1 Hipertensión Arterial en el paciente Diabético Consideraciones en el Manejo Clínico Carlos Chiurchiu Servicio de Nefrología y Programa de Trasplantes Renales Hospital Privado - Centro Médico de Córdoba

2 PREVALENCIA DE HIPERTENSIÓN EN INDIOS LATINOAMERICANOS Tobas: población urbana Aymara: población rural Yanomamo: población de la foresta/selva 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 Aymara (Chile) Tobas (Argentina) Yanomamo (Brasil) % 0.0

3 Edad e Hipertensión Arterial en Argentina > 140/90

Hypertension in Diabetic Study J Hyperten 11:309– Prevalence of hypertension in newly presenting type 2 diabetic patients % /90 < 160/90 160/ Rate of CV events before diagnosis of diabetes (%) p= % 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 < 6 g salt/day (2,3 g / Na o 100 mmol/ Na)

7 Objetivos de Presión Arterial en el paciente Diabético

8 INDICATIONS FOR INITIAL TREATMENT AND GOALS FOR ADULT HYPERTENSIVE DIABETIC PATIENTS Goal (mmHg) < 130< 80 Behavioral therapy alone(maximum 3 months) then add pharmacologic treatment Behavioral therapy pharmacologic treatment SystolicDiastolic 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:

10 Rate/1000 person/year 25 – 20 – 15 – 10 – 5 – 0 – P <0.005 for trend 25 – 20 – 15 – 10 – 5 – 0 – Diabetic n: 1501 All patients n: < 90 < 85 < 80 DBP Goal P <0.5 for 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

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 Arterial en 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

17 Neter 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:

20 Isquemia Miocárdica e HTA Prospective Studies Collaboration, Lancet 2002

21 Stroke e HTA Prospective Studies Collaboration, Lancet 2002

GFR (ml/min/year) /85 140/90 Untreated HTN r = 0.69; p < 0.05 MAP (mmHg) 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 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 Diabetes Non-diabetes

23 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

24 ¿Qué beneficios aportaría reducir 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 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

26 ¿ Todos los hipotensores le darían iguales beneficios?

27 ACE inhibitors versus dihydropyridine calcium channel blockers in diabetic patients % ABCD trial 470 Hipertensive patients 5 years follow up MI: secondary end point Nisoldipine Enalapril % 4 Amlodipine Fosinopril FACET trial 380 Hipertensive patients 3.5 years follow up Combined End Point: MI, stroke, angina

28 Smith et al., Kidney Int, 1998 Nifedipine (n = 10) Diltiazem (n = 11) SBP DIFFERENTIAL EFFECTS OF 21 MONTHS OF CCBs THERAPY IN TYPE 2 DIABETICS WITH NEPHROPATHY DBP 24 h proteinuira

29 CAPPP study: ACE inhibitor therapy associated with reduction in endpoints : Diabetic vs Total population Hansson L, et al. Lancet 1999

30 EFFECTS ON RAMIPRIL ON CARDIOVASCULAR AND MICROVASCULAR OUTCOMES IN 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

%- 50% THEMICROHOPE 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 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, 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: mmHg and/or DBP: mmHg - Left ventricular hypertrophy - Randomized, double blind - Losartan ( mg/day) n = Atenolol ( mg/day) n = ± 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 A NTIHYPERTENSIVE AND L IPID- L OWERING TREATMENT TO PREVENT H EART A TTACK T RIAL (ALLHAT) n = 33,357 Patients Design Treatment* Follow-up Primary end-point Age > 55 years At least 1 risk factor Randomized, double blind Chlortalidone 12,5 – 25 mg/day Amlodipine 2,5 – 10 mg/day Lisinopril 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 Coronary Heart Disease All-Cause Mortality Combined CHD Stroke Heart Failure Combined CVD ESRD Favors LisinoprilFavors Chlortalidone Coronary Heart Disease All-Cause Mortality Combined CHD Stroke Heart Failure Combined CVD ESRD Favors LisinoprilFavors Chlortalidone Diabetes Mellitus Normoglycemia

38 THE ALLHAT STUDY Throughout the whole study period, systolic blood pressure was significantly lower (2 mmHg) with chlorthalidone than with lisinopril Lisinopril Chlorthalidone mmHg Years Mean Systolic Blood Pressure * p < * * * * * * * 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

43 Jacobsen 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) mmHg Placebo Blood Pressure 0 BenazeprilValsartanCombination mg/24 hs Placebo Albuminuria 0 BenazeprilValsartanCombination

Tight BP control Tight glucose control% MicrovascularComplications Any diabetic endpoint Stroke DMdeath * * * * UKPDS 38. BMJ, 1998 * p<0.05 Comparison between the cardiovascular risk reduction between tight glucose control vs tight BP control