Ο ΡΟΛΟΣ ΤΗΣ ΜΑΝΙΔΙΠΙΝΗΣ Η ΔΙΑΧΕΙΡΙΣΗ ΤΗΣ ΥΠΕΡΤΑΣΗΣ ΜΕΣΑ ΑΠΟ ΤΟ ΠΡΙΣΜΑ ΤΟΥ ΣΥΝΟΛΙΚΟΥ ΚΑΡΔΙΑΓΓΕΙΑΚΟΥ ΚΙΝΔΥΝΟΥ Ο ΡΟΛΟΣ ΤΗΣ ΜΑΝΙΔΙΠΙΝΗΣ ΜΩΥΣΗΣ ΕΛΙΣΑΦ, ΚΑΘΗΓΗΤΗΣ ΠΑΘΟΛΟΓΙΑΣ ΙΑΤΡΙΚΗΣ ΣΧΟΛΗΣ ΠΑΝΕΠΙΣΤΗΜΙΟΥ ΙΩΑΝΝΙΝΩΝ

ΜΑΝΙΔΙΠΙΝΗ Αποκλείει τους L-type διαύλους Ca2+, αλλά επίσης και τους T-type διαύλους Ca2+ Τρίτης γενεάς διυδροπυριδίνη Μεγάλη λιποφιλικότητα Αγγειοεκλεκτικό φάρμακο Μακρά διάρκεια δράσης Λιγότερες ανεπιθύμητες ενέργειες (οιδήματα) Μεγάλη αποτελεσματικότητα (10-20mg/d) Απεκκρίνεται κυρίως με τα κόπρανα

ΕΝΑ ΑΠΟΤΕΛΕΣΜΑΤΙΚΟ ΑΝΤΙΥΠΕΡΤΑΣΙΚΟ ΦΑΡΜΑΚΟ ΜΑΝΙΔΙΠΙΝΗ ΕΝΑ ΑΠΟΤΕΛΕΣΜΑΤΙΚΟ ΑΝΤΙΥΠΕΡΤΑΣΙΚΟ ΦΑΡΜΑΚΟ

MANIDIPINE (20mg) VS AMLODIPINE (10mg) A meta-analysis of head to head trials 4 τυχαιοποιημένες μελέτες, n=838 (436 manidipine, 402 amlodipine) ΠΑΡΟΜΟΙΑ ΜΕΙΩΣΗ ΤΗΣ ΑΠ (κατά 18.3 και 17.3mmHg/ 8.5 και 10.5mmHg) ΛΙΓΟΤΕΡΕΣ ΑΝΕΠΙΘΥΜΗΤΕΣ ΕΝΕΡΓΕΙΕΣ ΜΕ MANIDIPINE (σχετικός κίνδυνος 0.69) ΜΙΚΡΟΤΕΡΟΣ ΚΙΝΔΥΝΟΣ ΕΜΦΑΝΙΣΗΣ ΠΕΡΙΦΕΡΙΚΩΝ ΟΙΔΗΜΑΤΩΝ (σχετικός κίνδυνος 0.35) Blood Pressure 2011;20:54-59

ΛΙΓΟΤΕΡΑ ΠΕΡΙΦΕΡΙΚΑ ΟΙΔΗΜΑΤΑ ΜΑΝΙΔΙΠΙΝΗ ΛΙΓΟΤΕΡΑ ΠΕΡΙΦΕΡΙΚΑ ΟΙΔΗΜΑΤΑ ΚΑΛΥΤΕΡΗ ΣΥΜΜΟΡΦΩΣΗ ΤΩΝ ΑΣΘΕΝΩΝ ΣΤΗΝ ΑΓΩΓΗ

ΣΧΕΤΙΚΟΣ ΚΙΝΔΥΝΟΣ ΕΜΦΑΝΙΣΗΣ ΠΕΡΙΦΕΡΙΚΩΝ ΟΙΔΗΜΑΤΩΝ Manidipine vs άλλες κλασικές διϋδροπυριδίνες: 0.38 J Hypertens 2011;29: 1270-1280

ΑΝΤΙΡΡΟΠΙΣΤΙΚΗ ΕΝΕΡΓΟΠΟΙΗΣΗ ΤΟΥ ΣΝΣ ΑΝΤΑΓΩΝΙΣΤΕΣ Ca2+ ΑΓΓΕΙΟΔΙΑΣΤΟΛΗ ΑΝΤΙΡΡΟΠΙΣΤΙΚΗ ΕΝΕΡΓΟΠΟΙΗΣΗ ΤΟΥ ΣΝΣ

MANIDIPINE VS AMLODIPINE Μικρότερη ενεργοποίηση του ΣΝΣ Λιγότερα περιφερικά οιδήματα J Hypertens 2000;18suppl2:S154-155

in type 2 diabetic patients Activation of SNS in diabetics: Manidipine vs amlodipine, both on top of RAS blockers Martinez-Martin F.J. – J Hypertens 2005; 23(suppl 2): S376 MANIDIPINE: safety in type 2 diabetic patients Safety assessment  activation of SNS MANIDIPINE AMLODIPINE    METAEPINEPHRINE  NOREPINEPHRINE BASAL µg/g Cr 200 250 24 WEEK 200,8 248,75 210,4* 295,5* SLIDE 46 Activation of the SNS was assessed by measuring both the metadrenaline (metaepinephrine) and noradrenaline (norepinephrine)/creatinine (Cr) ratios in overnight urine. After 24 weeks of therapy, among patients treated with manidipine (on top of RAS inhibitors) the sympathetic activity remains unchanged, while with amlodipine there was a significant increase in both adrenergic and noradrenergic levels. These results confirm the lack of SNS activation with manidipine. Accordingly, the use of calcium antagonists, such as manidipine, that do not stimulate the sympathetic system should be beneficial in treating hypertensive patients by reducing the incidence of sympathetic related cardiovascular complications. * p < 0.05 vs manidipine Cr = creatinine

10

11

Manidipine: tolerability Lipophilic behaviour Lack of sympathetic activation Both pre-capillary arterioles and post-capillary venules relaxation Less incidence of ankle oedema SLIDE 8 The rapid onset of vasodilatory effects is likely to be associated with activation of the baroreflex, causing stimulation of the sympathetic nervous system and associated increases in plasma norepinephrine levels. In particular, venular side is very sensitive to norepinephrine due to the presence of alpha-adrenergic receptors. For this reason, in case of SNS activation, venular constriction occurs. This phenomenon leads to an increase in intracapillary pressure, that results, as a final step, in pedal oedema. Manidipine, thanks to its lipophilic profile, is not associated with a rapid and intense increase in its plasmatic concentration leading to an abrupt vasodilation. As a consequence, both the baroreflex activation and the consequent venular constriction are markedly blunted: less venular constriction  less increase in intracapillary pressure  less ankle edema.

13

THE MAISH STUDY MANIDIPINE (10-20mg/d) vs AMLODIPINE (5-10mg/d) IN ELDERLY PATIENTS WITH ISOLATED SYSTOLIC HYPERTENSION SBP -19.5+11.8mmHg vs -18.4+11.1mmHg ΠΕΡΙΦΕΡΙΚΑ ΟΙΔΗΜΑΤΑ 4% vs 9% Clin Drug Invest 2007;27:623-632

ΠΛEIΟΤΡΟΠΙΚΕΣ ΔΡΑΣΕΙΣ ΤΩΝ ΔΙΥΔΡΟΠΥΡΙΔΙΝΩΝ: Ο ΡΟΛΟΣ ΤΗΣ MANIDIPINE

MANIDIPINE & ΟΜΟΙΟΣΤΑΣΙΑ ΤΩΝ ΥΔΑΤΑΝΘΡΑΚΩΝ AMLODIPINE (5mg) MANIDIPINE (20mg) ΓΛΥΚΟΖΗ (mg/dl) 101 99 105 103 HbA1C(%) 5.8 5.7 Intern Med 2004;43:561-563

MANIDIPINE (10mg/d) vs ENALAPRIL (10mg/d) MONOTHERAPY IN PATIENTS WITH HYPERTENSION AND TYPE 2 DIABETES ΠΑΡΟΜΟΙΕΣ ΜΕΙΩΣΕΙΣ ΤΗΣ ΑΠ HbA1c (%) από 6.7% σε 6.2%, p<0.05 MANIDIPINE ΓΛΥΚΟΖΗΣ από 152 σε 143mg/dl, p<0.05 Clin Ther 2005;27:166-173

ALBUMIN/CREATININE (-28.2%) THE MARCADOR STUDY MANIDIPINE (20mg/d) ως μονοθεραπεία και σε συνδυασμό με lisinopril (10mg/d) INSULIN HOMA (-26.5%) ADIPONECTIN OXLDL FFA hsCRP ΚΥΤΤΑΡΟΚΙΝΩΝ ALBUMIN/CREATININE (-28.2%) Clin Drug Invest 2011;31:201-211

ΔΥΣΜΕΝΗΣ ΕΠΙΔΡΑΣΗ ΣΤΗΝ ΟΜΟΙΟΣΤΑΣΙΑ ΤΩΝ ΥΔΑΤΑΝΘΡΑΚΩΝ ΣΤΑΤΙΝΕΣ ΔΥΣΜΕΝΗΣ ΕΠΙΔΡΑΣΗ ΣΤΗΝ ΟΜΟΙΟΣΤΑΣΙΑ ΤΩΝ ΥΔΑΤΑΝΘΡΑΚΩΝ  ΑΝΤΙΣΤΑΣΗΣ ΣΤΗ ΔΡΑΣΗ ΤΗΣ ΙΝΣΟΥΛΙΝΗΣ  ΕΠΙΠΤΩΣΗΣ ΤΟΥ ΝΕΟΕΜΦΑΝΙΖΟΜΕΝΟΥ ΣΑΚΧΑΡΩΔΗ ΔΙΑΒΗΤΗ

EFFECTS OF MANIDIPINE PLUS ROSUVASTATIN VERSUS OLMESARTAN PLUS ROSUVASTATIN ON MARKERS OF INSULIN RESISTANCE IN PATIENTS WITH IMPAIRED FASTING GLUCOSE, HYPERTENSION AND MIXED DYSLIPIDEMIA Ασθενείς (n=40) Patients with impaired fasting glucose, mixed dyslipidemia, and stage 1 hypertension were included. ROSUVASTATIN (10 mg)+ OLMESARTAN (20 mg) (n=20) ROSUVASTATIN (10 mg) + MANIDIPINE (20 mg) (n=20) METEOR is a randomised, double-blind, placebo-controlled, parallel-group, multicentre phase III study of rosuvastatin 40 mg in the prevention of atherosclerosis among asymptomatic patients assessed as being at low risk of CHD. Patients are asymptomatic for atherosclerosis and are considered at low risk of CHD according to conventional risk factors; 10-year CHD risk is assessed using the Framingham Risk Index. 984 patients were recruited from approximately 30 US and European centres and randomised to receive rosuvastatin or placebo in a 5:2 ratio. The 5:2 randomisation ratio in METEOR is due to the primary endpoint consisting of a two-stage test. See the following slide. Reference Crouse III JR et al. Measuring Effects on Intima Media Thickness: an Evaluation of Rosuvastatin in Subclinical Atherosclerosis – The Rationale and Methodology of the METEOR Study. Cardiovasc Drugs Ther 2004; 18: 231–238. Adapted from Cardiovasc Drugs Ther 2004; 18: 231–238, with permission from Springer. Επίσκεψη: Εβδομάδα: 1 –6 2 –4 3 –2 4 5 6 6 13 Run in / eligibility BP Lipids HOMA-IR BP Lipids HOMA-IR BP=Blood pressure Liberopoulos E et al. JCPT 2013; 18: 113-8

MANIDIPINE + ROSUVASTATIN vs OLMESARTAN + ROSUVASTATIN (3 μήνες αγωγής) MANI + ROSUVA OLME + ROSUVA (n=20) (n=20) HOMA-IR 0% +14.0% p=0.04 Insulin +3.0% +8.0% p=0.02 Liberopoulos E et al. JCPT 2013; 18: 113-8

+ ΟΥΔΕΤΕΡΗ ΕΠΙΔΡΑΣΗ ΣΤΗΝ ΟΜΟΙΟΣΤΑΣΙΑ ΤΩΝ ΥΔΑΤΑΝΘΡΑΚΩΝ ΜΑΝΙΔΙΠΙΝΗ ΕΥΝΟΪΚΗ ΕΠΙΔΡΑΣΗ ΣΤΗΝ ΟΜΟΙΟΣΤΑΣΙΑ ΤΩΝ ΥΔΑΤΑΝΘΡΑΚΩΝ ΣΤΑΤΙΝΕΣ ΔΥΣΜΕΝΗΣ ΕΠΙΔΡΑΣΗ ΣΤΗΝ ΟΜΟΙΟΣΤΑΣΙΑ ΤΩΝ ΥΔΑΤΑΝΘΡΑΚΩΝ + ΟΥΔΕΤΕΡΗ ΕΠΙΔΡΑΣΗ ΣΤΗΝ ΟΜΟΙΟΣΤΑΣΙΑ ΤΩΝ ΥΔΑΤΑΝΘΡΑΚΩΝ

ΜΑΝΙΔΙΠΙΝΗ & ΟΡΓΑΝΟΠΡΟΣΤΑΣΙΑ

MANIDIPINE VS ENALAPRIL ΣΕ ΔΙΑΒΗΤΙΚΟΥΣ ΑΣΘΕΝΕΙΣ ΜΕ ΜΙΚΡΟΑΛΒΟΥΜΙΝΟΥΡΙΑ 24 εβδομάδες MANIDIPINE ENALAPRIL LVMI -14.9g/m2 -10.8g/m2 LVMI σε ασθενείς με υπερτροφία της αριστεράς κοιλίας -19.8g/m2 -12.8g/m2 p<0.05 SBP/DBP (mmHg) -22.3/15.5 -21.4/15.7 AER (mg/24h) -29.9 -37.2 Eur J Clin Pharmacol 2005;61:483-490

Cardioprotective efficacy  LVMI reduction more protection Cardioprotection in diabetics: Manidipine vs lisinopril Fogari R. et al - Eur J Clin Pharmacol 2005; 61: 483-490 Cardioprotective efficacy  LVMI reduction SLIDE 38 The picture clearly illustrate a higher effect of manidipine on LVMI reduction compared to lisinopril.

Lack of sympathetic activation Cardiovascular protection Manidipine: safety Lipophilic behaviour Slow onset of action Lack of sympathetic activation (Reduction in circulating catecholamines & avoidance of heart rate increase) SLIDE 7 In hypertension, the sympathetic nervous system (SNS) activation is a key factor in the pathogenesis of the disorder. However, it also promotes both comorbidities (i.e. atherosclerosis, cardiac arrhythmias) and organ damage (i.e. cardiovascular hypertrophy), conditions often associated with hypertension. The potent vasodilator effect exerted by dihydropyridines may lead to marked activation of the baroreflex and, in turn, to an increase in heart rate and sympathetic nervous system (SNS) activity. Sympathetic activation is not confined to rapid, short-acting calcium antagonists but may occur also with certain slow-onset, long-acting dihydropyridines and may persist over longer periods of time. It is now clear that not all dihydropyridines are created equal in terms of sympathetic activation. For instance, manidipine thanks to its lipophilic, highly vasculature-selective properties, ensures a slow onset, smooth and prolonged duration of action. This prevents the abrupt fall in blood pressure and the accompanying sympathetic activation and reflex tachycardia. Accordingly, the use of calcium antagonists, such as manidipine, that do not stimulate the sympathetic system should be beneficial in treating hypertensive patients by reducing the incidence of sympathetic related cardiovascular complications Cardiovascular protection

Aim of the study Study design Results more efficacy 5 – Antihypertensive efficacy in diabetics: AMANDHA study: add-on manidipine vs amlodipine, Martinez-Martin F. J. & Saiz-Satjes M - Expert Rev Cardiovasc Ther 2008; 6(10): 1347-1355 more efficacy Aim of the study To compare the antihypertensive efficacy of the addition of manidipine 20 mg/day or amlodipine 10/day in type 2 diabetic patients with uncontrolled hypertension (BP >130/80 mmHg) despite full-dose treatment with a renin-angiotensin system (RAS) blocker (ACE-I or ARB) Study design Parallel, Randomized, Open, Blind Endpoint (PROBE) trial Number of patients = 91. Duration = 24 weeks, after at least 24 weeks of treatment with RAS blockers SLIDE 26 The aim of the study was to evaluate the blood pressure lowering effect of manidipine or amlodipine in type 2 diabetic patients with uncontrolled hypertension (BP >130/80 mmHg) despite higher doses of renin-angiotensin system blockers (i.e ACE inhibitors or ARBs). Patients were randomised to receive manidipine (20mg/day) or amlodipine (10mg/day) on top of a renin-angiotensin blocker medication. Although the study was not specifically designed to evaluate the efficacy of Vivace, the beneficial effects deriving from the combination of a calcium channel blocker, such as manidipine, and an inhibitors of RAS (the class of drugs which delapril belongs to) add a further piece of evidence on the clinical benefit of Vivace. Results Both combination treatments produced a similar significant reduction in systolic and diastolic blood pressure Manidipine reduced pulse pressure more effectively than amlodipine (p<0.001) ACEI or ARB treatments: each drug was given at full-dose

Manidipine Amlodipine P value 5 – Antihypertensive efficacy in diabetics: AMANDHA study: add-on manidipine vs amlodipine, Martinez-Martin F. J. & Saiz-Satjes M - Expert Rev Cardiovasc Ther 2008; 6(10): 1347-1355 more efficacy Antihypertensive efficacy  Blood pressure reduction Manidipine Amlodipine P value BP reduction (mm Hg) 19.1/7.7 12.7/10.9 < 0.001 vs baseline MAP* reduction 11.5 11.5 Pulse pressure reduction 11.3 1.8 < 0.001 between treatments SLIDE 27 Both regimens demonstrated to be equally effective in reducing both systolic and diastolic blood pressure versus baseline. However, manidipine differently from amlodipine, when administered on top of RAS inhibitors, significantly reduced pulse pressure (PP), a parameter that has been shown to predict cardiovascular mortality.1 References 1. Arch Intern Med. 2000; 160: 1085–1089. * MAP: Mean Arterial Pressure

5 – Antihypertensive efficacy in diabetics: AMANDHA study: add-on manidipine vs amlodipine, Martinez-Martin F. J. & Saiz-Satjes M - Expert Rev Cardiovasc Ther 2008; 6(10): 1347-1355 more efficacy Antihypertensive efficacy in diabetic patients Manidipine, differently from amlodipine, when given on top of RAS blockers significantly reduces pulse pressure, a CV risk factor SLIDE 28 In diabetic patients with hypertension, Manidipine differently from amlodipine, when administered on top of a RAS inhibitor, significantly reduced pulse pressure, a parameter that has been shown to predict cardiovascular mortality.

 ΕΝΔΟΣΠΕΙΡΑΜΑΤΙΚΗΣ ΠΙΕΣΗΣ ΑΓΓΕΙΟΔΙΑΣΤΟΛΗ ΣΤΟ ΠΡΟΣΑΓΩΓΟ ΑΡΤΗΡΙΟΛΙΟ  ΛΕΥΚΩΜΑΤΟΥΡΙΑΣ ΔΙΥΔΡΟΠΥΡΙΔΙΝΕΣ ΑΓΓΕΙΟΔΙΑΣΤΟΛΗ ΣΤΟ ΠΡΟΣΑΓΩΓΟ ΑΡΤΗΡΙΟΛΙΟ  ΛΕΥΚΩΜΑΤΟΥΡΙΑΣ

Αγγειοδιαστολή στο προσαγωγό και στο απαγωγό αρτηριόλιο MANIDIPINE Αγγειοδιαστολή στο προσαγωγό και στο απαγωγό αρτηριόλιο Ενδοσπειραματικής πίεσης Λευκωματουρίας

Albumin excretion rate reduction more protection Nephroprotection in diabetics: AMANDHA study: add-on manidipine vs. amlodipine Martinez-Martin F.J. – Expert Rev Cardiovasc Ther 2008; 6(10):1347-1355 Albumin excretion rate reduction Albumin excretion rate (AER) reduction after 24-week treatment with manidipine or amlodipine in type 2 diabetic hypertensive patients not adequately controlled with either ACE-Is or ARBs SLIDE 32 The picture shows, once again, how manidipine, on top of an ACE inhibitor or ARB, results to be more effective than amlodipine in reducing the albumin excretion rate (AER)

more protection Nephroprotection in diabetics: AMANDHA study: add-on manidipine vs. amlodipine Martinez-Martin F.J. – Expert Rev Cardiovasc Ther 2008; 6(10):1347-1355 SLIDE 33 Changes in urinary albumin excretion during 2 years of treatment with manidipine 20 mg vs. amlodipine 10 mg in hypertensive type 2 diabetes patients3

1 – Nephroprotection in diabetics: AMANDHA study: add-on manidipine vs 1 – Nephroprotection in diabetics: AMANDHA study: add-on manidipine vs. amlodipine Martinez-Martin F.J. – Expert Rev Cardiovasc Ther 2008; 6(10):1347-1355 more protection Nephroprotection  Albumin excretion rate reduction Manidipine shows a better nephroprotection compared to amlodipine, when both administered on top of RAS blockers SLIDE 34 Because of its pre- and post-glomerular vasodilatory effect, manidipine confirms in this study a superior nephroprotective profile when compared to amlodipine.

MANIDIPINE FOR HYPERTENSION NOT CONTROLLED BY DUAL THERAPY IN PATIENTS WITH DIABETES MELLITUS MANIDIPINE (20mg/d) SBP από 158.6 σε 136.8mm Hg, p<0.001 DBP από 86.7 σε 78 mm Hg p<0.001 σφύξεων από 75.1 σε 72.8, p=0.06 γλυκόζης κατά 10.2mg/dl, p<0.05 HβΑ1c κατά 0.19%, p=0.05 LDL CHOL κατά 8.1mg/dl, p=0.002 TRG κατά 10.8mg/dl, p=0.018

ΔΙΥΔΡΟΠΥΡΙΔΙΝΗ + ΑΜΕ (ΣΑΡΤΑΝΗ) Ο ΠΙΟ ΔΟΚΙΜΟΣ ΣΥΝΔΥΑΣΜΟΣ ΑΝΤΙΥΠΕΡΤΑΣΙΚΩΝ ΦΑΡΜΑΚΩΝ, ΚΥΡΙΩΣ ΣΕ ΑΣΘΕΝΕΙΣ ΜΕ ΚΑΡΔΙΟΜΕΤΑΒΟΛΙΚΕΣ ΔΙΑΤΑΡΑΧΕΣ

DELAPRIL AME/προφάρμακο Δόση 30mg/d 24h διάρκεια δράσης Μεγάλη λιποφιλικότητα Απεκκρίνεται από τους νεφρούς-προσαρμογή δόσης σε ασθενείς με έκπτωση της νεφρικής λειτουργίας Επίπτωση βήχα σε σύγκριση με άλλους ΑΜΕ? Βελτίωση της ευαισθησίας στη δράση της ινσουλίνης?

Manidipine/Delapril (10/30mg): product description Vivace (Manidipine/Delapril 10/30 mg) is a new oral, once-daily, fixed combination of a dihydropyridine calcium antagonist (CCB) and an ACE inhibitor for the treatment of hypertension SLIDE 3

Manidipine/Delapril : Clinical benefits with the combination The aim of the following section is to demonstrate the additive or complementary clinical benefits, deriving from the combination of manidipine and delapril, in terms of: ADDITIVE ANTIHYPERTENSIVE EFFICACY TARGET-ORGAN PROTECTION INCREASED SAFETY & TOLERABILITY SLIDE 11

ΒΕΛΤΙΩΣΗ ΤΗΣ ΙΝΩΔΩΛΥΤΙΚΗΣ ΙΚΑΝΟΤΗΤΑΣ ΜΕ MANIDIPINE/DELAPRIL (10/30mg/d) vs IRBESARTAN-HCTZ (150+12.5mg/d) ΣΕ ΥΠΕΡΤΑΣΙΚΟΥΣ ΔΙΑΒΗΤΙΚΟΥΣ ΑΣΘΕΝΕΙΣ SBP -27.6mmHg -26.4mmHg DBP -21.8mmHg -20.2mmHg PAΙ-1 (IU/ml) 25.5 15.6 26.1 35.6 t-PA (IU/ml) 0.49 0.78 0.47 0.40 p<0.01 p<0.05 ΒΕΛΤΙΩΣΗ ΤΗΣ ΙΝΩΔΩΛΥΤΙΚΗΣ ΙΚΑΝΟΤΗΤΑΣ ΜΕ MANIDIPINE/DELAPRIL J Hum Hypertens 2004;18:687-691

Antihypertensive efficacy  Blood pressure reduction 2 – Antihypertensive efficacy in diabetics: Vivace vs other combinations Mugellini A.et al - J Hum Hypertens 2004; 18(10): 687-691 more efficacy Antihypertensive efficacy  Blood pressure reduction Placebo VIVACE Irbesartan plus HCTZ SBP (mmHg) 161.9 ± 10.1 134.3 ± 7.9* 134.4 ± 8.0* DBP (mmHg) 101.2 ± 4,5 80.0 ± 3.6* 80.2 ± 3.5* *P <0.001 vs placebo SLIDE 18 Self-explaining slide

DELAPRIL/MANIDIPINE VS OLMESARTAN/HCTZ n=88 παχύσαρκοι υπερτασικοί ασθενείς, τυχαιοποίηση σε delapril/manidipine (30/10mg) vs olmesartan/HCTZ (20/12.5mg) BP (mmHg) -22.3/16.4 vs -22.6/17.2 Ευαισθησία στην ινσουλίνη (mg/Kg/min) +3.01 vs -0.09, p<0.05 Ινσουλίνη (pmol/L) -17.8 vs +2.4, p<0.05 Ινωδογόνο (mg/dl) -67.5 vs +8, p<0.05 Intern Med 2008;47:361-366

ΣΥΝΔΥΑΣΜΟΣ ΑΝΤΑΓΩΝΙΣΤΩΝ Ca2+ ΜΕ ΑΜΕ 45

Tolerability  incidence of ankle oedema Incidence of ankle oedema: manidipine/delapril vs manidipine Fogari R. et al. – Clin Ther 2007; 29:413-418 more tolerability 25 20 15 10 5 Tolerability  incidence of ankle oedema SLIDE 42 In the second study - a randomized, crossover study of 80 patients with grade 1–2 essential hypertension (diastolic BP >90 mmHg and <110 mmHg and systolic BP >140 mmHg) - amlodipine 10 mg was found to significantly increase ankle-foot volume (+23%, p<0.01 vs. baseline). By comparison, Amlodipine/Valsartan was associated with a significantly less pronounced increase in ankle-foot volume (+6.8%, p<0.01 vs. amlodipine). These results provide supporting evidence that also angiotensin receptor blockers, such as valsartan, partially counteract the microcirculatory changes induced by calcium channel blockers such as amlodipine, but the resulting ankle oedema incidence is undoubtedly higher compared to that observed with Vivace. Interestingly, the ankle oedema in amlodipine / valsartan recipients is comparable to that of manidipine alone.. Ankle-foot volume increase (%) Amlo Amlo/Vals 10 mg 10/160 mg Manidipine VIVACE 10 mg 10/30 mg Fogari et al. J Hum Hypertens 2007;21:220–4 The combination with a RAS blocker induced a significant reduction of ankle oedema incidence, also in patients treated with amlodipine Amlodipine/Valsartan Speaker Slide Resource Item code: EXF09.203; Release Date: March 2009

Incidence of ankle oedema: manidipine/delapril vs manidipine Fogari R. et al. – Am J Hypertens. 2003; 16 (5 suppl 1): 113A more tolerability Tolerability  less incidence of ankle oedema Manidipine/delapril demonstrates an excellent tolerability profile even when compared to other CCB+ACE therapies SLIDE 43 Self-explaining slide

MANIDIPINE/DELAPRIL (10/30mg/d) ΑΠΟΤΕΛΕΣΜΑΤΙΚΟΤΗΤΑ ΑΡΙΣΤΗ ΑΝΟΧΗ (ΛΙΓΟΤΕΡΑ ΟΙΔΗΜΑΤΑ) ΣΕ ΔΙΑΒΗΤΙΚΟΥΣ ΑΘΕΝΕΙΣ: ΟΡΓΑΝΟΠΡΟΣΤΑΣΙΑ ΝΕΦΡΟΠΡΟΣΤΑΣΙΑ (ΑΓΓΕΙΟΔΙΑΣΤΟΛΗ ΤΟΥ ΑΠΑΓΩΓΟΥ ΑΡΤΗΡΙΟΛΙΟΥ) ΚΑΡΔΙΟΠΡΟΣΤΑΣΙΑ (ΑΠΟΥΣΙΑ ΕΝΕΡΓΟΠΟΙΗΣΗΣ ΤΟΥ ΣΝΣ) ΧΩΡΙΣ ΜΕΤΑΒΟΛΙΚΕΣ ΑΝΕΠΙΘΥΜΗΤΕΣ ΕΝΕΡΓΕΙΕΣ

ΜΑΝΙΔΙΠΙΝΗ Νεφροπροστασία Καρδιοπροστασία Καλύτερο προφίλ ασφαλείας Μείωση της αντίστασης στην ινσουλίνη Μερική ενεργοποίηση των PPARγ υποδοχέων Μείωση της υπερτροφίας της αριστεράς κοιλίας Αγγειοδιαστολή του προσαγωγού και απαγωγού αρτηριολίου Μικρότερη ενεργοποίηση του ΣΝΣ C. Rizos and M. Elisaf: World J Hypertens 2011;1: 3-6