1

Hipertensión Arterialen el paciente Diabético

Consideraciones en el Manejo Clínico

Carlos Chiurchiucchiurchiu@hospitalprivadosa.com.ar

Servicio de Nefrología y Programa de Trasplantes RenalesHospital Privado - Centro Médico de Córdoba

21-11-2008

2

PREVALENCIA DE HIPERTENSIÓNEN INDIOS LATINOAMERICANOS

Tobas: población urbanaAymara: población ruralYanomamo: población de la foresta/selva

Mancilha J et al. J Hum Hypertens 1989Perez F et al. Rev Med Chil 1999Bianchi M et al. XIII Latin American Congress of Nephrology and Hypertension 2004

0

15.0

30.0

Aymara (Chile)

6.4

27.0

Tobas(Argentina)

Yanomamo(Brasil)

%

0.0

3

Edad e Hipertensión Arterial en Argentina > 140/90

Hypertension in Diabetic Study J Hyperten 11:309–317 1993

Prevalence of hypertension in newly presenting type 2 diabetic patients

0

40

20

60

%50

30

10

70

160/90< 160/90

< 160/90 160/90

2.5

5.0

0

Rate of CV events before

diagnosis of diabetes

(%)

p=0.001

39 %

61 %

5

Rol del riñón en el mantenimiento de la HTA crónica

Hall J. Hypertension 2003

6

Increased renal sodium reabsorption and hypertension in obesity

Hall J. Hypertension. 2003

< 6 g salt/day(2,3 g / Na

o100 mmol/ Na)

7

Objetivos de Presión Arterialen el paciente Diabético

8

INDICATIONS FOR INITIAL TREATMENT AND GOALS FOR ADULT HYPERTENSIVE DIABETIC PATIENTS

Goal (mmHg) < 130 < 80

Behavioral therapy 130-139 80-89alone (maximum 3 months) then add pharmacologic treatment

Behavioral therapy + 140 90pharmacologic treatment

Systolic Diastolic

American Diabetes Association, Diabetes Care 2008

9

The risk of macrovascular and microvascular complications in diabetes is strongly

associated with blood pressure

UKPDS (36): BMJ 2000;321:412-419

10

Rat

e/10

00 p

erso

n/y

ear

25 –

20 –

15 –

10 –

5 –

0 –

P <0.005 for trend

25 –

20 –

15 –

10 –

5 –

0 – Diabetic

n: 1501All patients

n: 18790

< 90

< 85

< 80

DBP Goal

P <0.5for trend

Rate of major cardiovascular events according to Diastolic Blood Pressure

HOT Study: Lancet 1998

11

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

12

La PA nocturna predice el desarrollo de microalbuminuria en DBT tipo 1 normotensos

13

- 530 type 1 diabetes

- Normotensive

- 86%: Normoalbum.

3 mmHg diferencia PA

Idem Hb glicosilada

The Lancet 1997

14

¿Qué pueden aportar las medidas higiénico-dietéticas para lograr los

objetivos de Presión Arterialen el paciente Diabético ?

15

Beneficios en la PA con dieta Hiposódica y alto contenido de Frutas y Vegetales (K+)

Sacks F, et al. N Engl J Med 2001

Sodio: Alta: 150 mmol/d Media: 100 mmol/d Baja: 50 mmol/d

16

Rol atribuible al sobrepeso y obesidad en los factores de riesgo y eventos cardiovasculares:

Framingham Study

Wilson P, et al. Arch Intern Med 2002

17Neter J, et al. Hypertension 2003

Influence of Weight Reduction on Blood Pressure: A Meta-Analysis of Randomized Controlled Trials

A net weight reduction of 5.1 kg

18

¿ 130 / 80 ?

19

The decrease in risk for each 10 mm Hg reduction of SBP for macro and microvascular complications

UKPDS (36): BMJ 2000;321:412-419

20

Isquemia Miocárdica e HTA

Prospective Studies Collaboration, Lancet 2002

21

Stroke e HTA

Prospective Studies Collaboration, Lancet 2002

22

0

-2

-4

-6

-8

-10

-12

-14

GF

R (

ml/m

in/y

ear)

95 98 113110107104101 119116

130/85 140/90 Untreated HTN

r = 0.69; p < 0.05

MAP (mmHg)

Parving et al., Br Med J, 1989Viberti et al., JAMA, 1993Hebert et al., Kidney Int, 1994Lebovitz et al., Kidney Int, 1994Bakris et al., Kidney Int, 1996Bakris et al., Hypertension, 1997

Klahr et al., N Engl J Med, 1993Maschio et al., N Engl J Med, 1996GISEN Group, Lancet, 1997

Bakris et al., Am J Kidney Dis, 2000

Diabetes Non-diabetes

23

CASO CLINICO II

Varón 58 años, comercianteDiabético tipo 2 (>15 años de diagnóstico)Obeso (BMI: 31), fumador, come saladoF de Ojos: RD (no prolif.)HVIEdemas en tobillos ++PA: 155/95

Creatinina: 1.35 mg/dl (MDRD: 58 ml/min)Albuminuria: 200 mg/gK: 5.0 mEq/lLDL: 160 mg/dlHb glicosilada: 9.1 %

Med: Amlodipina 10 mg/d, ADO, AAS, Atorvastatina 10

24

¿Qué beneficios aportaríareducir la PA a este

paciente?

25

EFFECTS OF CALCIUM-CHANNEL BLOCKADE IN OLDER PATIENTS WITH DIABETES AND SYSTOLIC HYPERTENSION

Syst-Eur trial(Post-hoc analysis)

492 patients60 years or older

Placebo vs Nitrendipine2 years follow up

Initial BP: 175 / 85BP fall: Placebo 14 / 3

BP fall: Nitrendipine 22 / 7

Tuomilheto J, et al. N Engl J Med 1999

26

¿ Todos los hipotensores le darían iguales beneficios?

27

ACE inhibitors versus dihydropyridine calcium channel blockers in diabetic patients

0

12

9

6

3

%

ABCD trial

470 Hipertensive patients5 years follow up

MI: secondary end point

Nisoldipine

Enalapril

0

16

12

8%

4

Amlodipine

Fosinopril

FACET trial

380 Hipertensive patients3.5 years follow up

Combined End Point: MI, stroke, angina

28Smith et al., Kidney Int, 1998

Nifedipine (n = 10)Diltiazem (n = 11)

SBP 10

-50

-40

-30

-20

-10

0

DIFFERENTIAL EFFECTS OF 21 MONTHS OF CCBs THERAPY IN TYPE 2 DIABETICS WITH NEPHROPATHY

DBP 24 h proteinuira 100

-500

-400

-300

-200

-100

0

29

CAPPP study: ACE inhibitor therapy associated withreduction in endpoints : Diabetic vs Total population

Hansson L , et al. Lancet 1999

30

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

31

0 25%- 50%

THE MICROHOPE STUDY

Relative Risk (95% CI)

Combined

Myocardial infarction

Stroke

Cardiovascular death

Total mortality

Revascularization

Overt nephropathy

Clinical outcomes for Ramipril and placebo group

Primary outcomes

Secondary outcomes

- 25%

HOPE Study Investigators, Lancet, 2002

32

THE DREAM STUDY

DREAM Trial Group, NEJM 2006

- 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)

33

ATENOLOL AND CAPTOPRIL IN REDUCING RISK OF MACRO AND MICROVASCULAR COMPLICATIONS: UKPDS 39

UKPDS (39) BMJ, 1998

- 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

34

Cardiovascular morbidity and mortality in patients with diabetes in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE):

Inclusion criteria

Design

Treatment

Follow-up

Main end point

- Diabetes (both types)- Hypertension SBP: 160 - 200 mmHg and/or DBP: 95 - 115 mmHg- Left ventricular hypertrophy

- Randomized, double blind

- Losartan (50 - 100 mg/day) n = 586- Atenolol (50 - 100 mg/day) n = 609

- 4.7 ± 1.1 years

- Combined cardiovascular mortality, stroke, miocardial infarction

Lindholm et al., Lancet, 2002

35

Blood pressure and metabolic control were comparable

in the two treatment groups throughout

the whole study period

Lingholm et al., Lancet, 2002

36

THE ANTIHYPERTENSIVE AND LIPID-LOWERING

TREATMENT TO PREVENT HEART ATTACK TRIAL (ALLHAT) n = 33,357

Patients

Design

Treatment*

Follow-up

Primary end-point

Age > 55 yearsAt least 1 risk factor

Randomized, double blind

Chlortalidone 12,5 – 25 mg/day Amlodipine 2,5 – 10 mg/dayLisinopril 10 – 40 mg/day

4 – 8 years

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 2002

37

ALLHAT Study: Clinical Outcomes in Type 2 Diabetic Patients

Whelton P et al., Arch Intern Med. 2005

Coronary Heart Disease

All-Cause Mortality

Combined CHD

Stroke

Heart Failure

Combined CVD

ESRD

20.5 1

Favors Lisinopril Favors Chlortalidone

Coronary Heart Disease

All-Cause Mortality

Combined CHD

Stroke

Heart Failure

Combined CVD

ESRD

20.5 1

Favors Lisinopril Favors Chlortalidone

Diabetes MellitusNormoglycemia

38

THE ALLHAT STUDY

Throughout the whole study period, systolic blood pressure was significantly lower (2 mmHg) with chlorthalidone than with lisinopril

Lisinopril

Chlorthalidone

mm

Hg

Years

145

1300 1 2 4 53 6

135

150

140

Mean Systolic Blood Pressure

* p < 0.0001

*

** * * *

*

ALLHAT Group, JAMA 2002

39

Número de drogas usadas por paciente para lograr los objetivos de PA en

diversos estudios

40

Asociar IECAs con ARAII

Beneficios sobre la PA?Beneficios en el riesgo CV ?Beneficios en la nefropatía ?

41

42

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

Mogensen et al., Br Med J, 2000

Candesartan Lisinopril Combination

n = 66 n = 64 n = 67

1

SBP (mmHg)

10 20 30 40 50

DBP (mmHg)

urinary A/C ratio (%)

1 10 20 30 40 50 1 10 20 30 40 50 60

16

20

16 + 20

mg/day

43Jacobsen et. al. J Am Soc Nephrol 2003

ADDITIVE EFFECT OF ACE INHIBITION AND ANGIOTENSIN II RECEPTOR BLOCKADE

- Crossover study

-Type 1 DM

-Overt nephropathy

-Treatment:

Placebo

Benazepril 20 mg/day

Valsartan 80 mg/day

Combination (full doses)

50

150

100

mm

Hg

Placebo

Blood Pressure

0

Benazepril Valsartan Combination

1000

500

mg/

24 h

s

Placebo

Albuminuria

0

Benazepril Valsartan Combination

44

-50

Tight BP controlTight glucose control

%%

MicrovascularMicrovascularComplicationsComplications

Any diabetic Any diabetic endpointendpoint

0

-10

-20

-30

-40

StrokeStrokeDMDM

deathdeath

**

****

**

UKPDS 38. BMJ, 1998

** p<0.05p<0.05

Comparison between the cardiovascular risk reduction Comparison between the cardiovascular risk reduction between tight glucose control vs tight BP controlbetween tight glucose control vs tight BP control