteins
 Study Design

Glimepiride 1-4mg QD

Screening

Pioglitazone 15-45mg QD

Week –7 W0 W4 W8 W16 W24 W32 W40 W48 W60 W72

CIMT CIMT CIMT CIMT
EBT EBT

* EBT: Examination Before Trial

 Study Endpoints

Primary Endpoint
• Change from baseline to final visit in mean
posterior wall CIMT mean value

Secondary Endpoints
• Change from baseline to final visit in posterior
wall CIMT maximum value
• Cardiovascular composite endpoints
(independently adjudicated)
 Subject Disposition

Randomized
N=462
Glimepiride Pioglitazone
N=230 N=232

Included in CIMT N=186 (81%) Included in CIMT N=175 (75%)

 Mean Change in CIMT
0.020 p=0.017
LS Mean Change from Baseline

0.015
Posterior Wall CIMT (mm)

Glimepiride Pioglitazone
0.010
0.012

0.005

0.000

-0.001
-0.005

-0.010

Baseline CIMT GLM (N=186) PIO (N=175) Treatment group difference, Final Visit
LS Mean (SE) 0.779 (0.0085) mm 0.771 (0.0085) mm -0.013 (95% CI: -0.024,-0.002)
 Mean Change in Maximal CIMT
0.04
Glimepiride Pioglitazone HCl
Posterior Wall Maximum CIMT (mm)
LS Mean Change from Baseline

0.03

0.02

0.01

0.00

*
-0.01

-0.02
*
Baseline Week 24 Week 48 Week 72
*P<0.01
Baseline CIMT (mm) GLM (N=186) PIO (N=175) Treatment group difference at Final Visit
LS Mean (SE) 1.042 (0.010) 1.038 (0.010) -0.024 (95% CI: -0.042, -0.006)
Subgroup Analysis of CIMT

(mm)
 HDL-Cholesterol Changes
10

Glimepiride Pioglitazone HCl

LS Mean Change from Baseline,

6
HDL-C (mg/dL)

12.8%

-1.1%

-2 * * *
Baseline Week 24 Week 48 Week 72
* P<0.0001
Baseline HDL-C (mg/dL) GLM (N=206) PIO (N=201) Treatment group difference, Final Visit
LS mean (SE) 47.6 (0.91) 47.1 (0.90) 6.45 (95% CI: 4.97, 7.93)
 Adjudicated First CV Events
Glimepiride Pioglitazone
CV Event or Event Category
N = 228 N = 230
Composite endpoint 2 0
Cardiovascular mortality, nonfatal MI, and nonfatal stroke

Cardiovascular mortality, nonfatal MI, nonfatal stroke,

coronary revascularization, carotid
endarterectomy/stenting, hospitalization for unstable 10 (4.4) 4 (1.7)
angina, and hospitalization for CHF (n [%])

Cardiovascular mortality 0 0
Nonfatal MI 1 0
Nonfatal stroke 1 0
Coronary revascularization 8 3
Carotid endarterectomy/stenting 0 0
Hospitalization for unstable angina 0 0
Hospitalization for CHF 0 1
‡
Noncardiovascular mortality 0 1
‡Pancreatic cancer in an 80-year-old woman
 Conclusion

• Diabetes is increasing in prevalence and is a major risk

factor for CV disease; whereas lipid and blood pressure
management have powerful benefits on such risk, new
approaches are needed for patients with T2DM.

• Although additional data are needed, our results

demonstrating the beneficial effect of pioglitazone
compared to glimepiride on CIMT, a validated surrogate
marker for CV risk, suggest a novel approach to
managing such risk.
Ideal Oral Anti-DM Agent

• Corrects hyperglycemia and

prevents microvascular
complications
• Improves known CVRFs and
prevents macrovascular
complications
 ACTOS® :
Rationale for Therapy in Type 2 Diabetes
• Proven Attributes
─ Really Improve insulin resistance
─ Improve glycemic control
─ Improve lipid profile
─ Preservation of β-cell function
─ Prevent progression of IGT T2DM
• Macrovascular Benefits
─ Prevention of ASCVD => PROactive Study
TZD is contraindicated in
CHF (NYHA Class III or IV)
 ACTOS® :
Rationale for Therapy in Type 2 Diabetes
• Proven Attributes
─ Really Improve insulin resistance
─ Improve glycemic control
─ Improve lipid profile
─ Preservation of β-cell function
─ Prevent progression of IGT T2DM
• Macrovascular Benefits
─ Prevention of ASCVD => PROactive Study
全民健康保險糖尿病專業醫療服務品質報告
中央健 保局 94 年 4 月

• 品質改善目標
– 血液生化值監測： Fasting Lipid 以及 HbA1C 。
• 建議初診 1 次，年度檢查 1 次；
• 建議初診 1 次，定期複診 3 次 / 年，異常者每 3-6 個月 1 次，年度檢查 1 次
– 眼底檢查及眼底彩色攝影檢查
• 建議初診 1 次，年度檢查 1 次
– 用藥品質
• TZDs 的使用建議
– 當無法並用 MET 以及 SU 時，例如：伴隨腎臟疾病的糖尿病病患，不建議使
用 MET ，當單用 SU 控制不良時，即考慮可以使用 TZDs 。
– 並用 MET 以及 SU 時， HbA1C 仍未達理想值。
仍未達理想值
HbA1C 理想值
• 中華民國糖尿病學會 『糖尿病照護指引』
– HbA1C <6.5%
– BP < 130/80mmHg
– TC < 174 mg/dL
– LDL < 100 mg/dL
– HDL > 40 mg/dL
– TG <150 mg/dL
– UACR < 30mg/g
– Exercise > 150 mins/week
Thank You