Behandling av h gt blodtryck vid diabetes mellitus Bo Carlberg Med Klin Norrlands Universitetssjukhus Ume

1. Behandling av h�gt blodtryck vid diabetes mellitusBo CarlbergMed KlinNorrlands UniversitetssjukhusUme�

2. H�gt blodtryck vid typ-2-diabetes F�rekomst Metabola effekter av blodtryckss�nkande l�kemedel Finns det anledning att behandla h�gt blodtryck hos diabetiker medd andra l�kemedel �n hos icke-diabetiker? ALLHAT Metaanalys BPLTTC Hur mycket skall blodtrycket s�nkas? ACE-h�mmare eller ARB vid diabetesnefropati? Riktlinjer

3. F�rekomst av Hypertoni i olika �ldrar och l�nder

4. Behandlingseffekt: betydelse av diabetes

5. Metabola effekter av diuretika-betablockare

6. ALPINE Design

7. ALPINE Mean of S-insulin at baseline and change at 12 months (mlU/L)

8. ALPINE Mean of P-glucose at baseline and change at 12 months (mmol/L)

9. Mean change of 2-h OGTT in a sub-sample from baseline to 12 months

10. Mean change of lipids from baseline to 12 months

11. L�gre nyinsjuknande i typ 2-diabetes med ACE-h�mmare och ARB Studie n Terapi �r uppf�ljning % Nyinsjuknande Absolut skillnad INSIGHT 6 321 CCB vs D 3,5 5,4 vs 7,0 �1,6 NORDIL 10 164 CCB vs BB/D 4,5 4,3 vs 4,9 �0,6 ALLHAT 24 283 CCB vs D 4,8 9,8 vs 11,6 �1,8 HOPE 5 720 ACEI vs P 4,5 3,6 vs 5,4 �1,8 ALLHAT 24 289 ACEI vs D 4,8 8,1 vs 11,6 �3,5 CAPPP 10 985 ACEI vs BB/D 6,1 6,5 vs 7,3 �0,8 SCOPE 4 937 ARB vs P/D 3,7 4,3 vs 5,3 �1,0 ALPINE 388 ARB vs D 1,0 0,5 vs 4,1 �3,6 LIFE 7 998 ARB vs BB 4,8 6,0 vs 8,0 �2,0 VALUE 15 745 ARB vs CCB 4,2 13,1 vs 16,4 �3,3

12. Hur p�verkar dessa metabola bieffekter insjuknaden i hj�rtk�rlsjukdom? ALLHAT BPLTTC SHEP Finns det anledning att behandla diabetikers h�ga blodtryck med andra l�kemedel �n icke-diabetiker? Finns anledning att behandla diabetikers blodtryck intensivare �n icke-diabetiker?

13. Randomized Designof ALLHAT Participants were men and women, age = 55 years, who had Stage 1 or Stage 2 hypertension with at least one additional risk factor for CHD events. Randomized participants were assigned to receive amlodipine, chlorthalidone, doxazosin, or lisinopril as their initial study antihypertensive drug. Participants with LDL-cholesterol values in the eligible range and who were otherwise eligible for the lipid-lowering component were randomized to 40 mg/day of pravastatin or usual care. This presentation focuses on the antihypertensive component of ALLHAT. Participants were men and women, age = 55 years, who had Stage 1 or Stage 2 hypertension with at least one additional risk factor for CHD events. Randomized participants were assigned to receive amlodipine, chlorthalidone, doxazosin, or lisinopril as their initial study antihypertensive drug. Participants with LDL-cholesterol values in the eligible range and who were otherwise eligible for the lipid-lowering component were randomized to 40 mg/day of pravastatin or usual care. This presentation focuses on the antihypertensive component of ALLHAT.

14. Diabetes Incidence Among participants without diabetes at baseline, diabetes incidence was higher among participants randomized to chlorthalidone than among those randomized to doxazosin (9.5% vs 4.7% at 2 years, 10.6% vs 8.8% at 4 years).Among participants without diabetes at baseline, diabetes incidence was higher among participants randomized to chlorthalidone than among those randomized to doxazosin (9.5% vs 4.7% at 2 years, 10.6% vs 8.8% at 4 years).

15. Combined CVD risk was 20% higher (4 year rates of 28.6 vs. 25.1/100) among participants randomized to doxazosin compared to chlorthalidone.Combined CVD risk was 20% higher (4 year rates of 28.6 vs. 25.1/100) among participants randomized to doxazosin compared to chlorthalidone.

16. Final Results Confirm That for Doxazosin / Chlorthalidone: 20% ? risk of combined CVD 80% ? risk of heart failure 26% ? risk of stroke No difference for CHD or for total mortality These final results confirm that for doxazosin vs chlorthalidone: 20% ? risk of combined CVD 80% ? risk of heart failure 26% ? risk of stroke No difference for CHD or for total mortality There is increased risk for some CV events for doxazosin in spite of lower total cholesterol and lower fasting glucose. These final results confirm that for doxazosin vs chlorthalidone: 20% ? risk of combined CVD 80% ? risk of heart failure 26% ? risk of stroke No difference for CHD or for total mortality There is increased risk for some CV events for doxazosin in spite of lower total cholesterol and lower fasting glucose.

17. Randomized Designof ALLHAT Participants were men and women, age = 55 years, who had Stage 1 or Stage 2 hypertension with at least one additional risk factor for CHD events. Randomized participants were assigned to receive amlodipine, chlorthalidone, doxazosin, or lisinopril as their initial study antihypertensive drug. Participants with LDL-cholesterol values in the eligible range and who were otherwise eligible for the lipid-lowering component were randomized to 40 mg/day of pravastatin or usual care. This presentation focuses on the antihypertensive component of ALLHAT. Participants were men and women, age = 55 years, who had Stage 1 or Stage 2 hypertension with at least one additional risk factor for CHD events. Randomized participants were assigned to receive amlodipine, chlorthalidone, doxazosin, or lisinopril as their initial study antihypertensive drug. Participants with LDL-cholesterol values in the eligible range and who were otherwise eligible for the lipid-lowering component were randomized to 40 mg/day of pravastatin or usual care. This presentation focuses on the antihypertensive component of ALLHAT.

18. Biochemical Results � Fasting Glucose � mmol/l (�SD) The respective mean fasting serum glucose levels at baseline were 123.5, 123.1, and 122.9 mg/dL (6.9, 6.8 and 6.8 mmol/L); at 4 years, the respective mean levels were 126.3, 123.7, and 121.5 mg/dL (7.0, 6.9, and 6.7 mmol/L). The comparison of the lisinopril and chlorthalidone groups was statistically significant at p<.05. Among individuals classified as nondiabetic at baseline, with baseline fasting serum glucose less than 126 mg/dl (7.0 mmol/L), incidence of diabetes (fasting serum glucose ?126 mg/dl) at four years was 11.6%, 9.8%, and 8.1%, respectively. Both comparisons with the chlorthalidone group were statistically significant at p<.05. The respective mean fasting serum glucose levels at baseline were 123.5, 123.1, and 122.9 mg/dL (6.9, 6.8 and 6.8 mmol/L); at 4 years, the respective mean levels were 126.3, 123.7, and 121.5 mg/dL (7.0, 6.9, and 6.7 mmol/L). The comparison of the lisinopril and chlorthalidone groups was statistically significant at p<.05. Among individuals classified as nondiabetic at baseline, with baseline fasting serum glucose less than 126 mg/dl (7.0 mmol/L), incidence of diabetes (fasting serum glucose ?126 mg/dl) at four years was 11.6%, 9.8%, and 8.1%, respectively. Both comparisons with the chlorthalidone group were statistically significant at p<.05.

19. Biochemical Results � Fasting Glucose � mmol/l (�SD) The respective mean fasting serum glucose levels at baseline were 123.5, 123.1, and 122.9 mg/dL (6.9, 6.8 and 6.8 mmol/L); at 4 years, the respective mean levels were 126.3, 123.7, and 121.5 mg/dL (7.0, 6.9, and 6.7 mmol/L). The comparison of the lisinopril and chlorthalidone groups was statistically significant at p<.05. Among individuals classified as nondiabetic at baseline, with baseline fasting serum glucose less than 126 mg/dl (7.0 mmol/L), incidence of diabetes (fasting serum glucose ?126 mg/dl) at four years was 11.6%, 9.8%, and 8.1%, respectively. Both comparisons with the chlorthalidone group were statistically significant at p<.05. The respective mean fasting serum glucose levels at baseline were 123.5, 123.1, and 122.9 mg/dL (6.9, 6.8 and 6.8 mmol/L); at 4 years, the respective mean levels were 126.3, 123.7, and 121.5 mg/dL (7.0, 6.9, and 6.7 mmol/L). The comparison of the lisinopril and chlorthalidone groups was statistically significant at p<.05. Among individuals classified as nondiabetic at baseline, with baseline fasting serum glucose less than 126 mg/dl (7.0 mmol/L), incidence of diabetes (fasting serum glucose ?126 mg/dl) at four years was 11.6%, 9.8%, and 8.1%, respectively. Both comparisons with the chlorthalidone group were statistically significant at p<.05.

21. ALLHAT

22. ALLHAT Patienter som behandlades med doxazosin, amlodipin eller lisinopril utvecklade mindre ofta diabetes �n chlortalidionbehandlade. D�remot gav dessa behandlingar inte f�rre kardiovakul�ra komplikationer �r klortalidon.

23. Effects of Different Blood Pressure-Lowering Regimens on Major Cardiovascular Events in Individuals With and Without Diabetes MellitusBPLTTCArch Intern Med 2005;165:1410-1419 Effekten av blodtrycksl�kemedel p� hj�rt-k�rlsjukdom Mer /mindre intensiv behandling Skillnad mellan olika l�kemedel diabetiker vs icke-diabetiker 27 studier, 33 000 diabetiker, 125 000 icke-diabetiker Metaanalyser

24. Stroke 0ACEh-placebo ACEh - D/BBCaA-placebo CaA - D/BB Mer/mindre ACEh - CaA

25. Hj�rtinfarkt 0ACEh-placebo ACEh - D/BBCaA-placebo CaA - D/BB Mer/mindre ACEh - CaA

26. Hj�rtsvikt 0ACEh-placebo ACEh - D/BBCaA-placebo CaA - D/BB Mer/mindre ACEh - CaA

27. ARB

28. 

29. ACE-h - PlaceboACEh m�jligen effektivare vid DM att f�rhindra Hj�rt-k�rld�dTotal d�dlighet

30. Intensivare behandling - mindre intensivM�jligen mer effektiv hos diabetiker i att f�rhindraHj�rt-k�rlsjukdomarHj�rt-k�rld�d

31. BPLTTC Effekterna av de olika blodtryckss�nkande l�kemedelsgrupperna var t�mligen j�mf�rbara f�r diabetiker j�mf�rt med icke-diabetiker. M�jligen har diabetiker mer nytta av intensivare behandling �n icks-diabetiker

32. SHEPSystolic Hypertension in the Elderly Program JAMA 1991;265:3255-3264 4732 patienter med ISH Klortalidon 12,5 - 25 mg + atenolol/reserpin vid behov Dubbelblind placebokontrollerad behandling under 4,3 �r BT aktiv 155/71 mmHg placebo 144/68 mmHg

33. SHEP - Diabetes JAMA 1996;276:1886-1892 Kardiovaskul�ra H�ndelser Aktiv behandl - Placebo Relativ risk (95% CI) NNT 5 �r Diabetiker (n=683) 0,66 (0,55-0,79) 10 Ej Diabetiker (n=4149) 0.66 (0.46-0.94) 20

34. Systolic Hypertension in the elderly trialAm J Cardiol 2005;95:29-95 4732 patienter med ISH Klortalidon 12,5 - 25 mg + atenolol/reserpin vid behov Dubbelblind placebokontrollerad behandling under 4,3 �r Uppf�ljning 10 �r senare (s:a 14,3 �r)

35. SHEP

36. SHEP Risk (HR, 95% CI) f�r hj�rt-k�rld�d efter 14,3 �r DM f�re start/no DM 1,66 (1.12-1.95) � - diuretika/placebo 0.69 (0.53-0.85) DM under studien - jfr m icke diabetiker -�- diuretikabeh 1,04 (0,75-1,46) -�- placebobeh 1,56 (1,12-2,18)

37. Behandling av h�gt blodtryck vid hos diabetiker F�r att f�rebygga hj�rt-k�rlsjukdom Kombinationen diuretika/betablockerare har negativa effekter p� glukosmetabolismen. Om detta medf�r negativa effekter p� l�ng sikt f�r patienten �r �nnu oklart Val av antihypertensivt l�kemedel som hos icke-diabetiker. (M�jligen viss f�rdel f�r ACE-h�mmare) Mer intensiv behandling f�refaller viktigare hos diabetiker �n hos icke-diabetiker

38. �r ARB (Angiotensinreceptorblockerare) b�ttre �n ACE-h�mmare vid diabetesnefropati?

39. Diabetesnefropathi Effects of ACE inhibitors and ARB on mortality and renal outcomes in diabetic nephropathy: systematic review Strippoli et al BMJ 2004;329:828-38 Typ1 och typ 2 diabetes, nefropathi 36 studier (4008 patienter) ACEh - Placebo 4 studier (3331 patienter) ARB - Placebo 3 studier (206 patienter ) ARB - ACE

40. ACE-h�mmare - Placebo F�rdubbling av S-Krea ESRD (End stage renal disease)

41. ARB - Placebo

42. Effects of ACE inhibitors and ARB on mortality and renal outcomes in diabetic nephropathy: systematic reviewStrippoli et al BMJ 2004;329:828-38 ACEh ARB

43. DETAILDiabetics Exposed to Telmisartan and Enalapril studyBarnett AH et al. NEJM 2004;351:1952-61 250 typ 2 diabetiker Minst mikroalbuminuri, S-Krea <141umol/l Mild-m�ttlig hypertoni 5 �r

44. DETAILDiabetics Exposed to Telmisartan and Enalapril studyBarnett AH et al. NEJM 2004;351:1952-61

45. ESH/ESC riktlinjer f�r totalriskhantering: Hantering av blodtryck vid diabetes DM typ 2 eller typ 1 med mikroalbuminuri Upprepade BT =140/90 mmHg Behandlingsm�l <130/80 mmHg

46. I genomsnitt s�nker ett l�kemedel blodtrycket med c:a 10/5 mm HgMetaanalys av 347randomiserade placebokontrollerade studier. 56 000 patienterLaw MR et al BMJ 2003:326:1427-33

47. DagskostnadBlodtryckss�nkande behandling2005-09-30www.lfn.se

48. Blodtrycksm�tning hod diabetiker 28 diabetiker vid V�nn�s V�rdcentral BT-m�tning cross-over i randomiserad ordning Liggande arm i hj�rth�jd 162/90 mmHg Sittande h�ngande arm 159/94 mmHg Sittande arm i hj�rth�jd 152/84 mmHg Roger Jonsson, V�nn�s VC

49. Sammmanfattning Diabetiker har st�rre nytta av blodtrycksbehandling �n icke-diabetiker Behandlingen b�r vara intensivare Vid diabetesnefropati f�refaller ACE-h�mmare fungera minst lika bra som ARB F�r �vrigt finns f� anledningar att behandla diabetikers blodtryck med andra l�kemedel �n icke-diabetiker