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Hipertensión Arterial en el paciente Diabético Consideraciones en el Manejo Clínico Carlos Chiurchiu cchiurchiu @hospit

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.

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Hipertensión Arterial en el paciente Diabético Consideraciones en el Manejo Clínico Carlos Chiurchiu cchiurchiu @hospit

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  1. 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

  2. PREVALENCIA DE HIPERTENSIÓNEN INDIOS LATINOAMERICANOS Tobas: población urbana Aymara: población rural Yanomamo: población de la foresta/selva 30.0 27.0 % 15.0 6.4 0.0 0 Aymara (Chile) Tobas (Argentina) 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

  3. Edad e Hipertensión Arterial en Argentina > 140/90

  4. Prevalence of hypertension in newly presenting type 2 diabetic patients p=0.001 70 5.0 61 % 60 Rate of CV events before diagnosis of diabetes (%) 50 2.5 % 39 % 40 30 0 < 160/90  160/90 20 10 0 < 160/90  160/90 Hypertension in Diabetic Study J Hyperten 11:309–317 1993

  5. Rol del riñón en el mantenimiento de la HTA crónica Hall J. Hypertension 2003

  6. Increased renal sodium reabsorption and hypertension in obesity < 6 g salt/day (2,3 g / Na o 100 mmol/ Na) Hall J. Hypertension. 2003

  7. Objetivos de Presión Arterial en el paciente Diabético

  8. INDICATIONS FOR INITIAL TREATMENT AND GOALS FOR ADULT HYPERTENSIVE DIABETIC PATIENTS Systolic Diastolic Goal (mmHg) < 130 < 80 Behavioral therapy 130-139 80-89 alone (maximum 3 months) then add pharmacologic treatment Behavioral therapy + 140  90 pharmacologic treatment 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. Rate of major cardiovascular events according to Diastolic Blood Pressure DBP Goal < 90 < 85 • 25 – • 20 – • 15 – • 10 – • 5 – • 0 – • 25 – • 20 – • 15 – • 10 – • 5 – • 0 – P <0.005 for trend < 80 P <0.5 for trend Rate/1000 person/year All patients n: 18790 Diabetic n: 1501 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 Arterial en el paciente Diabético ?

  15. 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

  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. 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

  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. MAP(mmHg) 95 98 101 104 107 110 113 116 119 0 r = 0.69; p < 0.05 -2 -4 -6 GFR (ml/min/year) -8 -10 -12 Untreated HTN 140/90 130/85 -14 Non-diabetes 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 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

  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 12 16 Nisoldipine Amlodipine 9 12 % 6 8 % Fosinopril Enalapril 4 3 0 0 FACET trial 380 Hipertensive patients 3.5 years follow up Combined End Point: MI, stroke, angina ABCD trial 470 Hipertensive patients 5 years follow up MI: secondary end point

  28. DIFFERENTIAL EFFECTS OF 21 MONTHS OF CCBs THERAPY IN TYPE 2 DIABETICS WITH NEPHROPATHY Nifedipine (n = 10) Diltiazem (n = 11) 10 100 D 24 h proteinuira DDBP DSBP 0 0 -10 -100 -20 -200 -30 -300 -40 -400 -50 -500 Smith et al., Kidney Int, 1998

  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 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. 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% 0 25% - 25% HOPE Study Investigators, Lancet, 2002

  32. 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

  33. 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

  34. Cardiovascular morbidity and mortality in patients with diabetes in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): • - 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 Inclusion criteria Design Treatment Follow-up Main end point 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 years At least 1 risk factor Randomized, double blind Chlortalidone12,5 – 25 mg/day Amlodipine 2,5 – 10 mg/day Lisinopril10 – 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. Coronary Heart Disease All-Cause Mortality Combined CHD Stroke Heart Failure Combined CVD ESRD Coronary Heart Disease All-Cause Mortality Combined CHD Stroke Heart Failure Combined CVD ESRD Favors Lisinopril Favors Chlortalidone Favors Lisinopril Favors Chlortalidone 0.5 1 2 0.5 1 2 ALLHAT Study:Clinical Outcomes in Type 2 Diabetic Patients Diabetes Mellitus Normoglycemia Whelton P et al., Arch Intern Med. 2005

  38. 150 145 140 135 130 0 1 2 4 3 5 6 Years THE ALLHAT STUDY Mean Systolic Blood Pressure * * * mmHg * * * * Lisinopril Chlorthalidone * p < 0.0001 Throughout the whole study period, systolic blood pressure was significantly lower (2 mmHg) with chlorthalidone than with lisinopril 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. D D D DBP urinary A/C ratio SBP (mmHg) (%) (mmHg) mg/day Candesartan 16 n = 66 Lisinopril 20 n = 64 Combination 16 + 20 n = 67 1 10 20 30 40 50 1 10 20 30 40 50 1 10 20 30 40 50 60 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

  42. ADDITIVE EFFECT OF ACE INHIBITION AND ANGIOTENSIN II RECEPTOR BLOCKADE Blood Pressure 150 • - Crossover study • Type 1 DM • Overt nephropathy • Treatment: • Placebo • Benazepril 20 mg/day • Valsartan 80 mg/day • Combination (full doses) 100 mmHg 50 0 Placebo Benazepril Valsartan Combination 1000 Albuminuria 500 mg/24 hs 0 Placebo Benazepril Valsartan Combination Jacobsen et. al. J Am Soc Nephrol 2003

  43. Tight glucose control Tight BP control Comparison between the cardiovascular risk reduction between tight glucose control vs tight BP control DM death Any diabetic endpoint Microvascular Complications Stroke 0 -10 -20 % * -30 * -40 * * p<0.05 -50 * UKPDS 38. BMJ, 1998

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