Novedades farmacológicas en riesgo cardiovascular

Novedades en Farmacología Riesgo CV 2010 1

1

José R. González Juanatey

Área Cardiovascular. Hospital Clínico Universitario de Santiago de Compostela J.R.G. JUANATEY C.H.U.Santiago

Farmacología CV- 2010 Riesgo CV Global Hipertensión Arterial Dislipemia Diabetes

J.R.G. JUANATEY C.H.U.Santiago

Blood Pressure, Blood Glucose and Heart Rate in AF and Cardiac Disease.

The “J” curve LBP HBP

LBG LHR

•

1

Myocardial Isch Renal failure Hypoperfusion etc J.R.G. JUANATEY C.H.U.Santiago

HBG HHR

mmHg, mg/dL, bpm

Atherosclerosis Vessel rupture Renal failure Cardiac failure Myocardial Isch

Farmacología CV- 2010 Riesgo CV Global Hipertensión Arterial Dislipemia Diabetes

J.R.G. JUANATEY C.H.U.Santiago

Incidence and Unadjusted CV Risk of Events in Deciles of In-treatment SBP Stroke 2

1

0

0 112

121

126

130

133

136

140

144

149

On-treatment SBP (mmHg)

J.R.G. JUANATEY C.H.U.Santiago

160

6

4 5 2

0

112

121

126

130

133

136

140

144

149

160

HR (95% CI)

5

10

Unadjusted risk of events (%)

10

HR (95% CI)

Unadjusted risk of events (%)

Myocardial infarction

0

On-treatment SBP (mmHg)

Sleight, et al., J Hypert 2009; 27: 1360-1369

ROADMAP. Lowest SBP and/or highest SBP reduction quartile are associated with increased CV mortality in CHD patients. The “J” curve effect again Last SBP before event

SBP reduction

1.6

2.5 1.0 1.0

mmHg <122.3 J.R.G. JUANATEY C.H.U.Santiago

122.3126.4

126.4132.2

>132.2

mmHg

<17.3

17.38.1

8.0<0.2

Cohort of patients with pre-existing CHD (1104)

>0.2

Objetivo del tratamiento antihipertensivo Población general hipertensa

) 9 0

H S PA < 140/90 mmHg (E g H m Pacientes diabéticos o de alto/muy alto riesgo m 5 8 PA < 130/80 mmHg 0 8 / 9 3 Pacientes con IR y proteinuria > 1g/24h 1 0 3 1 PA < 125/75 mmHg J.R.G. JUANATEY C.H.U.Santiago

ESH/ESC Guidelines. Rev Esp Cardiol 2007; 60: 968.e1-e94

Reduction in Mortality with Anti-hypertensive Agents: evidence from clinical trials in at-risk hypertensive patients 1

Concomitant pathology (% of patients) HR=0.97 >50% DM/RI 0.91 (0.83-1.00) 0.05 (95% CI: 0.94-1.00; p=0.031) <50% DM/RI 0.97 (0.94-1.01) 0.108 >45% of CVD/CAD 1.01 (0.97-1.05) 0.641 0.89 (0.81-0.99) ASCOT p=0.025 <45% of CVD/CAD 0.93 (0.89-0.97) 0.001 HYVET ASCOT: 19275 Hypertensives (amlodipine/perindopril) HYVET: 3845 Old Hypertensives (indapamide/perindopril) ADVANCE: 11140 Diabetics (perindopril/indapamide)

21 clinical trials (194.621 patients): all-cause mortality reduction

J.R.G. JUANATEY C.H.U.Santiago

0.79 (0.65-0.95) P=0.02

ADVANCE

0.86 (0.75-0.98) p=0.025)

TOTAL

0.87 (0.81-0.94) p<0.001

Active Better

Control Better

Devices in Hypertension. BP changes with renal

sympathetic denervation in patients with refractory HT

J.R.G. JUANATEY C.H.U.Santiago

Devices in Hypertension. BP changes with renal sympathetic denervation in patients with refractory HT SBP 1 Month Change in BP (mmHg)

J.R.G. JUANATEY C.H.U.Santiago

DBP 3 Months 6 Months 9 Months 12 Months

Devices in Hypertension.

J.R.G. JUANATEY C.H.U.Santiago

Devices in Hypertension. The implantable system for HT (baroreflex activation therapy)

J.R.G. JUANATEY C.H.U.Santiago

Devices in Hypertension.

The implantable system for HT (baroreflex activation therapy) Systolic

Diastolic

Baseline=192 mmHg

Baseline=108 mmHg

Change in mmHg

gr/m2

-21

-35 -37

-18

-21

132

116

108

Baseline 3 m

6m

12 months

-38

24 months 36 months

J.R.G. JUANATEY C.H.U.Santiago

LVH Regression

Farmacología CV- 2010 Riesgo CV Global Hipertensión Arterial Dislipemia Diabetes

J.R.G. JUANATEY C.H.U.Santiago

Estabilización vs Regresión de la Ateroesclerosis Coronaria

JAPAN-ACS: IVUS results LDL-C

Pitavastatin 130.9+33.3 Atorvastatin 133.8+31.4

81.1+23.4 84.1+27.4

Change from baseline (%) Hiro T, et al. J Am Coll Cardiol 2009;5 : 293-302 J.R.G. JUANATEY C.H.U.Santiago

Estabilización vs Regresión de la Ateroesclerosis Coronaria Pitavastatina vs Atorvastatina Mean (95% CI) : 1.11 (-2.27 – 4.48)

Pitavastatin better J.R.G. JUANATEY C.H.U.Santiago

Atorvastatin better Hiro T, et al. JACC 2009; 54: 293-302

Apo A-1 Basal: 108.4+18

*p<0.01

HDL-C (mg/dL)

12 Months: 115.7+17.7*

<0.01

<0.001 40.5+9.1

36+5.9

12 Months J.R.G. JUANATEY C.H.U.Santiago

Int J Cardiol 2008; 130: 320-322

Nanoparticle-mediated endothelial cellselective delivery of pitavastatin induces functional collateral arteries (therapeutic angiogenesis)

Pitavastatin

Pitavastatin

Pravastatin

J.R.G. JUANATEY C.H.U.Santiago

Atorvastatin

Fluvastatin

Rosuvastatin

Simvastatin

J Vasc Surg 2010; 52: 412-420

Pitavastatin NT

Pitavastatin NT

Future studies: Randomized Evaluation of Aggressive or moderate Lipid lowering therapy with pitavastatin in NIH ClinicalTrials.gov : NCT01042730

Coronary Artery Disease (REAL-CAD)

Study Objective

To evaluate the prevention of cardiovascular disease by moderate cholesterol lowering therapy or aggressive cholesterol lowering therapy 4mg/day in patients with stable coronary artery disease.

Study Patients

Stable coronary artery disease

Primary Endpoint

Composite outcome consisting of; Cardiovascular death, Non-fatal Myocardial Infarction, Non-fatal Cerebral Infarction, Unstable angina requiring urgent hospitalization

Arms

Pitavastatin 1mg/day

Estimated Enrollment

12,600

Study Period

January 2010 - January 2015 (enrollment; 2 years, follow-up; 3 years)

Informed Consent

Pitavastatin 1mg/day

vs.

Pitavastatin 4mg/day

Pitavastatin 1mg/day Randomized

Pitavastatin 4mg/day

LDL-C<120mg/dL J.R.G. JUANATEY C.H.U.Santiago

Run-in period (≥1 month)

Follow-up period (36 – 60 months)

Ezetimibe alone or in combination with simvastatin increases small dense low-density lipoproteins in healthy men: a randomized trial •

J.R.G. JUANATEY C.H.U.Santiago

1

CV Risk beyond LDL LDL treatment reduces CV Risk Risk factors

Overall RR

Age Gender CV disease HT treat DM

Etc..

Chol T

TG

LDL

Diabetes

HDL

Physical inact

TG

Diet Obesity HT HDL Tobacco

Residual Risk J.R.G. JUANATEY C.H.U.Santiago

CV Risk beyond LDL Etc..

TG Diabetes Physical inact Diet Obesity HT HDL Tobacco

Residual Risk J.R.G. JUANATEY C.H.U.Santiago

CV Risk beyond LDL Etc..

TG Diabetes Physical inact Diet Obesity HT

HDL Tobacco

Residual Risk J.R.G. JUANATEY C.H.U.Santiago

Atheroprotective and Vasculoprotective Actions of HDL Reverse cholesterol transport Cellular cholesterol Anti-infectious activity

HDL

Antiinflammator y activity Antiapoptotic activity

Antithrombotic activity Endothelial Antirepair; proteolitic vasodilation activity

J.R.G. JUANATEY C.H.U.Santiago

Antioxidative activity

Innate immune system

Endothelial-Vasoprotective Effects of High-Density Lipoprotein Are Impaired in Patients With Type 2 Diabetes Mellitus but Are Improved After Extended-Release Niacin Therapy (A), Effect of HDL (50 μ/mL, 60 minutes, 37°C) from

(A), Endothelium-dependent relaxations of aortic

healthy subjects (n=10) and diabetic patients (n=33) on endothelial cell NO production as determined by ESR spectroscopy analysis

rings of wild-type mice in response to increasing concentrations of HDL isolated from healthy subjects (n=5) or diabetic patients (n=5) are shown

Diabetics

J.R.G. JUANATEY C.H.U.Santiago

(B)

PBS

P < 0.0001

HDL

HDL Healthy

HDL from Diabetic Patients P = 0.007

(%; aortic rings)

P < 0.0001

Endothelium-dependent Relaxation

(% of buffer- treated cells)

Endothelial NO Production

(A)

HDL from Healthy Subjects

HDL (μg/ml)

Sorrentino SA et al. Circulation. 2010;121:110-122

Farmacología CV- 2010 Riesgo CV Global Hipertensión Arterial Dislipemia Diabetes

J.R.G. JUANATEY C.H.U.Santiago

Prevalence of diagnosed or undiagnosed diabetes

Spain

J.R.G. JUANATEY C.H.U.Santiago

43.3%

Evolución de la prevalencia de Diabetes en las cardiopatías INSUFICIENCIA CARDIACA Incremento 100% (X2)

J.R.G. JUANATEY C.H.U.Santiago

CARDIOPATIA ISQUEMICA Incremento 110% (X2)

Cardiotens 2009

Prevention of CV events by risk factor control in 200 DM Patients treated by 5 years 12.5 for 1 mmol/l LDL reduction 8.2 for 1 mmHg RR reduction 2-3 for 0.9% HbA1c (starting from 7.8%)

J.R.G. JUANATEY C.H.U.Santiago

When hyperglycemia is prolonged during illness, it may have caused cellular damage that cannot be reversed after achieving normoglycemia, as is demonstrated in diabetes (Metabolic Memory/Legacy Effect)

Aspirin for Primary Prevention of CV events in Diabetics Coronary heart disease events

Overall (95% CI)

J.R.G. JUANATEY C.H.U.Santiago

0.91 (0.79-1.05)

Stroke

Overall (95% CI)

0.85 (0.66-1.11)

JACC 2010; 55: 2878-86

The effect of combination lipid therapy in T2 DM The ACCORD Trial Primary Outcome

Proportion with Event (%)

Placebo

Fenofibrate

P=0.32

Years

Accord Study Group. New Engl J Med 2010; 362: 1563

J.R.G. JUANATEY C.H.U.Santiago

Incretin-based therapy GLP-1 R agonists

DPP-4 Inhibitors i.e. Sitagliptin Vildagliptin Saxaglitin Alogliptin ...........

J.R.G. JUANATEY C.H.U.Santiago

GLP-1 Analogues i.e. exenatide

Preserved Human GLP-1 i.e. liraglutide

HbA1c <7.0% + No weight gain + No confirmed hypoglycaemia (minor or major) + Cardiovascular safety J.R.G. JUANATEY C.H.U.Santiago

Patients reaching target (%)

Zinman et al, Diabetologia 2009;52(Suppl 1):S292 (A743)

45 40

39% 32%*

35 30

24%*

25 20

15%**

15

8%**, 

8%**, 

6%**, 

SU

Placebo

TZD

10 5 0

Liraglutide Liraglutide 1.8 mg 1.2 mg (n=1363)

(n=896)

Exenatide

Glargine

(n=231)

(n=232)

(n=490)

(n=524)

(n=231)

Liraglutide 1.8 mg is superior (*p<0.01; ** p<0.0001) Liraglutide 1.2 mg is superior ( p<0.0001) J.R.G. JUANATEYPercentages are from logistic regression model adjusted for trial, previous treatment and with baseline HbA1c and weight as C.H.U.Santiago covariates

Risk of AMI, stroke, HF and death in elderly Medicare patients treated with Rosiglitazone or Pioglitazone Acute Myocardial Infarction Rosiglitazone

Stroke Rosiglitazone

Pioglitazone

Pioglitazone P = 0.18

J.R.G. JUANATEY C.H.U.Santiago

P < 0.001

JAMA 2010; 304: 411-418

Farmacología CV- 2010 Riesgo CV Global Hipertensión Arterial Dislipemia Diabetes

J.R.G. JUANATEY C.H.U.Santiago