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藥師:陳翊齊
報告日期:103. 04. 18
Why this Topic ??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
聲明本人無與任何廠商有關係
本人無領任何廠商的演講費
本人無購買任何廠商的股票
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®
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