Il trattamento dell’Ipertensione nel paziente

diabetico

Francesco Vittorio Costa

Università degli Studi di Bologna

Diabete e ipertensione

1. Diabete+ipertensione: dimensione del problema

2. La terapia antipertensiva produce vantaggi nei diabetici?

3. Quale la PA da raggiungere nei diabetici?

4. Quali antipertensivi utilizzare?

Prevalence of Hypertension in Type 2 Diabetes

Prevalence ofhypertension

(%)

0

50

100

Normoalbuminuria (n = 323)

Microalbuminuria (n = 151)

Macroalbuminuria (n = 75)

Total (n = 549)

Hypertension defined as BP 140/90 mm Hg.Tarnow L et al. Diabetes Care 1994;17:1247-1251.

71

9093

80

L’EVIDENZA:

DM + HT È PERICOLOSA

Relative Risk of DM + HTN

Diabetes + HTN versus Diabetes

• Neuropathy 1.6

• Nephropathy 2.0

• Retinopathy 2.0

• Stroke 4.0

• CHD 3.0

. Mortality 2.0

CV Mortality Risk Doubles withEach 20/10 mm Hg BP Increment

Lewington S, et al. Lancet. 2002; 60:1903-1913.JNC VII. JAMA. 2003.

CV

Mo

rtal

ity

Ris

k

SBP/DBP (mm Hg)

0

1

2

3

4

5

6

7

8

115/75 135/85 155/95 175/105

Terapia dell’ipertensione e diabete

2- la terapia antiipertensiva produce vantaggi nei diabetici ?

Confronto con placebo

Risk reduction in meta-analyses of placebo RCTs. Diabetic hypertensives

-90

-80

-70

-60

-50

-40

-30

-20

-10

0

Ris

k re

duct

ion

%

low

high

block.

CCBs

ACE-Is

*

*

**

**

*

**

** *

Diuretics

-b

dose

dose

Stroke CHF CHD Death

Psaty et al JAMA 1997;277:739BPLT Lancet 2000;356:1955

*p<0.05

SI

La terapia antipertensiva produce vantaggi nei diabetici ?

Confronto con placebo

La terapia antipertensiva riduce gli eventi in maniera

significativa nei pazienti diabetici

Terapia dell’ipertensione e diabete

Risultati ottenuti nel controllo pressorio

dei pazienti diabetici

Awareness, treatment and control of hypertension according to diabetes status. aP<0.05

vs. nondiabetes mellitus (non- DM), BP<0.05 vs. known-DM.

Diabetes Metab J 2014;38:51-57

Failure to Intensify Antihypertensive Treatment by

Primary Care Providers: A Cohort Study in Adults with

Diabetes Mellitus

and Hypertension

In this highly adherent cohort of adults with diabetes and hypertension, failure to

intensify treatment for high blood pressure was a common problem: primary care

providers intensified treatment at only 13% of visits where blood pressure was

unequivocally elevated.

J Gen Intern Med 2008, 23(5):543–50

Terapia dell’ipertensione e diabete

1. Diabete+ipertensione: dangerous duo

2. La terapia antipertensiva produce vantaggi nei diabetici ?

3. Quale la PA da raggiungere nei diabetici?

4. Quali antipertensivi utilizzare?

UKPDS Event Rates for Select Endpoints With Tight vs Less Tight Blood Pressure Control

0

10

20

30

40

50

60

70

80

Any diabetes-related endpoint

Diabetes-related death

Stroke Microvascular complications

Eve

nts

per

100

0 p

atie

nt

yrs

P=0.005

P=0.02P=0.01

P=0.009

Less tight (n=390) mean achieved BP 154/87 mmHg

Tight (n=758) mean achieved BP 144/82 mmHg

UKPDS Group. BMJ. 1998;317:703–713.

0

5

10

15

20

25

HOT Diabetic Subgroup Reduction in Cardiovascular Events

Hansson L, et al. Lancet. 1998;351:1755–1762.

Nu

mb

er o

f ev

ents

*p

er 1

000

pat

ien

t-yr

s

P=0.005

*Includes all myocardial infarction, all strokes, and all other cardiovascular deaths

Target

diastolic BP

(mmHg)

Achieved†

systolic

BP

(mmHg)

Achieved†

diastolic

BP

(mmHg)

# of patients

with diabetes

90 143.7 85.2 501

85 141.4 83.2 501

80 139.7 81.1 499†mean of all blood pressures for all study patients in BP subgroups from 6 months of follow-up to end of study

UKPDS Effetto sugli eventi del controllo stretto vs. meno stretto di glicemia e di PA

Ch

an

ge f

rom

baselin

e (

mm

Hg

)

†

UKPDS Group. BMJ. 1998;317:703–713.

UKPDS: NNT per i diversi end-point (controllo PA vs controllo glicemia)

End point NNT1 NNT2

Qualunque complicanza del diabete 9 31

Mortalità correlata al diabete 16 112

Mortalità totale 23 125

IMA 23 46

ICTUS 23 169

Complicanze microvascolari 17 42

(da Snow et Al, Ann Intern Med 2003)

NNT1 = “ tight blood pressure control”NNT2 = “tight glicemic control”

Hazard Ratios for Events, According to Blood-Pressure–Lowering Study Group

Follow-up of Blood-Pressure Lowering and Glucose Control in Type 2 Diabetes (ADVANCE)

The New England Journal of Medicine

September 24, 2014.

Hazard Ratios for Events, According to Glucose-Control Study Group.

Follow-up of Blood-Pressure Lowering and Glucose Control in Type 2 Diabetes (ADVANCE)

The New England Journal of Medicine

September 24, 2014.

Terapia dell’ipertensione e diabete

Ci sono vantaggi addizionali se il

trattamento antiipertensivo è più aggressivo?

SI

A una maggior riduzione pressoria corrisponde una maggior riduzione

degli eventi

FINO A CHE VALORI SCENDERE?

Cosa dicono le Linee guida?

Blood Pressure Targets in Subjects With Type 2 Diabetes

Mellitus/Impaired Fasting Glucose

Observations From Traditional and Bayesian Random-Effects Meta-

Analyses of Randomized Trials

“In patients with type 2 diabetes mellitus/impaired fasting

glucose/impaired glucose tolerance, a systolic BP treatment goal of

130 to 135 mm Hg is acceptable. However, with more aggressive

goals (<130mm Hg), the risk of stroke continued to fall, but there

was no benefit on the risk of other macrovascular or microvascular

(cardiac, renal and retinal) events, and the risk of serious adverse

events even increased.

(Circulation. 2011;123:2799-2810.)

C’è un aumento di rischio per pressioni più basse?

Proportion of Outcome Events by Achieved SBP, Divided Into Deciles

Safety and Efficacy of Low Blood Pressures Among Patients With Diabetes

Subgroup Analyses From the ONTARGET

JACC Vol. 59, No. 1, 2012

Terapia dell’ipertensione e diabete

1. Diabete+ipertensione: dangerous duo

2. La terapia antipertensiva produce vantaggi nei diabetici ?

3. Quale la PA da raggiungere nei diabetici?

4. Quali antipertensivi utilizzare?

Effetti degli antipertensivi sul metabolismo glucidico

22 clinical trials, 143 153 patients. Initial diuretic used as referent agent. Size of squares (representing the point estimate for each class

of antihypertensive drugs) is proportional to number of patients who developed incident diabetes.

Incident diabetes in clinical trials of antihypertensive drugs: a

network meta-analysis

Lancet 2007; 369: 201–07

Tutti i sartani producono lo stesso effetto sul

metabolismo glucidico?

-10

0

-20

-30

FPGlucose

Ch

ange

fro

m b

asel

ine

(%)

P<0.05

FPInsulin HOMA IR HbA1c

P<0.06

P<0.05

P<0.05

Effects of Telmisartan & Losartan in Patients with metabolic syndrome

Vitale et al. Cardiovasc Diabetol. 2005;15:6.

Telmisartan (n=20)Losartan (n=20)

30

Effetti di Telmisartan e Eprosartan sui lipidi plasmatici

-35

-30

-25

-20

-15

-10

-5

0

Total cholesterol LDL-cholesterol Triglycerides

Ch

an

ge

fro

m b

ase

line

(m

g/d

L)

Eprosartan 600 mg (n=39)

Telmisartan 40 mg (n=40)

* P<0.05 vs EprosartanStudy duration = 1 year

*

Derosa et al. Hypertens Res 2004;27:457–464

*

*

ComparativeCardio-Metabolic Studies with

Telmisartan

Trial Patients N Duration (weeks)

ComparatorAgent(s)

BP differential

ImprovedInsulin

Sensitivity

Improved Lipid

Profile

Anti-oxidant/ Inflammatory

Action

Derosa 2004a HT, T2DM 119 52 Eprosartan/Placebo No (P yes) No Yes -

Derosa 2004b HT, T2DM 116 52 Nifedipine GITS No No Yes -

Vitale 2005 HT, MS 40 12 Losartan Yes? Yes - -

Miura 2005 HT, T2DM 18 12 Candesartan/Valsartan No Yes Yes Yes

Koulouris 2005 NT, T2DM 40 12 Ramipril No No No Yes

Honjo 2005 HT, T2DM 38 12 Candesartan - Yes - -

Benndorf 2006 HT 37 6 Nisoldipine No? Yes - -

Negro 2006a HT, T2DM 40 16 Amlodipine No Yes Yes -

Negro 2006b HT, obese,IR 46 26 Irbesaratn No Yes Yes -

Bahadir 2007 HT, MS 42 10 Losartan No? Yes? No -

Derosa 2007 HT, T2DM 188 52 Irbesartan No Yes Yes Yes

Sharma 2007 HT, obese 840 10 Valsartan HCTZ Yes No No -

Protezione dagli eventi

e dal danno d’organo

ABCDCAPPPFACETSTOP2UKPDS

0.83 (0.69,1.00)

1 5 10.2.1

Study (95% CI) OR

Het. p=.0073

z=1.97 p=.05

0.570.550.500.881.29

ACE- I vs altri Farmaci nei pazienti diabetici: effetti su tutti gli eventi cardiovascolari

(modificato da Pahor et al. Diabetes Care 2000;23:888)

0 6 12 18 24 30 36 42 48 54 60 66

Study Month

Pro

po

rtio

n o

f p

ati

ents

, %24

20

16

12

8

4

0

Adjusted Risk Reduction = 39%; p=0·002Unadjusted Risk Reduction = 40%; p=0·001

LIFE: Diabetes – Total Mortality

AtenololLosartan

LH Lindholm, et al Lancet 2002; 359:1004-1010

Zanchetti A et al., J Hypertens 2002

Effetti sugli eventi CV maggiori, morti CV e Mortalità Totale in Trial che Confrontano Regimi Basati su Classi Differenti di Antipertensivi in Pazienti con Diabete tipo

2

0.1 1.0Favours

drug class A

0.3

CA vs D/B

INSIGHT 1302 +2/-1 0.99 (0.70-1.39) 0.93 (0.54-1.60) 0.75 (0.52-1.09)

NORDIL 727 +3/0 1.21 (0.84-1.74) 0.24 (0.60-2.56) 1.15 (0.69-1.93)

STOP-2 484 0/-2 0.91 (0.72-1.14) 0.80 (0.53-1.21) 0.82 (0.59-1.13)

ACEI vs D/B

UKPDS 758 +1/+1 1.21 (0.89-1.63) 1.34 (0.88-2.05) 1.14 (0.83-1.55)

CAPPP 572 0/0 0.64 (0.44-0.94) 0.51 (0.23-1.51) 0.57 (0.33-0.98)

STOP-2 488 -1/0 0.86 (0.68-1.9) 0.93 (0.63-1.38) 0.90 (0.66-1.22)

ACEI vs CA

ABCD-NT 480 0/0 0.95 (0.74-1.21) 1.66 (0.71-3.89) 0.95 (0.52-1.75)

ABCD-HT 470 0/0 0.60 (0.39-0.92) 0.55 (0.21-1.45) 0.78 (0.40-1.53)

STOP-2 466 -1/+2 0.93 (0.74-1.21) 1.16 (0.76-1.78) 1.10 (0.79-1.54)

AIIA vs D/

LIFE 1195 -3/0 0.76 (0.58-0.98) 0.63 (0.42-0.95) 0.61 (0.45-0.84)

AIIA vs CA

IDNT 1146 -1/0 1.03 (0.81-1.32) 1.36 (0.89-2.07) 1.05 (0.78-1.42)

0.5 2.00.7 3.0

CV deathMajor CV events Total mortalityFavours

drug class B

ComparisonTrial N

SBP/DBP diff.A vs B

Major CV eventsRR (95% CI)

CV deathRR (95% CI)

Total mortalityRR (95% CI)

Scegliere un sartano o un ACEI?

Confronto efficacia ACE-I vs. sartani

Sospensione del trattamento per reazioni avverse : ACEI vs Sartani

0.5 1.0 2.0

Diuretics

Beta-blockers

Alpha-blockers

Calcium channel blockers

ACE-inhibitors

ARBs

1.83 (1.81-1.85)

1.64 (1.62-1.67)

1.23 (1.20-1.27)

1.08 (1.06-1.09)

0.92 (0.90-0.94)

- +

Corrao G et al J Hypertens. 2008;26(4):819-24.

Interruzioni del trattamento antipertensivo con monoterapia iniziale a 1 anno

(Lombardia Data-base: n=445356)

I sartani garantiscono i livelli migliori di persistenza

Rischio relativo di non-persistenza a seconda del farmaco prescritto inizialmente

+970%

FV Costa et al, 2009 High Blood Press Cardiovasc Prev 2009; 16 (4): 1-10

NB: ogni 10 paz, che interrompono il sartano ce ne sono 21 che interrompono l’ACEI.

Ogni 10 paz che interrompono Sartano+diur ce ne sono 24 che interrompono ACEI+diur

Confronto sartani

Ca-antagonisti

Calcium Channel Blocker Compared With Angiotensin Receptor Blocker for Patients

With Hypertension: A Meta-Analysis of Randomized Controlled Trials

J Clin Hypertens (Greenwich). 2014:1–8.

Heart failure

P<0.06

Stroke

J Clin Hypertens (Greenwich). 2014:1–8.

Calcium Channel Blocker Compared With Angiotensin Receptor Blocker for Patients With

Hypertension: A Meta-Analysis of Randomized Controlled Trials

P<0.04

Number of Drugs Needed to Achieve a Goal BP Value in Pts with HBP and Diabetes

0 1 2 3 5

Drugs (Nr.)

LIFE (<90mmHg)

MDRD (<92mmHg)

HOT (<80mmHg)

UKPDS (<85mmHg)

IDNT (<85mmHg)

RENAAL (<90mmHg)

ABCD (<75mmHg)

4

2.7

3.3

3.4

2.8

2.7

3.6

3.3

Valutare nel tempo l’efficacia della terapia

Diabetologia, DOI 10.1007/s00125-014-3330-9 July 2014

Adjusted HRs according to global effects of albuminuria, glycaemia and BP status.

Mortality and morbidity in relation to changes in albuminuria, glucose status and systolic blood

pressure: an analysisof the ONTARGET and TRANSCEND studies

Conclusions/interpretation

Patients who showed improvement to normoalbuminuria over 2

years were at lower risk of all-cause and cardiovascular mortality

and of cardiovascular and renal events than those who deteriorated

to microalbuminuria over time. Albuminuria over time was

significantly better than glucose status and BP control in predicting

mortality and both cardiovascular and renal outcomes in patients at

a high cardiovascular risk.

Mortality and morbidity in relation to changes in albuminuria, glucose status and

systolic blood pressure: an analysisof the ONTARGET and TRANSCEND studies

Reno-protective effects of renin–angiotensin system blockade in type 2 diabetic patients:

Diabetologia (2012) 55:566–578

Macroalbuminuria

Microalbuminuria

Metanalisi (25425 paz) degli effetti di telmisartan e altri farmaci su proteinuria o albuminuria

Take home message 1

- La associazione Diabete+ ipertensione è estremamente comune e particolarmente rischiosa

- Una riduzione pressoria + stretta riduce maggiormente il rischio CV e lo riduce maggiormente rispetto al controllo

+ stretto della glicemia

- Le percentuali di diabetici con PA ben controllata sono di gran lunga insufficienti e ciò dipende soprattutto da atteggiamenti terapeutici poco aggressivi

- L’ottenimento di un buon controllo pressorio richiede quasi sempre terapie di associazione

Take Home message 2

- ACE-i e ancor più i sartani non producono effetti sfavorevoli sul metabolismo glucidico . Il Temisartan migliora alcuni parametri metabolici glucidici e lipidici

- ACE-i e sartani sono egualmente efficaci nel prevenire gli eventi ma i sartani garantiscono livelli più elevati di aderenza al trattamento

- L’indice migliore per valutare l’efficacia del trattamento in termini di prevenzione degli eventi, è l’andamento della albuminuria

- Telmisartan migliora l’albuminuria più degli altri sartani, più degli ACE-i e delle altre classi di farmaci

Journal of Hypertension 2013, 31:1281–1357

Cosa dicono le Linee Guida?