Dott.ssa B. Bassi Dr. G. Bondi Dr. C. Camporesi Dott.ssa L. Gardelli Dr. F. Girelli Dr. V. Mazzeo

Premessa Il principale obiettivo di una terapia è quello di trarre il massimo beneficio e di ridurre al minimo i rischi La terapia antiipertensiva, nel paziente diabetico e nefropatico ha in particolare come obiettivo “in primis” quello ridurre la mortalità e gli eventi CV, ma anche quello potenziale di ridurre l’eventuale incidenza e/o evoluzione delle complicanze micro- vascolari per il DM e prevenire e/o ritardare il deterioramento della funzione renale

Prospective Studies Collaboration. Lancet. 2002;360: CHD and Stroke Mortality vs. Usual BP by Age

Cumulative incidence of cv events in subjects without hypertension Vasan RS et al, NEJM 2001

Age-adjusted 16-year Incidence of all cause end-stage renal disease by systolic and diastolic blood pressure in white men and African-American men MRFIT Study Klag M.J.JAMA. 1997;277:

Relative risk for kidney disease progression based on current level of systolic blood pressure and current urine protein excretion. A Patient-Level Meta-Analysis Jafar TH Ann Intern Med. 2003;139:

HOT Study: significant benefit from intensive treatment in the diabetic subgroup Hansson L et al. Lancet  90  85  80 Major cardiovascular events/1,000 patient-years p=0.005 for trend mm Hg Target Diastolic Blood Pressure

Any clinical end point, fatal or non-fatal, related to diabetes. Mortality for disease related to diabetes (myocardial infarction, sudden death, stroke, peripheral vascular disease, and renal failure). Microvascular end points (mostly retinal photocoagulation), fatal or non-fatal myocardial infarction or sudden death, and fatal or non-fatal strokes. UKPDS study British Medical Journal Publishing Group et al. BMJ 1998;317: Less tight control: 154/87 mmHg Tight control: 144/82 mmHg -24% -32% -37% -44% -21%

Blood pressure and cardiovascular death < >160 Systolic blood pressure (mmHg) Cardiovascular death (%) Diabetics n=3,305 death rate - 5.3% Non-diabetics n=88,257 death rate - 2.2% Asia-Pacific Cohort Studies Collaboration. Diabetes Care. 2004;27:

✓  Uno studio osservazionale ci può dare interessanti informazioni, ma è suscettibile di possibili errori, come quello di selezione dei pazienti ✓  L’interpretazione dei risultati in studi “post hoc” in base al target PA raggiunto, tradisce il principio della randomizzazione e “intention to treat analysis” ✓  Comparare targets pressori raggiunti in diversi trials può non essere appropriato (terapia concomitante, diverso profilo di rischio cardiovascolare) I LIMITI DEGLI STUDI

Estimated mean changes (SE) in glomerular filtration rate (GFR) (mL /min per 1.73 m2) from baseline through follow-up in the 2 blood pressure goal interventions AASK Study P=0.24 J.T. Wright et al. JAMA, November 20, 2002—Vol 288, No. 19 Usual BP goal: 141/85 mmHg Lower BP goal: 128/78 mmHg 1094 African Americans aged 18 to 70 years with hypertensive renal disease (GFR, mL/min per 1.73m2

(P<0.001) Estimated percentage changes in the urine protein/creatinine ratio from baseline throughout follow-up by blood pressure AASK study J.T. Wright et al. JAMA, November 20, 2002—Vol 288, No. 19 Usual BP goal: 141/85 mmHg Lower BP goal: 128/78 mmHg 1094 African Americans aged 18 to 70 years with hypertensive renal disease (GFR, mL/min per 1.73m2

Usual BP :…….. <140/90 mmHg Low BP : <125/75 mmHg p= p= Samak M.J. et al. Ann Intern Med. 2005;142: Cumulative probability of kidney failure (top) and cumulative probability of the composite of kidney failure or all-cause mortality before kidney failure (bottom). MDRD Study 840 persons with predominantly nondiabetic kidney disease and a glomerular filtration rate of 13 to 55 mL/minper 1.73 m2.

Cruickshank JM. Cardiovasc Drugs Ther 2000;14(4):373—9. Fenomeno della curva J

Incidence of total MI and total stroke by DBP pressure strata in patients with HBP and CAD enrolled in the INVEST Messerli FH et Al, Ann Intern Med 2006;144:

Studio PROGRESS: curva J non evidente per l’ictus ischemico ed emorragico (p = 0,0005)(p < 0,0001) Arima H, et al. J Hypertens 2006;24(6):1201—8.

Sintesi degli studi clinici favorevoli alla curva J

Messerli F, Mancia G, et al. Ann Intern Med 2006 Dogma discusso: Un uso aggressivo degli agenti ipotensivanti nei pazienti ipertesi con malattia coronarica può essere pericoloso?

JNC VIIESH/ESC 2007 JAMA 2003; 289: J Hypertens 2007; 25: < 140/90 mmHg < 130/80 mmHg nei diabetici 1 g/die < 130/80 mmHg nella insufficienza renale cronica

Average BP during follow-up Placebo arm: 140.3/77 mmHg Perindopril-Indapamide arm: 134.7/74.8 mmHg Effects of blood pressure lowering on death and macrovascular and microvascular disease (coronary and renal) : the ADVANCE Trial Advance collaborative Group Lancet 2007; 370: 829–40

PAS vs Δ 3.9 mmHg PAD 81.7 vs 85.1 Δ 3.4 mmHg Seven trials (22,089 subjects) AASK, ABCD (H), ABCD (N), HOT, MDRD, REIN-2, TOTO Arguedas JA et al, Cochrane Database Syst Rev 2009: CD Mortality and morbidity associated with lower vs standard blood pressure targets (Review)

Law, M R et al. BMJ 2009;338:b1665 Relative risk estimates of coronary heart disease events and stroke in blood pressure difference trials according to pre-treatment diastolic and systolic blood pressures (taken as average in placebo group over course of trial).

Effects of active treatment vs. placebo on recurrent stroke in patients with different baseline BP values in the PROGRESS trial Arima H et al, J Hypertens 2006

Prognostic between changes in SBP from baseline to follow up of blood pressure in patients with high vascular risk ONTARGET STUDY Sleight P. et al, Journal of Hypertension. 27(7): , July Quartile 1: baseline SBP  130 mmHg Quartile 2: baseline SBP mmHg Quartile 3: baseline SBP mmHg Quartile 4 baseline: SBP > 154 mmHg

SBPAchieved(mmHg) % CV event reduction S. Eur DMSHEPDMUKPDSHOTDM HOPE ADVABCDHTABCDNT Blood Pressure Lowering and Cardiovascular Prevention in Diabetes Zanchetti et al. J Hypertens 2009; 27:

Achieved SBP in patients randomized to a more active or less active treatment in clinical trials in hypertension Mancia G et al, J Hypertens 2009

ESH reappraisal 2009 J Hypertens 2009; 27: < 140/90 mmHg in tutti i pazienti ipertesi < 130/80 mmHg nei diabetici e nei pazienti a rischio molto elevato (pregressi eventi cardiovascolari) (può essere una raccomandazione ‘saggia’, sebbene ‘non supportata in misura consistente dai trials’) /80-85 in tutti i pazienti ipertesi (possibilmente ai limiti bassi di questo range)

HR = % CI ( ) P 0.20 Primary Outcome Nonfatal MI, Nonfatal Stroke or CVD Death Total Mortality HR = % CI ( ) P 0.55 CVD Deaths HR = % CI ( ) P 0.74 PAS : mmHg PAS: mmHg ACCORD study N Engl J Med 2010; /NEJMoa

Non Fatal MI HR = % CI ( ) P 0.25 Nonfatal Stroke HR = % CI ( ) P 0.03 Total Stroke HR = % CI ( ) P 0.01 PAS : mmHg PAS: mmHg ACCORD study N Engl J Med 2010; /NEJMoa

Intensive N (%) Standard N (%) P Serious AE77 (3.3)30 (1.3)< Hypotension 17 (0.7)1 (0.04)< Syncope 12 (0.5)5 (0.2)0.10 Bradycardia or Arrhythmia 12 (0.5)3 (0.1)0.02 Hyperkalemia 9 (0.4)1 (0.04)0.01 Renal Failure5 (0.2)1 (0.04)0.12 eGFR ever <30 mL/min/1.73m 2 99 (4.2)52 (2.2)<0.001 Any Dialysis or ESRD59 (2.5)58 (2.4)0.93 Dizziness on Standing † 217 (44)188 (40)0.36 † Symptom experienced over past 30 days from HRQL sample of N=969 participants assessed at 12, 36, and 48 months post-randomization ADVERSE EVENTES ACCORD STUDY

Arch Intern Med. 2012;172(17): BP to intensive targets (< 130/80 mm Hg ) compared BP to standard targets (< / mmHg)

Mortality Myocardial infarction Stroke Intensive and Standard Blood Pressure Targets in Patients With Type 2 Diabetes Mellitus Systematic Review and Meta-analysis Arch Intern Med. 2012;172(17): RR 0.76; 95% CI, RR 0.93; 95%CI, ) RR 0.65; 95% CI, )

Effects of intensive blood pressure lowering on progressive kidney failure. Lv J et al. CMAJ 2013;185: ©2013 by Canadian Medical Association HR overall : 0.82 ( ) HR overall : 0.79 ( )

Subgroup analysis of the effect of intensive blood pressure lowering on kidney failure in patients with proteinuria compared with those without proteinuria. Lv J et al. CMAJ 2013;185: ©2013 by Canadian Medical Association

Occurrence of Microalbuminuria during the 48-Month Follow-up Period ROADMAP STUDY Risk reduction in favour of Olmesartan: 23% (p=0.01) Risk reduction only in patients with baseline SBP> 135 mmHg (p=0.03) Haller H. et al. N Engl J Med 2011;364:

Haller H. N Engl J Med 2011;364: ROADMAP Study

✓ Uno studio osservazionale ci può dare interessanti informazioni, ma è suscettibile di possibili errori, come quello di selezione dei pazienti ✓ L’interpretazione dei risultati in studi “post hoc” in base al target PA raggiunto, tradisce il principio della randomizzazione e “intention to treat analysis” ✓ Comparare targets pressori raggiunti in diversi trials può non essere appropriato (terapia concomitante, diverso profilo di rischio cardiovascolare) I LIMITI DEGLI STUDI

Adjusted incidence RRs (95% CI) for stroke, myocardial infarction (MI), and other major cardiovascular (CV) events estimated based on mean level of blood pressure control in the year after hypertension onset. O’Connor P J et al. Dia Care 2013;36: ,665 adults with diabetes but no diagnosed coronary or cerebrovascular disease at baseline mean 38-month follow-up period.

2007 ESH/ESC Guidelines: Initiation of Antihypertensive Treatment Established CV or renal disease Lifestyle changes + Immediate drug treatment Lifestyle changes + Immediate drug treatment Lifestyle changes + Immediate drug treatment Lifestyle changes + Immediate drug treatment Lifestyle changes + Immediate drug treatment Lifestyle changes + Immediate drug treatment Lifestyle changes + Drug treatment Lifestyle changes + Drug treatment Lifestyle changes and consider drug treatment Lifestyle changes ≥ 3 Risk Factors, MS or OD Lifestyle changes + Immediate drug treatment Lifestyle changes for several weeks then drug treatment if BP uncontrolled Lifestyle changes for several weeks then drug treatment if BP uncontrolled Lifestyle changes 1-2 risk factors Lifestyle changes + Immediate drug treatment Lifestyle changes for several weeks then drug treatment if BP uncontrolled Lifestyle changes for several months then drug treatment if BP uncontrolled No BP intervention No other risk factors Grade 3 HT SBP ≥ 180 or DBP ≥ 110 Grade 2 HT SBP or DBP Grade 1 HT SBP or DBP High Normal SBP or DBP Normal SBP or DBP Other risk factors OD or disease Diabetes Blood Pressure (mmHg) Established CV or renal disease Lifestyle changes + Drug treatment

Summary of recommendations on initiation of antihypertensive drug treatment BP = blood pressure; CKD = chronic kidney disease; CV = cardiovascular; CVD = cardiovascular disease; DBP = diastolic blood pressure; HT = hypertension; OD = organ damage; RF = risk factor; SBP = systolic blood pressure ESH/ESC Guidelines for the managment of arterial hypertension

2013 ESH/ESC Guidelines for the management of arterial hypertension Treatment strategies in patients with diabetes

2013 ESH/ESC Guidelines for the management of arterial hypertension Therapeutic strategies in hypertensive patients with nephropathy

OBIETTIVI PRESSORI (LG ESH/ESC 2013) Obiettivo Generale < 140/90 mmHg Diabetici < 140/85 mmHg Nefropatici I A SBP < 140 mmHgIIa B Anziani < 80 aa SBP mmHg I A Anziani < 80 aa In buone condizioni SBP < 140 mmHg IIb C Anziani > 80 aa In buone condizioni fisiche e mentali SBP mmHg I B Nefropatici con franca proteinuria SBP <130 mmHgIIb B

 People with diabetes and hypertension should be treated to a systolic blood pressure (SBP) goal of < 140 mmHg. B  Lower systolic targets, such as <130 mmHg, may be appropriate for certain individuals, such as younger patients, if it can be achieved without undue treatment burden. C  Patients with diabetes should be treated to a diastolic blood pressure (DBP) < 80 mmHg. B

Clinical Practice Guidelines for the management of blood pressure in chronic kidney diseases Nefropatia diabetica e non con albuminuria < 30 mg/24h ≤ 140/90 mmHg Nefropatia diabetica e non con albuminuria fra 30 e 300 mg/24h o proteinuria franca ≤ 130/80 mmHg Nefropatia diabetica e non con albuminuria fra 30 e 300 mg/24h o proteinuria franca ARB/ ACEi Kidney International supplements vol. 2, issue 5, Dec 2012

TAKE HOME MESSAGE Nel diabete mancano chiare evidenze di benefici nell’iniziare un trattamento antiipertensivo per valori di PAS < 140 mmHg o addirittura <130 mmHg ed anzi una riduzione troppo aggressiva e rapida potrebbe rivelarsi pericolosa La riduzione della proteinuria è globalmente considerata come un target terapeutico (studi osservazionali da RCTs  variazioni della proteinuria sono predittori di eventi CV e renali) ✓ Mancano comunque solide evidenze in gruppi randomizzati di una relazione fra riduzione della proteinuria ed eventi CV e renali ✓ Malgrado ciò le ultime LG incoraggiano globalmente la riduzione della PAS < 130 mmHg nella nefropatia diabetica e non, in presenza di proteinuria franca. ✓ Obiettivi pressori più rigorosi potrebbero essere ricercati in pazienti selezionati (ad alto rischio di ictus, diabete di recente insorgenza, assenza di coronaropatia) ✓ La letteratura più recente sembra infatti suggerire di spostare l’attenzione dal “target pressorio” al “momento temporale” in cui questo obiettivo pressorio deve essere raggiunto (importanza di una diagnosi tempestiva di ipertensione)

TAKE HOME MESSAGE (2) I farmaci più indicati per ridurre la PA nei pazienti diabetici e/o nefropatici sono rappresentati dagli ACEi e sartani il doppio blocco con ACEi e sartani non è praticamente mai indicato ✓ prudenza nell’associare ACEi e sartani con diuretici antialdosteronici

<140/90? <130/90?