Practical upates in Diabetes & CV risk management: Brief ... · Slides presented during CDMC in...

Practical upates in Diabetes & CV risk management: Brief Updates Understanding new guideline of AACE，analyzing clinical advantages of AGI

Yu Hu, MD Zhong Shan Hospital Fudan University China

Slides presented during CDMC in Almaty, Kazakhstan on Sunday April 13 , 2014 and prepared by:

Main contents

1

AGI is listed as alternative first-line agent 2

Interpretation for new idea and highlight of

AACE, 2013

AACE in 2013: a guideline to emphasize

comprehensive management

1.AACE Consensus Statement.ENDOCRINE PRACTICE Vol 19 (Suppl 2) May/June 2013 1.

1. Management of obesity

2. Management of prediabetes

3. Lifestyle intervention, medication and management of insulin

for hyperglycemia

4. Management of hypertension

5. Management of hyperlipidemia

6. Management of other risk factors

AACE 2013 elevated management for overweight/obesity

and prediabetes to height of prevention and treatment for

macrovascular complications

1. AACE Consensus Statement.ENDOCRINE PRACTICE Vol 19 (Suppl 2) May/June 2013 1.

AACE 2013

recommended

Studies of DCCT (1993), Kumamoto (1995) and UKPDS (1998) demonstrated

that controlling glucose strictly can reduce incidence of diabetic microvascular

complications.

Subsequently, in 2008, large-scale ACCORD study, VADT study and

ADVANCE study didn’t demonstrate that intensively reducing level of blood

glucose can reduce incidence of diabetic macrovascular complications.

Reducing level of blood

glucose can reduce

incidence of diabetic

microvascular complications

How to prevent and

treat macrovascular

complications?

Nip it in the bud……

Management for obesity and

prediabetes is associated

with outcome of

macrovascular complications

Lifestyle treatment is essential and

involved through all stages for all

patients with diabetes

1.AACE Consensus Statement.ENDOCRINE PRACTICE Vol 19 (Suppl 2) May/June 2013 1.

AACE 2013 pointed out: Lifestyle is a basis of comprehensive treatment for

diabetes

Lifestyle intervention can be simultaneously

initiated with medications Gradual treatment program is once again verified

to be unreasonable

Lifestyle optimization is essential for all patients with diabetes. Lifestyle

optimization is multifaceted, ongoing, and should engage the entire

diabetes team. However, such efforts should not delay needed

pharmacotherapy, which can be initiated simultaneously and adjusted

based on patient response to lifestyle efforts. The need for medical therapy

should not be interpreted as a failure .

6

Colesevelam

α-GI

Insulin ±

other drugs

= Fewer adverse events or

obtaining benefits possibly

Single medication*

Entry A1c level < 7.5% Entry A1c level ≥ 7.5% Entry A1c level > 9.0%

Without symptoms With symptoms

Progression of diseases

* Sequence of drugs listed above indicates recommended rank order of medication

* * Data based on phase 3 clinical trials

Cutline

metformin

Combined treatment with 2 drugs*

If target isn’t still

achieved after 3

months, intensive

insulin treatment will

be carried out


Lifestyle intervention including that reduction of bodyweight is

conducted via medical intervention

DPP4-inhibitors

TZD

** SGLT-2

Basal insulin

metformin

or other

first-line

drugs SU/GLN

Quick release type

bromocriptine


achieved after 3 months,

combined treatment with

3 drugs will be carried

out

metformin

or other

first-line

drugs

Colesevelam

α-GI

GLP-1 RA

TZD

** SGLT-2

Basal insulin

Quick release type

bromocriptine

DPP4-inhibitors

SU/GLN

Combined

treatment with 2

drugs

Combined

treatment with 3

drugs

Or

Adding drugs or intensive insulin

treatment

= Using cautiously

Management of blood glucose is conducted according to

stratification of baseline A1c levels of patients

GLP-1 RA

DPP4- inhibitors

α-GI

SGLT-2 **

TZD

SU/GLN

If A1c level is over 6.5%

after treatment is

conducted for 3 months,

second drug is added (2

drugs are combined)

GLP-1 RA

Primary principle of treatment stated by AACE 2013


Minimizing risk of

hypoglycemia and

weight gain

PRINCIPLES OF THE AACE ALGORITHM

FOR THE TREATMENT OF TYPE 2

DIABETES MELLITUS Minimizing risk of hypoglycemia is a priority.

It is a matter of safety, adherence, and cost.

Minimizing risk of weight gain is also a

priority. It too is a matter of safety,

adherence, and cost

Highlight evaluation of cardiovascular risk

factors of patients with T2DM


highlights of AACE guideline, 2013

Lifestyle intervention is essential for every diabetics and

medication can be simultaneously initiated with lifestyle

modification.

Management of cardiovascular risk factors to reduce the

CV events of T2DM patients. Such kind of management

needs to start early and maintain for the disease whole

process.

Achieve the glucose target safely with minimized risk of

hypoglycemia and weight gain

Main contents

Interpretation for new idea and highlight of

AACE, 2013 1

AGI is listed as alternative first-line agent 2

11

Colesevelam

α-GI

Insulin ±

other

drugs

= fewer adverse events or

obtaining benefits possibly

Single medication*

Entry A1c level < 7.5% Entry A1c level≥7.5% Entry A1c level > 9.0%

Without symptoms With symptoms

Progression of diseases

*Sequence of drugs listed above indicates

recommended rank order of medication

**Data based on phase 3 clinical trials

Cutline

metformin



achieved after 3

months, intensive

insulin treatment will

be carried out


Lifestyle intervention including that reduction of bodyweight is

conducted via medical intervention

DPP4 inhibitor

TZD

** SGLT-2

Basal insulin

metformin

or other

first-line

drugs SU/GLN

Quick release type bromocriptine


achieved after 3 months,

combined treatment with

3 drugs will be carried

out

metformin

or other

first-line

drugs

DPP4 inhibitor

α-GI

GLP-1 RA

TZD

** SGLT-2

Basal insulin

Quick release type bromocriptine

SU/GLN

Combined

treatment with 2

drugs

Combined

treatment with 3

drugs

or

Adding drugs or intensive insulin

treatment

= Using cautiously

AGI can be at first-line used singly or combined with other drugs

for patients with various level of A1c

GLP-1 RAs

DPP4 inhibitors

α-GI

SGLT-2

TZD

SU/GLN

If A1c level is over 6.5% after

treatment is conducted for 3

months, second drug is added

(2 drugs are combined)

GLP-1 RA

Colesevelam

Mechanism of α-glycosidase inhibitors –

Reduction of postprandial blood glucose

*Compared with single α-amylase, starch can produce more oligosaccharides and maltose under the coaction

of α-amylase and α-glycosidase

#Small parts of starch can directly produce glucose under coaction of α-glycosidase

1.http://en.wikipedia.org/wiki/Acid_%CE%B1-glucosidase 2.http://en.wikipedia.org/wiki/Alpha-Amylase.

3.Dhital S, Lin AH, Hamaker BR, et al. PLoS One. 2013 Apr 25;8(4):e62546.

α-glycosidase#

Indicates glucose

Starch

α- amylase

Cooperate with α-glycosidase*

Maltose

Oligosaccharide

α-glycosidase

multiply

decomposed by

α-glycosidase

AGIs delay absorption of glucose

Voglibose can significantly decrease the PPG excursion

Satoh N ,et al. Metabolism.2006,55,786-93.

Obese T2DM，basen 0.9mg/d

**p<0.01 **

** **

Before TX

After TX

BG

(mg/d

l)

Before B After B Before L After L

mean±SE

100

150

200

250

50

0

（mg/dL）

血糖水平

300

250

200

150

100

50

Before B 2hr Before L Before d 2hr 2hr bedtime

*p<0.05 2W vs 3W

2W

3W

4W

acarbose

voglibose

〔before〕

（n=13）

* *

AGIs flatten BG fluctuation

阿部隆三（太田西ノ内医院・糖尿病中心）：第41届日本糖尿病学会、 ‘98.5和歌山

AGI can reduce HbA1c significantly

1. Lu Juming. Chinese Journal of Endocrinology and Metabolism 2009; 25(2):2a-6-8

-0.5

-1.0

-1.5 Falli

ng a

mplit

ude o

f H

bA

1c (

%)

Westerner Chinese

-0.5~-0.8%

-1.3~-1.7%

Treatment with α-glycosidase inhibitors

Postprandial glucose and cardiovascular death

DECODE

19991

Pacific and

Indian Ocean

19992

Funagata

Diabetes Study 19993

Whitehall, Paris and

Helsinki Study

19984

Diabetes

Intervention Study

19965

The

Rancho-Bernardo Study

19986

pPG

Honolulu

Heart Programme

19877

CVD Death

1 DECODE Study Group. Lancet 1999;354:617. 2 Shaw JE et al. Diabetologia 1999;42:1050. 3 Tominaga M et al. Diabetes Care 1999;22:920. 4 Balkau B et al. Diabetes Care 1998;21:360. 5 Hanefeld M et al. Diabetologia 1996;39:1577. 6 Barrett-Connor E et al. Diabetes Care 1998;21:1236. 7Donahue, et al., Diabetes, 1987; 36:689

Toshihiko Y, et al. Intern Med. 2007, 46: 543-546

The relationship of 2 hours blood glucose

level and coronary heart diseases

2 hours blood suger level was significantly high in CHD group.

Blood sugar levels from OGTT in CHD and control groups

PPG but not FPG is associated with Myocardial infarction and death － the Diabetes

Intervention Study, 11-year follow-up （DIS）

Hanefeld M, et al. Diabetologia 1996, 39:1577-83

0

150

300

4.4 <7.8 >7.8

心肌梗死

死亡率

0

150

300

4.4 <7.8 >7.8

心肌梗死

死亡率

发生率

/1000人

发生率/100

0人

FPG PPG

P=NS P<0.05

MI

death

MI

death

40-114 mg/dL

115-133 mg/dL

134-156 mg/dL

157-189 mg/dL

190-532 mg/dL

1hr PBG

0

10

20

30

40

50

60

Fatal CHD fatal CHD +

nonfatal MI

发生

率/ 1000人

p<0.01

p<0.001

Postprandial glucose and fatal CHD and nonfatal

MI － Honolulu heart study

Donahue, et al., Diabetes, 1987; 36:689.

8000 japanese males, follow up for 11 years

Glucose Metabolism and Coronary

Heart Disease in Patients

With Normal Glucose Tolerance

80

81

82

83

84

85

86

87

88

89

90

91

0 1 2 3

100

110

120

130

0 1 2 3

Factor R P

Postload glucose 0.667 <0.001

HbA1c 0.561 <0.001

HOMA-IR 0.278 <0.001

Postload insulin 0.221 <0.001

Fasting insulin 0.297 <0.001

Triglycerides 0.531 <0.001

Total cholesterol 0.432 <0.001

HDL-C -0.156 0.009

Fasting glucose -0.003 0.83

LDL-C 0.501 <0.01

DBP 0.067 <0.01

SBP 0.004 0.76

Age 0.020 0.14

smoking 0.087 <0.001

Numbers of Coronary artery narrowing

FP

G

PP

G

Ferdinando CS et al. JAMA, 2004,291:1857 N=234

Numbers of Coronary artery narrowing

Acarbose treatment and the risk of cardiovascular

disease and hypertension in patients with impaired

glucose tolerance: the STOP-NIDDM trial

Hazard ratio (%)

p acarbose

(n=682)

placebo

(n=686)

No. experiencing event

Favors

0 0.5 1.0 1.5 2.0

Coronary heart disease

Myocardial infaction 1 12 91

Angina 5 12 55

Revascularization 11 20 39

CV death 1 2 5

Congestive heart failure 0 2 –

Cerebrovascular E./ stroke 2 4 44

Peripheral vascular Disease 1 1 –

Any CV events 15 32 49

0.02

0.13

0.18

0.63

–

0.51

0.93

0.03

acarbose placebo

Chiasson JL, et al. JAMA 2003;290:486–94.

Hanefeld M, et al. Eur Heart J 2004;25:10

Acarbose reduces the risk for MI and any CV-events in type 2

diabetic patients: meta-analysis of seven long-term studies

α-glycosidase inhibitors can reduce level of

postprandial blood glucose to help to protect

heart and blood vessels Home P. Diabetes Technol Ther. 2012 Jun;14 Suppl 1:S33-42.

1.Home P. Diabetes Technol Ther. 2012 Jun;14 Suppl 1:S33-42.

α-glycosidase inhibitors can play certain protective role for

heart and blood vessels through reducing postprandial

blood glucose. Although there are relatively fewer large

scale of hard endpoint studies for α-glycosidase inhibitors,

their delayed action for CIMT of alternative endpoint can

also evidence the benefit.

Overview for adverse reactions of

antidiabetes drugs

1.AACE Consensus Statement.ENDOCRINE PRACTICE Vol 19 (Suppl 2) May/June 2013 .

Brief introduction of antidiabetes drugs

Dimethylbig

uanide DPP-4 inhibitors GLP-1RA TZD

α-

glycosi

dase

inhibit

ors

COLSVL BCR-

QR

SU or

glinides Insulin SGLT-2 PRAML

hypoglycem

ia Neutral Neutral Neutral Neutral Neutral Neutral

Neutr

al

Moderate/se

rious, mild

Moderate-

serious Neutral Neutral

Body weight

Decreased

body weight

a bit

Neutral Decreased Increased Neutral Neutral Neutr

al Increased Increased Decreased

Decrea

sed

Renal

function

Forbidden

to use in 3B,

4 and 5

stages

Can need to

adjust dosage as

necessary (apart

from Linagliptin)

Exenatide is

forbidden

when CrCl＜30

Can

aggravate

fluid

retention

Neutral Neutral Neutr

al

More risk

for

hypoglycem

ia

More risk

for

hypoglycem

ia and fluid

retention

Infection Neutral

Gastrointest

inal adverse

reaction

Moderate Neutral Moderate Neutral Modera

te Mild

Mode

rate Neutral Neutral Neutral

Modera

te

Congestive

heart failure Neutral Neutral Neutral Moderate Neutral Neutral

Neutr

al Neutral Neutral Neutral Neutral

CVD Obtain

benifits Neutral Neutral Neutral Neutral Neutral Safe ？ Neutral Neutral Neutral

Sclerotin Neutral Neutral Neutral

Moderate

osteoporo

sis

Neutral Neutral Neutr

al Neutral Neutral

？

骨质疏松

Neutral

Fewer adverse

reactions or benifits Use cautiously

Possible adverse

reactions

Only a short board

AGI has lower risk for hypoglycemia even can

reduce the hypo when combined with INS

123 T2DM were randomly received Gansulin 30R+voglibose 0.2mg tid(treatment group,n=60) or Gansulin 30R (control group,n=63) for 6 weeks. Measure the change of FPG、

2hPG、insulin doses and rate of hypo.

1. Basen presicriber information. 2. 朱易.医学理论与实践.2012;25(16):1992-93.

20

10

control treatment

8.36 %

30

13.16%

* p<0.05 vs. control

control

treatment

Rate

of

hyp

og

lyce

mic

a（

%）

Extremely lower

hypoglycemia risk（<0.1%）

when monotherapy1

May reducing the risk of

hypo when combination

especially with insulin2

Mechanism α-glycosidase inhibitors –

why GI side effects

*Compared with single α-amylase, starch can produce more oligosaccharides and maltose under the coaction

of α-amylase and α-glycosidase

#Small parts of starch can directly produce glucose under coaction of α-glycosidase

1.http://en.wikipedia.org/wiki/Acid_%CE%B1-glucosidase 2.http://en.wikipedia.org/wiki/Alpha-Amylase.

3.Dhital S, Lin AH, Hamaker BR, et al. PLoS One. 2013 Apr 25;8(4):e62546.

α-glycosidase#

Indicates glucose

Starch

α- amylase

Cooperate with α-glycosidase*

Maltose

Oligosaccharide

α-glycosidase

multiply

decomposed by

α-glycosidase

Gastrointestinal adverse reactions of AGI

results from its inhibition to amylase

H2O & CO2

Undecomposed

polysaccharide

Colon

Decomposed by

intestinal flora

High glucose Hyperosmosis

Voglibose has more stronger inhibition

and higher selection to α-glycosidase

小高裕之（武田薬品）.日本栄養・食糧学会誌(1992)45, 27

Half

in

hib

ito

ry c

on

ce

ntr

ati

on

*

(IC

50

) (m

mo

/L)

10-9

10-8

10-7

10-6

10-5

10-4

10-2

6.4×10-9

7.3×10-7

10-1

10-3

1.2×10-5

1.7×10-6

3.9×10-9

>4.5×10-2 Voglibose Acarbose

Maltase# Sucrase# α-amylase

*The smaller value of IC50 is, the more easily drugs are combined with enzymes,

the stronger inhibitory action is # Maltase and sucrase all are α-glycosidase

Maltase# Sucrase# α-amylase

Voglibose has much less GI side effects as compard to acarbose

1.来自倍欣®在日本申请上市时的研究报告 2.来自拜唐苹®在日本申请上市时的研究报告

voglibose acarbose

No. studied 965 603

Incidence of GI SE 15.96% 56.38%

Summary

• AACE Guideline for Comprehensive

management for Diabetes 2013: safely lower

glucose, comprehensive management

• AGI listed as alternative first-line medication by

AACE 2013, which can effectively lower BG

without hypoglycemia and weight gain.

Voglibose shows better tolerance.

Practical upates in Diabetes & CV risk management: Brief ... · Slides presented during CDMC in...

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