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

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

•