how to link glucose control to cv outcomes

藥師：陳翊齊

報告日期：103. 04. 18

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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®

CanagliflozinDapagliflozin

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 deathDiabetes 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

2,729Intensive

with sulfonylurea(glibenclamide or chlorpropramide)/insulin

1,138 (411 overweight)

Conventionalwith diet

342 (all overweight)

Intensivewith metformin

UKPDS 33

Trial end1997

P

5,102Newly-diagnosedtype 2 diabetes

744Diet failure

FPG >15 mmol/l

149Diet satisfactory

FPG <6 mmol/l

DietaryRun-in

4209

Randomisation1977-1991

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 relatedendpoint

Any DM relateddeath

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

Myocardialinfraction

Stroke Amputation ordeath from

PVD

Microvascularendpoint

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.

P<0.001

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%

End point HbA1c：6.9% vs 8.4%

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?eevtid=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

End point HbA1c：6.3% vs 6.5%

N Engl J Med 2012;367:319-28.

European Heart Journal doi:10.1093/eurheartj/eht332

Total mortality in ACCORD

Diabetes Care 33:983–990, 2010

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

0.10.20.30.40.50.60.70.80.9

1

Any DMrelated End

point

DM relateddeath

All-causemortality

MyocardialInfraction

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 DMrelated End

point

DM relateddeath

All-causemortality

MyocardialInfraction

End point (SU/Insulin)

0

0.5

1

1.5

2

2.5

Stroke Peripheral vasculardisease

Microvasculardisease

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.navDOI: 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 patientHR = 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.

Dr. Steven Nissen

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 MellitusA Meta-analysis of Randomized Trials

JAMA. 2007;298(10):1180-1188

Bladder Cancer of PioglitazoneNews of 103.04.08

Bladder Cancer of Pioglitazone

Diabetes Care 34:916–922, 2011

Bladder Cancer of Pioglitazone Retrospective cohort study (Case-control analysis)

115,727 new users of oral hypoglycaemic agents

BMJ 2012;344:e3645

Bladder Cancer of PioglitazoneStudy of Taiwanese 2006 - 2009

1,000,000 individuals were randomly sampled from the National Health Insurance database

Diabetes Care 35:278–280, 2012

Aleglitazar (PPAR α/γ Agonist)

Late Breaking Clinical Trials – ACC 2014Unpublished 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 ofDPP-4 inhibitor & GLP-1 agonistTrial 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 ofSGLT-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