How to link glucose control to cv outcomes

藥師：陳翊齊
報告日期：103. 04. 18

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糖尿病共照網納入藥師
小弟熟悉的領域
流行病學
藥物流行病學

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MOS早餐是由本人自掏腰包購買
逐片吐司審查，絕無下毒，安心食用
藥師陳翊齊

Outline
 CV risk of DM patient
 Glucose - Intensive control vs Conventional control
 Hypoglycemia
 Different drugs, different outcomes
 Expect to Future

糖尿病藥物發展
 1980 年代以前
 SulfonylUrea
 Insulin (NPH & RI)
 1990 年代
 Metformin
 α-glucosidase inhibitor
 Meglitinide
 2000 年代至今
 PPAR-γ agonist
 新型胰島素
 DPP-4 inhibitor
 GLP-1 agonist
 SGLT-2 antagonist
Exubera®
Afrezza®
Bydureon®
Tanzeum®
Canagliflozin
Dapagliflozin

Mortality and Causes of Death in a National
Sample of Diabetic Patients in Taiwan
Diabetes Care 27:1605–1609, 2004
28.8% + 9.0% + 10.5% +0.3% = 48.6%

Diabetes Care 23:1103–1107, 2000
49.4% Cardiovasucular death
49.1% Cardiovasucular death
Diabetes Care July 1998 vol. 21 no. 7 1138-1145

7-year incidence rates of MI
(fatal and nonfatal)
0
5
10
15
20
25
30
35
40
45
50
no DM, no prior MI no DM, prior MI DM, no prior MI DM, prior MI
N Engl J Med 1998;339:229-34.)
3.5%
18.8% 20.2%
45%
P<0.001 P<0.001

UK Prospective Diabetes Study
 Multicenter RCT
 1977 to 1997
 5,102 patients with newly-diagnosed type 2 diabetes
recruited between 1977 and 1991

UKPDS Study design
Intensive
Conventional
Intensive
2,729
Intensive
with
sulfonylurea(glibenclamide
or chlorpropramide)/insulin
1,138 (411 overweight)
Conventional
with diet
342 (all overweight)
Intensive
with metformin
UKPDS 33
Trial end
1997
P
5,102
Newly-diagnosed
type 2 diabetes
744
Diet failure
FPG >15 mmol/l
149
Diet satisfactory
FPG <6 mmol/l
Dietary
Run-in
4209
Randomisation
1977-1991
UKPDS 34
N Eng J Med 2008; 359

Association of glycemia with macrovascular and
microvascular complications of type 2 diabetes
(UKPDS 35)
 Prospective observational study
 3642 patients
BMJ 2000;321:405–12

UKPDS 33
 Multicenter RCT
 3867 newly diagnosed type 2 DM
 Intensive (SU/insulin) vs conventional
 Follow 10 years
 HbA1c 7.0% vs 7.9%
0
0.2
0.4
0.6
0.8
1
1.2
DM related
endpoint
Any DM related
death
All cause mortality
End point
RR=0.88(0.79-0.99)
P=0.029
0
0.2
0.4
0.6
0.8
1
1.2
1.4
1.6
Myocardial
infraction
Stroke Amputation or
death from
PVD
Microvascular
endpoint
End point
RR=0.84(0.71-1.00)
P=0.052 RR=0.75(0.60-0.93)
P=0.0099
Lancet 1998; 352: 837–53

UKPDS 80
 10-year Post-Trial Monitoring from 1997 to 2007
 Annual follow-up of the survivor cohort
 Clinic-based for first five years
 Questionnaire-based for last five years
 Median overall follow-up 17 (16 to 30) years
Intensive (SU/Ins) vs. Conventional glucose control
N Engl J Med 2008;359:1577-89.

ACCORD study
 Action to Control CardiOvascular Risk in Diabetes study
 10,251 type 2 DM patients (Mean history 10 years)
 Primary outcome：CVD event
 Baseline HbA1c 8.3% (Mean)
 End of the trial HbA1c：6.4% vs 7.5%
N Engl J Med 2008;358:2545-59.

ACCORD study
N Engl J Med 2008;358:2545-59.

ADVANCE study
 Action in Diabetes and Vascular Disease: Preterax
and Diamicron Modified Release Controlled
Evaluation
 11,140 type 2 DM patients (Mean history 8 years)
 5 years of follow-up
 Primary outcome：Macro and Microvascular event
 Baseline HbA1c：7.5%
 End point HbA1c：6.5% vs 7.3%
N Engl J Med 2008;358:2560-72.

ADVANCE study
N Engl J Med 2008;358:2560-72.

VADT study
 investigators in the Veterans Affairs Diabetes Trial
 1791 military veterans (type 2 DM history:11.5 years)
 5.6 years follow-up
 Primary outcome：CVD event
 Baseline HbA1c：9.4%

META-ANALYSIS
 UKPDS
 ACCORD
 ADVANCE
 VADT
Diabetologia (2009) 52:2288–2298

Intensive Glucose Control
 Lowering Macrovascular outcomes
 Longer follow up
 Early intervention (Legacy effect)
 Meta - Analysis
 Lowering Microvascular outcomes
 QOL improve
 Early intervention

Revisiting the links between
glycaemia, diabetes and cardiovascular
disease
Diabetologia (2013) 56:686–695

Emergency Hospitalization for Adverse
Drug Events in Older Americans
N Engl J Med 2011;365:2002-12.

Association of Clinical Symptomatic
Hypoglycemia With Cardiovascular Events and
Total Mortality in Type 2 Diabetes
Diabetes Care 36:894–900, 2013
 Taiwan Data base (10 years)
 PAI-FENG HSU MD

Hypoglycemia
 ADVANCE group
 Severe Hypoglycemia and Risks of Vascular Events
and Death
N Engl J Med 2010;363:1410-8.
BMJ 2010;340:b4909

Hypoglycemia – a major predictor
of cardiovascular death in VADT
http://spo.escardio.org/eslides/view.aspx?ee
vtid=48&fp=3914

Hypoglycemia & Arrhythmia
Diabetes Care Volume 37, January 2014

Hypoglycemia
 ORIGIN study
 12537 IFG, IGT, Type 2 DM patients
 Insulin Glargine vs. Standard care
 Follow 6.2 years
N Engl J Med 2012;367:319-28.
European Heart Journal doi:10.1093/eurheartj/eht332

Total mortality in ACCORD

UKPDS 34 (Metformin)
 Multicenter RCT
 753 Overweight type 2 DM patients (New diagnosed )
 Intensive (Metformin) vs. Conventional
 Follow 10 years
 End point HbA1c： 7.4% vs 8.0%
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
Any DM
related End
point
DM related
death
All-cause
mortality
Myocardial
Infraction
End point (Metformin)
HR = 0.68 (0.53-0.87)
HR = 0.58 (0.37-0.91)
HR = 0.64 (0.45-0.91)
HR = 0.61 (0.41-0.89)
HR = 0.58 (0.37-0.91)
HR = 0.64 (0.45-0.91)
HR = 0.61 (0.41-0.89)
0
0.2
0.4
0.6
0.8
1
1.2
1.4
Any DM
related End
point
DM related
death
All-cause
mortality
Myocardial
Infraction
End point (SU/Insulin)
0
0.5
1
1.5
2
2.5
Stroke Peripheral vascular
disease
Microvascular
disease
End point (Metformin)
Lancet 1998; 352: 854–65

Metformin 使用限制
 GI upset (20-30%)
 Chronic Heart Failure
 Creatinine > 1.5 mg/dL in males & >1.4mg/dL in
females
 Radiologic Contrast study for 48 hr after

Metformin treatment is associated with a low
risk of mortality in diabetic patients with heart
failure: a retrospective nationwide cohort study
 10,920 hospitalised for first time HF with DM
 Observational time：2.5 years
Diabetologia (2010) 53:2546–2553

Creatinine ??
 Metformin Maxium dose：3000 mg
 eGFR > 30 mL/min per 1.73 m2
 Metformin
 eGFR > 60：Safe
 eGFR 60-45：Increase Creatinine monitor frequence
 eGFR 45-30：Half dose initially
 eGFR < 30：Stop Metformin
Diabetes Care 2011; 34: 1431-7.
• ADA
• EASD
• NICE
• Diabetes Australia
• CDA
• JDS • NKF KDOQI

Sulfonylurea
 Association of sulfonylurea treatment with all-cause and
cardiovascular mortality：A systematic review and
meta-analysis of observational studies
 20 studies (n = 551,912 patients)
 SU vs non-SU
Sagepub.co.uk/journalsPermissions.nav
DOI: 10.1177/1479164112465442

Sulfonylurea
 Retrospective nationwide cohort study
 Danmark
 1997-2006
 9876 users of GLDs admitted with MI
Cardiovascular Diabetology 2010, 9:54

European Heart Journal (2011) 32, 1900–1908

Data From the CPRD
 New analysis reported at the EASD meeting,
 UK Clinical Practice Research Datalink (CPRD)
 More than 10 million patients
 SU vs Metformin (Monotherapy)
European Association for the Study of
Diabetes. Abstracts 200 and 201, presented
Thursday, September 26, 2013.
All-cause mortality 1000 person-years
Metformin 13.6 death
Sulfonylurea 44.6 death

Sulfonylurea receptor
 Sulfonylurea Receptor-1
 Sulfonylurea Receptor-2A
J Am Coll Cardiol. 1998;31(5)950-956

Acarbose
 STOP-NIDDM
 Acarbose vs. Placebo
 IGT patient
HR = 0.51(0.28-0.95) p=0.03
JAMA 2003; 290:486-494

Alpha-glucosidase inhibitors for
type 2 diabetes mellitus
 It remains unclear whether alpha-glucosidase inhibitors
influence mortality or morbidity in patients with type 2
diabetes.
 Conversely, they have a significant effect on glycemic
control and insulin levels.
DOI: 10.1002/14651858.CD003639.pub2

Ace study
 Multicentre, RCT
 China & Hong Kong
 7500 patients with CVD or IGT
 Hu Dayi (Cardiology)
 Pan Changyu (Endocrine)

Thiazolidinedione
 IGT Prevent to T2DM
 Mono-therapy failure in T2DM
 Pioglitazone
 Rosiglitazone：DREAM, ADOPT, RECORD
 Pioglitazone：PROACTIVE

Rosiglitazone (DREAM)
 The DREAM (Diabetes REduction Assessment with ramipril
and rosiglitazone Medication) Trial
 Prevent IGT progress to Type 2 DM
 5269 IFT or IGT patient
HR = 0.40 (0.35-0.46)
Increase BW = +2.2 kg (p<0.0001)
The Lancet 2006 DOI:10.1016/S0140-6736(06)69420-8

Rosiglitazone (ADOPT)
 4360 patients Newly type 2 DM
 Rosiglitazone, Metformin, Glyburide
Edema：14.1% vs 7.2% vs 8.5%
N Engl J Med 2006;355:2427-43.

Meta-Analysis of Rosiglitazone
N Engl J Med 2007;356:2457-71.

JAMA. 2007;298(10):1189-1195
Meta-Analysis of Rosiglitazone

RECORD study
N Engl J Med 2007;357:28-38.

Pioglitazone (PROACTIVE)
 PROspective pioglitAzone Clinical Trial In macroVascular
Events
 5238 patients with type 2 diabetes
 primary endpoint was the composite of all-cause
mortality, non-fatal myocardial infarction (including
silent myocardial infarction), stroke, acute coronary
syndrome, endovascular or surgical intervention in the
coronary or leg arteries, and amputation above the
ankle.
Lancet 2005; 366: 1279–89

Pioglitazone and Risk of Cardiovascular Events in
Patients With Type 2 Diabetes Mellitus
A Meta-analysis of Randomized Trials
JAMA. 2007;298(10):1180-1188

Bladder Cancer of Pioglitazone
News of 103.04.08

 Retrospective cohort study (Case-control analysis)
 115,727 new users of oral hypoglycaemic agents
BMJ 2012;344:e3645

Study of Taiwanese
 2006 - 2009
 1,000,000 individuals were randomly sampled from the
National Health Insurance database

Aleglitazar (PPAR α/γ Agonist)
Late Breaking Clinical Trials – ACC 2014
Unpublished DATA

SAVOR TIMI-53
N Engl J Med 2013;369:1317-26.

EXAMINE
N Engl J Med 2013;369:1327-35.
Sattar N, Results from SAVOR and EXAMINE.
DPP-4 inhibitors and CVD, EASD 2013 Sep 26

Why we failure in DPP-4 inhibitor??
N Engl J Med 2013;369:1317-26.
N Engl J Med 2013;369:1327-35.

CV outcome trials of
DPP-4 inhibitor & GLP-1 agonist
Trial Name Drug Number of patients Publish date
SAVOR Saxagliptin 16500 Online 2013/09
EXAMINE Alogliptin 5400 Online 2013/09
TECOS Sitagliptin 14500 2014
CAROLINA Linagliptin (vs SU) 6000 2018
EXSCEL Exenatide QW 9500 2018
LEADER Liraglutide 8754 2017

CV outcome trials of
SGLT-2 inhibitor
Trial Name Drug Number of patients Publish date
CANVAS Canagliflozin Ongoing
DECLARE
TIMI 58
Dapagliflozin Ongoing

Summary
 Half of T2DM patient died from Cardiovascular Events
 DM patient’s MI risk was equal to post-MI patient
 UKPDS 35 shows that HbA1c was a risk marker in T2DM
 Intensive glucose control
 Lowering Macrovascular outcomes
 Longer follow up & Meta – Analysis
 Lowering Microvascular outcomes
 Early intervention
 Risk maker relationship：BP > LDL > HbA1c

Summary
 Hypoglycemia was main reason of emergency
Hospitalizated Adverse Drug event
 Hypoglycemia link to poor CV outcomes in cohort
studies, arrhythmia may be a main concern
 Metformin is still First line choice of T2DM
 eGFR may be better to limit Metformin use
 Sulfonylurea increased risk of CV mortality & All-cause
mortality (not included Gliclazide )
 Acarbose remains unclear in T2DM, but could reduce CV
risk in IGT or IFG patients

Summary
 TZD may prevented that IGT or IFG progress to T2DM,
but increased HF risk
 Rosiglitazone increased MI risk in Meta-analysis, but
Pioglitazone didn’t
 Bladder cancer may be a concern of Pioglitazone, but
didn’t show in TW data
 DPP-4 inhibitor was safe in CV outcomes, but not in HF
hospitalization
 Expect GLP-1 Agnoist & SGLT-2 Inhibitor

How to link glucose control to cv outcomes

How to link glucose control to cv outcomes

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