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
Normoalbuminuria (n = 323)
Macroalbuminuria (n = 75)
Microalbuminuria (n = 151)
Total (n = 549)
100
90
93
80
71
Prevalence of
hypertension
50
(%)
0
Hypertension defined as BP 140/90 mm Hg.
Tarnow L et al. Diabetes Care 1994;17:1247-1251.
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
CV Mortality Risk Doubles with
Each 20/10 mm Hg BP Increment
8
7
6
5
4
3
2
1
0
115/75
135/85
155/95
175/105
SBP/DBP (mm Hg)
Lewington S, et al. Lancet. 2002; 60:1903-1913.JNC VII. JAMA. 2003.
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
Risk reduction %
0
Stroke
CHF
CHD
-10
-20
-30
-40
-50
-60
*
* **
* *
*
-70
*
*
*
*p<0.05
-80
-90
Death
*
Psaty et al JAMA 1997;277:739
BPLT Lancet 2000;356:1955
*
Diuretics
low dose
high dose
b-block.
CCBs
ACE-Is
La terapia antipertensiva
produce vantaggi nei diabetici ?
Confronto con placebo
SI
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?
Events per 1000 patient yrs
UKPDS Event Rates for Select Endpoints With Tight vs Less
Tight Blood Pressure Control
80
70
P=0.005
Tight (n=758) mean achieved
BP 144/82 mmHg
60
Less tight (n=390) mean
achieved BP 154/87 mmHg
50
40
30
P=0.02
20
P=0.01
P=0.009
10
0
Any diabetesrelated endpoint
Diabetesrelated death
UKPDS Group. BMJ. 1998;317:703–713.
Stroke
Microvascular
complications
HOT Diabetic Subgroup
Reduction in Cardiovascular Events
P=0.005
25
Achieved†
Achieved†
# of
patients
with
diabetes
diastolic BP
systolic
diastolic
(mmHg)
BP
BP
(mmHg)
(mmHg)
 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
*Includes all myocardial infarction, all
strokes, and all other cardiovascular
deaths
Hansson L, et al. Lancet. 1998;351:1755–1762.
20
Number of events*
per 1000 patient-yrs
Target
15
10
5
0
Change from baseline (mmHg)
UKPDS Effetto sugli eventi del controllo stretto vs. meno
stretto di glicemia e di PA
†
UKPDS Group. BMJ. 1998;317:703–713.
UKPDS: NNT per i diversi end-point (controllo
PA vs controllo glicemia)
End point
NNT1
NNT2
9
31
Mortalità correlata al diabete
16
112
Mortalità totale
23
125
IMA
23
46
ICTUS
23
169
Complicanze microvascolari
17
42
Qualunque complicanza del diabete
NNT1 = “ tight blood pressure control”
NNT2 = “tight glicemic control”
(da Snow et Al, Ann Intern Med 2003)
Follow-up of Blood-Pressure Lowering and Glucose Control in Type 2 Diabetes (ADVANCE)
Hazard Ratios for Events, According to Blood-Pressure–Lowering Study Group
The New England Journal of Medicine
September 24, 2014.
Follow-up of Blood-Pressure Lowering and Glucose Control in Type 2 Diabetes (ADVANCE)
Hazard Ratios for Events, According to Glucose-Control Study Group.
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 RandomEffects 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?
Safety and Efficacy of Low Blood Pressures Among Patients With Diabetes
Subgroup Analyses From the ONTARGET
Proportion of Outcome Events by Achieved SBP, Divided Into Deciles
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
Incident diabetes in clinical trials of antihypertensive
drugs: a network meta-analysis
Lancet 2007; 369: 201–07
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.
Tutti i sartani producono lo
stesso effetto sul
metabolismo glucidico?
Effects of Telmisartan & Losartan in Patients with
metabolic syndrome
FPGlucose
FPInsulin
HOMA IR
HbA1c
Change from baseline (%)
0
-10
P<0.05
P<0.05
P<0.06
-20
P<0.05
Telmisartan (n=20)
Losartan (n=20)
-30
Vitale et al. Cardiovasc Diabetol. 2005;15:6.
30
Effetti di Telmisartan e Eprosartan sui lipidi plasmatici
Total cholesterol
LDL-cholesterol
Triglycerides
Change from baseline (mg/dL)
0
-5
-10
*
-15
-20
*
-25
-30
-35
Eprosartan 600 mg (n=39)
Telmisartan 40 mg (n=40)
*
* P<0.05 vs Eprosartan
Study duration = 1 year
Derosa et al. Hypertens Res 2004;27:457–464
Comparative
Cardio-Metabolic Studies with Telmisartan
Trial
Patients
N
Duration
(weeks)
Comparator
Agent(s)
BP
differential
Improved
Insulin
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
-
-
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
-
Benndorf 2006
Protezione dagli eventi
e dal danno d’organo
ACE- I vs altri Farmaci nei pazienti diabetici:
effetti su tutti gli eventi cardiovascolari
Study
(95% CI) OR
ABCD
CAPPP
FACET
STOP2
UKPDS
z=1.97 p=.05
Het. p=.0073
.1 .2
0.57
0.55
0.50
0.88
1.29
0.83 (0.69,1.00)
1
5 10
(modificato da Pahor et al. Diabetes Care 2000;23:888)
LIFE: Diabetes – Total Mortality
Proportion of patients, %
24
20
Atenolol
Losartan
16
12
8
4
Adjusted Risk Reduction = 39%; p=0·002
Unadjusted Risk Reduction = 40%; p=0·001
0
0
6
12
18
24
30
36
Study Month
LH Lindholm, et al Lancet 2002; 359:1004-1010
42
48
54
60
66
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
Comparison
Trial
N
SBP/DBP diff.
A vs B
Major CV events
RR (95% CI)
CV death
RR (95% CI)
Total mortality
RR (95% CI)
CA vs D/bB
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)
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)
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)
1195
-3/0
0.76 (0.58-0.98)
0.63 (0.42-0.95)
0.61 (0.45-0.84)
1146
-1/0
1.03 (0.81-1.32)
1.36 (0.89-2.07)
1.05 (0.78-1.42)
ACEI vs D/bB
ACEI vs CA
AIIA vs D/b
LIFE
AIIA vs CA
IDNT
0.1
Major CV events
CV death
Total mortality
Zanchetti A et al., J Hypertens 2002
0.3
0.5 0.7 1.0
Favours
drug class A
2.0 3.0
Favours
drug class B
Scegliere un sartano
o un ACEI?
Confronto efficacia ACE-I vs. sartani
Sospensione del trattamento per reazioni avverse : ACEI vs Sartani
Interruzioni del trattamento antipertensivo con
monoterapia iniziale a 1 anno
(Lombardia Data-base: n=445356)
Diuretics
1.83 (1.81-1.85)
Beta-blockers
1.64 (1.62-1.67)
Alpha-blockers
1.23 (1.20-1.27)
Calcium channel blockers
1.08 (1.06-1.09)
ACE-inhibitors
ARBs
0.5
0.92 (0.90-0.94)
-
1.0
+
2.0
I sartani garantiscono i livelli migliori di persistenza
Corrao G et al J Hypertens. 2008;26(4):819-24.
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
Heart failure
P<0.06
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
Stroke
P<0.04
J Clin Hypertens (Greenwich). 2014:1–8.
Number of Drugs Needed to Achieve
a Goal BP Value in Pts with HBP and Diabetes
2.7
UKPDS (<85mmHg)
3.3
IDNT (<85mmHg)
3.4
RENAAL (<90mmHg)
2.8
ABCD (<75mmHg)
2.7
LIFE (<90mmHg)
3.6
MDRD (<92mmHg)
3.3
HOT (<80mmHg)
0
1
2
Drugs (Nr.)
3
4
5
Valutare nel tempo
l’efficacia della terapia
Mortality and morbidity in relation to changes in albuminuria, glucose status and systolic
blood pressure: an analysisof the ONTARGET and TRANSCEND studies
Adjusted HRs according to global effects of albuminuria, glycaemia and BP status.
Diabetologia, DOI 10.1007/s00125-014-3330-9 July 2014
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.
Reno-protective effects of renin–angiotensin system blockade in type 2 diabetic patients:
Macroalbuminuria
Microalbuminuria
Diabetologia (2012) 55:566–578
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?