What can new glucose lowering add to cardiovascular risk … · 2018. 4. 6. · total CV MI Stroke Non-Diabetes Diabetes Mortality rate in diabetes ar ... LDL cholesterol, mg/dL 84.9
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What can new glucose lowering add to
cardiovascular risk management in
diabetes?
28,6
12,9
63,8
0,9
15,4
12,3
1,2
0
5
10
15
20
25
30
35
total CV MI Stroke
Non-Diabetes
Diabetes
Mortality rate in diabetes
10
00
pe
rso
ns
/ ye
ar
Multiple Risk Factor Intervention Trial. Diabetes Care, 1993
Retinopathy: 76% reduction Microalbuminuria*: 34% reduction
00
60
40
20
2 4 6 8 10
Conventional
Intensive
Pati
en
ts (
%)
Pati
en
ts (
%)
00
30
20
10
2 4 6 8 10
Years
*urinary albumin excretion ≥40 mg per 24 hours
Estudio STENO –2
La intervención multifactorial reduce el riesgo cardiovascular y los
eventos microvasculares en 50%
HbA1c colesterol
TA sistólica
TA diastólica
LDL-col
trigliceridos
Muerte cardiovascular
nefropatia
retinopatia
neuropatia
New Engl J Med 2003
Fluctuations and postprandial
Excessive Glucose FluctuationsWith Same A1C Values
24-h CGMS glucose sensor data in 9 subjects with type 1 diabetes
Type 1 diabetes (N = 9)
CGMS = Continuous Glucose Monitoring System
100
200
300
400
12:00 AM 4:00 AM 8:00 AM 12:00 PM 4:00 PM 8:00 PM 12:00 AM
Glu
co
se
Co
nc
en
tra
tio
n
(mg
/dL
)
0
Mean A1C = 6.7%
Postprandial spikes and glucose ‘swings’ linked to oxidative stress generation
NSFree fatty acids
NSTriglycerides
NSLDL-C
NSHDL-C
NSTotal Cholesterol
= 0.009AUCpp (area under curve attributable to PPG)
<0.001MAGE (mean amplitude of glycaemic excursions)
NSFasting plasma insulin level
NSHbA1C
NSMean glucose level
NSFPG (fasting glucose plasma)
Multiple regression analysis (P value)Factor
Monnier et al. JAMA 2006; 295:1681–1687
Cu
mu
lative
in
cid
en
ce
(%
)
0 4321 5
Years after randomisation
Acarbose
Placebo
5
4
3
2
1
0
Log rank p=0.04
Chiasson, J.-L. et al. JAMA 290: 486-494, 2003
Incidence of CV events
Risk red. (%) pAc
(n=682)Pl
(n=686)
No. of patients Favoursacarbose
Favoursplacebo
0 0.5 1.5 2.0
Coronary heart disease
myocardial infarction 1 12 91angina 5 12 55
revasc. procedure 11 20 39
cardiovascular death 1 2 45
Congestive heart failure 0 2 —
Cerebrovascular event or
stroke 2 4 44
Peripheral vascular 1 1 —
disease
Any CV event 15 32 49
0.020.13
0.18
0.63
—
0.51
0.93
0.03
1.0
Chiasson JL et al. JAMA 2003;290:486–94.
Time to develop first CV event
Hypoglycemia
VADT (2009) N Engl J Med 360:129
Predictor HR P-value
Hypoglycemia 4.04 0.01
HbA1c 1.21 0.02
HDL 0.69 0.02
Age 2.09 <0.01
Previous event 3.12 <0.01
VADT: Severe Hypoglycemia is a Major Predictor of Cardiovascular Death
Hypoglycemia is more likely than Hyperglycemia to be associated with Cardiac Ischaemia
54
59
10
1
6
00
10
20
30
40
50
60
70
Hypoglycaemia Hyperglycaemia
Total episodes
Episodes with angina
ECG abnormalities detected
Desouza et al (2003) Diabetes Care 26:1485
Num
ber
of epis
odes
21 patients with type 2 diabetes and coronary heart disease were studied using simultaneous CGMS (for 72 hours) and cardiac ECG (Holter) monitoring
“The Metabolic Memory”Evidence for a long-term persistence of
hyperglycemia-induced damage
N Engl J Med, 2005
DCC/EDIC Research Group
Early HbA1c control including insulin treatment is key in preventing
microvasculardisease and long term macrovascular complications.
-
No treatment
Early HbA1c control including insulin treatment is key in preventing
microvasculardisease and long term macrovascular complications.
No treatment
Early HbA1c control including insulin treatment is key in preventingmicrovascular disease and long term macrovascular complications
No treatment
Holman R,R. et al, UKPDS 35 10 year follow up. NEJM 2008
10-Year follow-up of intensive glucose control in type 2 diabetes
“good glucose control should be started as early as possible to delay or prevent
serious diabetes-related complications”
The take-home message is that
said Alan D. Cherrington, PhD, president, American Diabetes Association.ADA S. Diego 2005
New drugs, new results, newquestions
The kidneys may offer an insulin-independent pathway for glucose removal
Kidneys
Blood glucose
Nutrition
Hepatic production
Fat and Muscle
Liver
Lessglucose uptake
Glucosuria
Glucose Imput
EMPA-REG Trial
18
Randomised and treated
(n=7020)Empagliflozin 10 mg
(n=2345)
Empagliflozin 25 mg (n=2342)
Placebo (n=2333)
Screening(n=11531)
Key inclusion and exclusion criteria
• Key inclusion criteria– Adults with type 2 diabetes
– BMI ≤45 kg/m2
– HbA1c 7–10%*
– Established cardiovascular disease
• Prior myocardial infarction, coronary artery disease, stroke, unstable angina or occlusive peripheral arterial disease
• Key exclusion criteria– eGFR <30 mL/min/1.73m2 (MDRD)
BMI, body mass index; eGFR, estimated glomerular filtration rate; MDRD, Modification of Diet in Renal Disease*No glucose-lowering therapy for ≥12 weeks prior to randomisation or no change in dose for ≥12 weeks prior
to randomisation or, in the case of insulin, unchanged by >10% compared to the dose at randomisation
Pre-specified primary and key secondary outcomes
• Primary outcome– 3-point MACE: Time to first occurrence of CV death, non-fatal MI or
non-fatal stroke
• Key secondary outcome– 4-point MACE: Time to first occurrence of CV death, non-fatal MI, non-
fatal stroke or hospitalisation for unstable angina
21CV, cardiovascular; MI, myocardial infarction; MACE, Major Adverse
Cardiovascular Event
Glucose-lowering medication
Metformin 1734 (74.3) 1729 (73.7) 1730 (73.9)
Sulphonylurea 992 (42.5) 985 (42.0) 1029 (43.9)
Thiazolidinedione 101 (4.3) 96 (4.1) 102 (4.4)
Insulin 1135 (48.6) 1132 (48.3) 1120 (47.8)
Placebo (n=2333)
Empagliflozin10 mg
(n=2345)
Empagliflozin25 mg
(n=2342)
HbA1c, % 8.08 (0.84) 8.07 (0.86) 8.06 (0.84)
Time since diagnosis of type 2 diabetes, years
≤5 423 (18.1) 406 (17.3) 434 (18.6)
>5 to 10 571 (24.5) 585 (24.9) 590 (25.2)
>10 1339 (57.4) 1354 (57.7) 1318 (56.3)
Baseline characteristics: type 2 diabetes
Systolic blood pressure, mmHg 135.8 (17.2) 134.9 (16.8) 135.6 (17.0)
Diastolic blood pressure, mmHg 76.8 (10.1) 76.6 (9.8) 76.6 (9.7)
Heart rate, bpm* 70.7 (0.2) 71.0 (0.2) 70.5 (0.2)
LDL cholesterol, mg/dL 84.9 (35.3) 86.3 (36.7) 85.5 (35.2)
HDL cholesterol, mg/dL 44.0 (11.3) 44.7 (12.0) 44.5 (11.8)
eGFR, mL/min/1.73m2 (MDRD) 73.8 (21.1) 74.3 (21.8) 74.0 (21.4)
≥90 mL/min/1.73m2 488 (20.9%) 519 (22.1%) 531 (22.7%)
60 to <90 mL/min/1.73m2 1238 (53.1%) 1221 (52.1%) 1204 (51.4%)
<60 mL/min/1.73m2 607 (26.0%) 605 (25.8%) 607 (25.9%)
Placebo (n=2333)
Empagliflozin10 mg
(n=2345)
Empagliflozin 25 mg
(n=2342)
Body mass index, kg/m2 30.7 (5.2) 30.6 (5.2) 30.6 (5.3)
Weight, kg 86.6 (19.1) 85.9 (18.8) 86.5 (19.0)
Waist circumference, cm 105.0 (14.0) 104.7 (13.7) 104.8 (13.7)
Baseline characteristics: CV risk factors
Baseline characteristics: CV complications
Placebo (n=2333)
Empagliflozin10 mg
(n=2345)
Empagliflozin 25 mg
(n=2342)
Any CV risk factor 2307 (98.9%) 2333 (99.5%) 2324 (99.2%)
Coronary artery disease 1763 (75.6%) 1782 (76.0%) 1763 (75.3%)
Multi-vessel coronary artery disease
1100 (47.1%) 1078 (46.0%) 1101 (47.0%)
History of MI 1083 (46.4%) 1107 (47.2%) 1083 (46.2%)
Coronary artery bypass graft 563 (24.1%) 594 (25.3%) 581 (24.8%)
History of stroke 553 (23.7%) 535 (22.8%) 549 (23.4%)
Peripheral artery disease 479 (20.5%) 465 (19.8%) 517 (22.1%)
Single vessel coronary artery disease
238 (10.2%) 258 (11.0%) 240 (10.2%)
Cardiac failure* 244 (10.5%) 240 (10.2%) 222 (9.5%)
Data are n (%) in patients treated with ≥1 dose of study drug.
Baseline characteristics: CV medication (1)
Placebo (n=2333)
Empagliflozin10 mg
(n=2345)
Empagliflozin 25 mg
(n=2342)
Anti-hypertensive therapy 2221 (95.2%) 2227 (95.0%) 2219 (94.7%)
ACE inhibitors/ARBs 1868 (80.1%) 1896 (80.9%) 1902 (81.2%)
Beta-blockers 1498 (64.2%) 1530 (65.2%) 1526 (65.2%)
Diuretics 988 (42.3%) 1036 (44.2%) 1011 (43.2%)
Calcium channel blockers 788 (33.8%) 781 (33.3%) 748 (31.9%)
Mineralocorticoid receptorantagonists
136 (5.8%) 157 (6.7%) 148 (6.3%)
Renin inhibitors 19 (0.8%) 16 (0.7%) 11 (0.5%)
Other 191 (8.2%) 193 (8.2%) 190 (8.1%)
ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blockers
Baseline characteristics: CV medication (2)
Placebo (n=2333)
Empagliflozin10 mg
(n=2345)
Empagliflozin 25 mg
(n=2342)
Lipid-lowering drugs 1864 (79.9%) 1926 (82.1%) 1894 (80.9%)
Statins 1773 (76.0%) 1827 (77.9%) 1803 (77.0%)
Fibrates 199 (8.5%) 214 (9.1%) 217 (9.3%)
Ezetimibe 81 (3.5%) 95 (4.1%) 94 (4.0%)
Niacin 35 (1.5%) 56 (2.4%) 35 (1.5%)
Other 175 (7.5%) 172 (7.3%) 193 (8.2%)
Anti-coagulants and anti-platelets 2090 (89.6%) 2098 (89.5%) 2064 (88.1%)
Acetylsalicylic acid 1927 (82.6%) 1939 (82.7%) 1937 (82.7%)
Clopidogrel 249 (10.7%) 253 (10.8%) 241 (10.3%)
Vitamin K antagonists 156 (6.7%) 141 (6.0%) 125 (5.3%)
HbA1c
6,0
6,5
7,0
7,5
8,0
8,5
9,0
Ad
just
ed m
ean
(SE
) H
bA
1c
(%)
Week
Placebo
Empagliflozin 10 mg
Empagliflozin 25 mg
2294
2296
2296
Placebo
Empagliflozin 10 mg
Empagliflozin 25 mg
2272
2272
2280
2188
2218
2212
2133
2150
2152
2113
2155
2150
2063
2108
2115
2008
2072
2080
1967
2058
2044
1741
1805
1842
1456
1520
1540
1241
1297
1327
1109
1164
1190
962
1006
1043
705
749
795
420
488
498
151
170
195
12 28 52 94 10880 12266 1360 150 164 178 192 20640
Weight
80
82
84
86
88
90
Ad
just
ed m
ean
(SE
) w
eigh
t (k
g)
Week
2285
2290
2283
Placebo
Empagliflozin 10 mg
Empagliflozin 25 mg
1915
1893
1891
2215
2238
2226
2138
2174
2178
1598
1673
1678
1239
1298
1335
425
483
489
Placebo
Empagliflozin 10 mg
Empagliflozin 25 mg
28 52 1080 164 22012
Systolic blood pressure
125
127
129
131
133
135
137
139
141
143
145
Ad
just
ed m
ean
(SE
) sy
sto
lic
blo
od
pre
ssu
re (
mm
Hg)
Week
2322
2322
2323
Placebo
Empagliflozin 10 mg
Empagliflozin 25 mg
2235
2250
2247
2203
2235
2221
2161
2193
2197
2133
2174
2169
2073
2125
2129
2024
2095
2102
1974
2072
2066
1771
1853
1878
1492
1556
1571
1274
1327
1351
1126
1189
1212
981
1034
1070
735
790
842
450
518
528
171
199
216
Placebo
Empagliflozin 10 mg
Empagliflozin 25 mg
16 28 52 94 10880 12266 1360 150 164 178 192 20640
Heart rate (ECG)
65
66
67
68
69
70
71
72
73
74
75
Ad
just
ed m
ean
(SE
) h
eart
rat
e (b
pm
)
Week
2174
2205
2192
Placebo
Empagliflozin 10 mg
Empagliflozin 25 mg
2127
2137
2127
2032
2064
2066
1928
2006
2006
1796
1877
1907
1300
1366
1383
1002
1045
1086
552
597
633
PlaceboEmpagliflozin 10 mg
Empagliflozin 25 mg
28 52 10880 1360 164 192
Cardiovascular outcomes
Primary outcome:3-point MACE
32
HR 0.86(95.02% CI 0.74, 0.99)
p=0.0382*
Cumulative incidence function. MACE, Major Adverse Cardiovascular Event; HR, hazard ratio. * Two-sided tests for superiority were conducted (statistical significance was indicated if p≤0.0498)
3-point MACE
Empagliflozin 10 mgHR 0.85
(95% CI 0.72, 1.01)p=0.0668
Empagliflozin 25 mgHR 0.86
(95% CI 0.73, 1.02)p=0.0865
Cumulative incidence function. MACE, Major Adverse Cardiovascular Event; HR,
hazard ratio
Patients with event/analysedEmpagliflozin Placebo HR (95% CI) p-value
3-point MACE 490/4687 282/2333 0.86 (0.74, 0.99)* 0.0382
CV death 172/4687 137/2333 0.62 (0.49, 0.77) <0.0001
Non-fatal MI 213/4687 121/2333 0.87 (0.70, 1.09) 0.2189
Non-fatal stroke 150/4687 60/2333 1.24 (0.92, 1.67) 0.1638
4-point MACE 599/4687 333/2333 0.89 (0.78, 1.01)* 0.0795
0,25 0,50 1,00 2,00
3-point MACE and 4-point MACE
Favours empagliflozin Favours placebo
Cox regression analysis. MACE, Major Adverse Cardiovascular Event; HR, hazard ratio; CV, cardiovascular; MI, myocardial infarction
*95.02% CI
CV death
HR 0.62(95% CI 0.49, 0.77)
p<0.0001
Cumulative incidence function. HR, hazard ratio
Hospitalisation for heart failure
HR 0.65(95% CI 0.50, 0.85)
p=0.0017
Cumulative incidence function. HR, hazard ratio
All-cause mortality
HR 0.68(95% CI 0.57, 0.82)
p<0.0001
Kaplan-Meier estimate. HR, hazard ratio
0,25 0,50 1,00 2,00
Patients with event/analysed
Empagliflozin Placebo HR 95% CI p-value
All-cause mortality 269/4687 194/2333 0.68 (0.57, 0.82) <0.0001
CV death 172/4687 137/2333 0.62 (0.49, 0.77) <0.0001
Non-CV death 97/4687 57/2333 0.84 (0.60, 1.16) 0.2852
All-cause mortality, CV death and non-CV death
Favours empagliflozin Favours placebo
Cox regression analysis. CV, cardiovascular; HR, hazard ratio
CANVAS trial
Take Home message
• Empaglifozin and canaglifozin reduced risk for 3 point MACE.
• Empaglifozin reduce CV death.
• Empaglifozin improve survival by reducing all-cause mortality
• Gràcies per la vostra atenció.
• Ramon Gomis
•
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