Hipertensión Arterial
en el paciente Diabético
Consideraciones en
el Manejo Clínico
Carlos Chiurchiu
cchiurchiu@hospitalprivadosa.com.ar
Servicio de Nefrología y Programa de Trasplantes Renales
Hospital Privado - Centro Médico de Córdoba
21-11-2008
1
PREVALENCIA DE HIPERTENSIÓN
EN INDIOS LATINOAMERICANOS
30.0
27.0
Tobas: población urbana
Aymara: población rural
Yanomamo: población de la foresta/selva
15.0
6.4
0.0
0
Tobas
(Argentina)
Aymara
(Chile)
Yanomamo
(Brasil)
Mancilha J et al. J Hum Hypertens 1989
Perez F et al. Rev Med Chil 1999
Bianchi M et al. XIII Latin American Congress of Nephrology and Hypertension 2004
2
Edad e Hipertensión Arterial
en Argentina > 140/90
3
Prevalence of hypertension in newly
presenting type 2 diabetic patients
p=0.001
70
5.0
61 %
60
50
%
39 %
40
30
Rate of CV
events before
2.5
diagnosis
of diabetes
(%)
0
< 160/90
 160/90
20
10
0
< 160/90
 160/90
Hypertension in Diabetic Study J Hyperten 11:309–317 1993
Rol del riñón en el mantenimiento
de la HTA crónica
Hall J. Hypertension 2003
5
Increased renal sodium reabsorption and
hypertension in obesity
< 6 g salt/day
(2,3 g / Na
o
100 mmol/ Na)
Hall J. Hypertension. 2003
6
Objetivos de Presión Arterial
en el paciente Diabético
7
INDICATIONS FOR INITIAL TREATMENT AND GOALS
FOR ADULT HYPERTENSIVE DIABETIC PATIENTS
Systolic
Goal (mmHg)
Diastolic
< 130
< 80
Behavioral therapy
alone (maximum
3 months) then add
pharmacologic treatment
130-139
80-89
Behavioral therapy +
pharmacologic treatment
 140
 90
American Diabetes Association, Diabetes Care 2008
8
The risk of macrovascular and microvascular
complications in diabetes is strongly
associated with blood pressure
UKPDS (36): BMJ 2000;321:412-419
9
Rate of major cardiovascular events
according to Diastolic Blood Pressure
DBP Goal
< 90
Rate/1000 person/year
25 –
< 85
25 –
< 80
20 –
15 –
20 –
P <0.5
for trend
15 –
10 –
10 –
5 –
5 –
0 –
0 –
All patients
n: 18790
P <0.005
for trend
Diabetic
HOT Study: Lancet 1998
n: 1501
10
CASO CLINICO I
•Mujer de 19 años, estudiante de medicina (cursillo)
•Diabética tipo 1 (5 años de diagnóstico)
•Sobrepeso (BMI: 27.5), sedentaria, come salado
•F de Ojos: normal
•Insulinoterapia (Hb glic: 8.2%)
•PA: 135/85 (idem en 2 consultas previas)
refiere PA domiciliaria de 110/70
no usa hipotensores
•Creatinina: 0.45 mg/dl
•Albuminuria: 14 mg/g
•K: 4.8 mEq/l
11
La PA nocturna predice el desarrollo de
microalbuminuria en DBT tipo 1 normotensos
12
- 530 type 1 diabetes
- Normotensive
- 86%: Normoalbum.
3 mmHg diferencia PA
Idem Hb glicosilada
The Lancet 1997
13
¿Qué pueden aportar las medidas
higiénico-dietéticas para lograr los
objetivos de Presión Arterial
en el paciente Diabético ?
14
Beneficios en la PA con dieta Hiposódica
y alto contenido de Frutas y Vegetales (K+)
Sodio: Alta: 150 mmol/d
Media: 100 mmol/d
Baja: 50 mmol/d
Sacks F, et al. N Engl J Med 2001
15
Rol atribuible al sobrepeso y obesidad en
los factores de riesgo y eventos cardiovasculares:
Framingham Study
Wilson P, et al. Arch Intern Med 2002
16
Influence of Weight Reduction on Blood Pressure:
A Meta-Analysis of Randomized Controlled Trials
A net weight reduction of 5.1 kg
Neter J, et al. Hypertension 2003
17
¿ 130 / 80 ?
18
The decrease in risk for each 10 mm Hg reduction of
SBP for macro and microvascular complications
UKPDS (36): BMJ 2000;321:412-419
19
Isquemia Miocárdica e HTA
Prospective Studies Collaboration, Lancet 2002
20
Stroke e HTA
Prospective Studies Collaboration, Lancet 2002
21
MAP (mmHg)
95
98
101
104
107
110
113
116
119
0
r = 0.69; p < 0.05
GFR (ml/min/year)
-2
-4
-6
-8
-10
-12
-14
130/85
140/90
Diabetes
Parving et al., Br Med J, 1989
Viberti et al., JAMA, 1993
Hebert et al., Kidney Int, 1994
Lebovitz et al., Kidney Int, 1994
Bakris et al., Kidney Int, 1996
Bakris et al., Hypertension, 1997
Untreated HTN
Non-diabetes
Klahr et al., N Engl J Med, 1993
Maschio et al., N Engl J Med, 1996
GISEN Group, Lancet, 1997
Bakris et al., Am J Kidney Dis, 2000
22
CASO CLINICO II
Varón 58 años, comerciante
Diabético tipo 2 (>15 años de diagnóstico)
Obeso (BMI: 31), fumador, come salado
F de Ojos: RD (no prolif.)
HVI
Edemas en tobillos ++
PA: 155/95
Creatinina: 1.35 mg/dl (MDRD: 58 ml/min)
Albuminuria: 200 mg/g
K: 5.0 mEq/l
LDL: 160 mg/dl
Hb glicosilada: 9.1 %
Med: Amlodipina 10 mg/d, ADO, AAS, Atorvastatina 10
23
¿Qué beneficios aportaría
reducir la PA a este
paciente?
24
EFFECTS OF CALCIUM-CHANNEL BLOCKADE IN OLDER
PATIENTS WITH DIABETES AND SYSTOLIC HYPERTENSION
Syst-Eur trial
(Post-hoc analysis)
492 patients
60 years or older
Placebo vs Nitrendipine
2 years follow up
Initial BP: 175 / 85
BP fall: Placebo 14 / 3
BP fall: Nitrendipine 22 / 7
Tuomilheto J, et al. N Engl J Med 1999
25
¿ Todos los hipotensores le
darían iguales beneficios?
26
ACE inhibitors versus dihydropyridine
calcium channel blockers in diabetic patients
12
Nisoldipine
Amlodipine
16
9
12
% 6
% 8
Fosinopril
Enalapril
3
4
0
0
ABCD trial
FACET trial
470 Hipertensive patients
5 years follow up
MI: secondary end point
380 Hipertensive patients
3.5 years follow up
Combined End Point:
MI, stroke, angina
27
DIFFERENTIAL EFFECTS OF 21 MONTHS OF CCBs THERAPY IN
TYPE 2 DIABETICS WITH NEPHROPATHY
Nifedipine (n = 10)
Diltiazem (n = 11)
10
0
DSBP
DDBP
100
D 24 h proteinuira
0
-10
-100
-20
-200
-30
-300
-40
-400
-50
-500
Smith et al., Kidney Int, 1998
28
CAPPP study: ACE inhibitor therapy associated with
reduction in endpoints : Diabetic vs Total population
Hansson L , et al. Lancet 1999
29
EFFECTS ON RAMIPRIL ON CARDIOVASCULAR
AND MICROVASCULAR OUTCOMES IN 3.577
PATIENTS WITH TYPE 2 DIABETES ENROLLED
IN THE HOPE STUDY
THE MICRO-HOPE STUDY
- age > 55 years
- no clinical proteinuria
- previous cardiovascular event or at least
one other cardiovascular risk factor
HOPE Study Investigators, Lancet, 2002
30
THE MICROHOPE STUDY
Clinical outcomes for Ramipril and placebo group
Relative Risk (95% CI)
Primary outcomes
Combined
Myocardial infarction
Stroke
Cardiovascular death
Secondary outcomes
Total mortality
Revascularization
Overt nephropathy
- 50%
- 25%
0
25%
HOPE Study Investigators, Lancet, 2002
31
THE DREAM STUDY
- 5269 participants without cardiovascular disease
- Impaired fasting glucose levels or impaired glucose tolerance
- Treatment: ramipril (up to 15 mg per day) or placebo
- Follow up: 3 years (median)
- Baseline BP: 136/83 (both groups)
DREAM Trial Group, NEJM 2006
32
ATENOLOL AND CAPTOPRIL IN REDUCING RISK OF MACRO
AND MICROVASCULAR COMPLICATIONS: UKPDS 39
- 1148 hypertensive type 2 diabetic patients
Myocardial infarction, sudden death,
stroke, peripheral vascular disease
and renal failure
-Less tight BP control: 154/87
-Captopril: 144/83
-Atenolol: 143/81
UKPDS (39) BMJ, 1998
33
Cardiovascular morbidity and mortality in patients with
diabetes in the Losartan Intervention For Endpoint reduction
in hypertension study (LIFE):
Inclusion criteria
- Diabetes (both types)
- Hypertension
SBP: 160 - 200 mmHg and/or
DBP: 95 - 115 mmHg
- Left ventricular hypertrophy
Design
- Randomized, double blind
Treatment
- Losartan (50 - 100 mg/day) n = 586
- Atenolol (50 - 100 mg/day) n = 609
Follow-up
- 4.7 ± 1.1 years
Main end point
- Combined cardiovascular mortality, stroke,
miocardial infarction
Lindholm et al., Lancet, 2002
34
Blood pressure and
metabolic control
were comparable
in the two treatment
groups throughout
the whole study period
Lingholm et al., Lancet, 2002
35
THE
ANTIHYPERTENSIVE
TREATMENT TO PREVENT
(ALLHAT) n = 33,357
AND
LIPID-LOWERING
HEART ATTACK TRIAL
Patients
Age > 55 years
At least 1 risk factor
Design
Randomized, double blind
Treatment*
Chlortalidone 12,5 – 25 mg/day
Amlodipine
2,5 – 10 mg/day
Lisinopril
10 – 40 mg/day
Follow-up
4 – 8 years
Primary end-point
Major (fatal and non fatal) cardiovascular events
* The doxazosin arm was prematurely interrupted because of the
significantly worse outcome as compared to the diuretic arm
ALLHAT Group, JAMA 200236
ALLHAT Study: Clinical Outcomes
in Type 2 Diabetic Patients
Diabetes Mellitus
Normoglycemia
Coronary Heart Disease
Coronary Heart Disease
All-Cause Mortality
All-Cause Mortality
Combined CHD
Combined CHD
Stroke
Stroke
Heart Failure
Heart Failure
Combined CVD
Combined CVD
ESRD
ESRD
Favors Lisinopril
0.5
Favors Chlortalidone
1
2
Favors Lisinopril
0.5
Favors Chlortalidone
1
2
Whelton P et al., Arch Intern Med. 2005
37
THE ALLHAT STUDY
150
Mean Systolic Blood Pressure
*
mmHg
145
*
140
*
*
*
*
*
135
Lisinopril
Chlorthalidone
* p < 0.0001
130
0
1
2
3
4
5
6
Years
Throughout the whole study period, systolic blood pressure
was significantly lower (2 mmHg) with chlorthalidone than with
lisinopril
ALLHAT Group, JAMA 2002
38
Número de drogas usadas por paciente para
lograr los objetivos de PA en
diversos estudios
39
Asociar IECAs con ARAII
Beneficios sobre la PA?
Beneficios en el riesgo CV ?
Beneficios en la nefropatía ?
40
41
CANDESARTAN
AND
LISINOPRIL
MICROALBUMINURIA (CALM) STUDY
Adjusted risk reduction (at 24 weeks) in SBP, DBP, and urinary A/C
ratio in 197 type 2 diabetics with hypertension and microalbuminuria
D SBP
D DBP
(mmHg)
(mmHg)
D urinary A/C ratio
(%)
mg/day
Candesartan 16
n = 66
Lisinopril
n = 64
20
Combination 16 + 20 n = 67
1
10 20 30 40 50
1
10 20 30 40 50
1
10 20 30 40 50 60
Mogensen et al., Br Med J, 2000
42
ADDITIVE EFFECT OF ACE INHIBITION AND
ANGIOTENSIN II RECEPTOR BLOCKADE
mmHg
- Crossover study
-Type 1 DM
Blood Pressure
150
100
-Overt nephropathy
50
-Treatment:
0
Placebo
Placebo
1000
mg/24 hs
Valsartan
Combination
Albuminuria
Benazepril 20 mg/day
Valsartan 80 mg/day
Benazepril
500
Combination (full doses)
0
Jacobsen et. al. J Am Soc Nephrol 2003
Placebo
Benazepril
Valsartan
Combination
43
Comparison between the cardiovascular risk reduction
between tight glucose control vs tight BP control
Stroke
DM
death
Any diabetic
endpoint
Microvascular
Complications
0
-10
-20
%
*
-30
*
-40
-50
*
Tight glucose control
*
*
p<0.05
Tight BP control
UKPDS 38. BMJ, 1998
44