Azelnidipine

Hypertension is a major concern & dreaded complication. It is known as the silent killer and responsible for a large number of cardiovascular morbidity and mortality. There are many antihypertensive drugs . Calcium channel blockers were the oldest one and widely used in the management. Azeldipine is the recent addition to this.

1. 1 Azelnidipine – A novel CCB Dr Awadhesh Sharma,DM,FACC,FSCAI Assistant Professor LPS Institute of Cardiology GSVM Medical College, Kanpur, UP

2. Hypertension – Silent Killer 2 A global brief on Hypertension by WHO

3. ACC/AHA – New Guideline 3 2019 ACC/AHA Guidelines BP Category SBP   DBP Normal <120 mm Hg and <80 mm Hg Elevated 120–129 mm Hg and <80 mm Hg Hypertension Stage 1 130–139 mm Hg or 80–89 mm Hg Stage 2 ≥140 mm Hg or ≥90 mm Hg New Goal for BP Levels

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5. L-type - main targets of CCBs - cardiac, smooth muscles & endocrine cells T-type – neurons & endocrine cells - pacemaker cells, atrial cells and purkinje fibers N-/P-/R type – brain, neuron & pituitary gland

6. Conventional CCB ’ s fails here… Reflex tachycardia More incidence of Pedal Edema Elevated Proteinuria level

7. Looking beyond the conventional CCB

8. Azelnidipine – Drug Profile of A Novel CCB 8 Drugs Blocking activity L-type N-type T-type Nifedipine + - - Amlodipine + - - Cilnidipine + + - Efonidipine + - + Azelnidipine + - + Keio J Med. September 2010 ; 59 (3) : 84－95.

9. Chemical Structure - Azelnidipine 9 Azelnidipine is a new dihydropyridine calcium channel antagonist It is L and T type of calcium channel blocker Composed of a racemic mixture containing a 1:1 ratio of the active R -enantiomer and the inactive S -enantiomer Drugs 2003; 63 (23): 2613-2621

10. Mechanism of Action of Azelnidipine Blocks L-Type calcium channel in blood vessel and T-type Calcium channel in heart Results in vasodilation and reduced heart rate Shows 17-folds higher lipophilicity than of amlodipine 10 Drugs 2003; 63 (23): 2613-2621

11. Mechanism of Action Azelnidipine acts on SA node Inhibits T-type Calcium channel activation It prolongs the late phase-4 depolarization 11 Azelnidipine block T-type Calcium channel present on zona glomerulosa Inhibit Aldosterone synthesis and release Drugs 2003; 63 (23): 2613-2621

12. Mechanism of Action on glomerulus Azelnidipine dilates Afferent and Efferent arterioles Reduces intra-glomerular pressure Offers reno-protective effect 12

13. Pharmacokinetic Profile 13 Parameters Azelnidipine Protein binding rate (%) ≈90% T max (Hr) 2.3-2.7 Terminal Elimination Half life ( Hr ) 19.2 Excretion 26 % in urine 63 % in feces Volume of distribution (L) 403.3 ± 710.4 Metabolism Undergoes extensive first-pass hepatic metabolism Primarily by cytochrome P450 (CYP) 3A4 AUC (h/ml) 81.6 ng C max (ng/ml) 3-13.1 Drugs 2003; 63 (23): 2613-2621

14. Dosage and Indications Azelnidipine tablets 16 mg For the treatment of Essential Hypertension. 14 CDSCO site Approved by DCGI Use in Specific Population Severe renal Impairment: Efficacy have not been established Severe hepatic impairment: Efficacy have not been established Pediatric Use: Efficacy have not been established Elderly Use: Low dose (8 mg once daily) is recommended Pregnancy: Not recommended Nursing mother: Not recommended

15. Contraindications Hypersensitivity to any of the ingredients Pregnant and nursing women Concomitant administration of systematic azole antifungal agent (e.g. fluconazole) Concomitant administration of HIV protease inhibitor ( e.g atazanavir ) 15 Drug / Class Action Azole anti-fungal agent These drugs Inhibits CYP3A4 and increases the concentration of Azelnidipine in body HIV protease inhibitor Cimetidine Erythromycin, Azithromycin Digoxin C max of digoxin increases http://www.kegg.jp/medicus- in/ japic_med?japic_code =00061591 Drug Interactions

16. Effects Proven in Pre-clinical Studies Negative chronotropic effect 1 Inhibit Aldosterone synthesis and secretion 2 Dilate efferent arterioles 3 Preserves insulin signaling and glucose uptake 3 16 Journal of Hypertension 2014, 32:1898–1904 Eur J Pharmacol. 2009 Mar 1;605(1-3):49-52 Drugs R D (2013) 13:63–73 Endocrine Journal 2015, 62 (8), 741-747

17. Azelnidipine BP Control & Cardio-protection 17 Clinical Evidences Azelnidipine Cardiac Perspective

18. Study 1: Sustained Blood Pressure-Lowering Effect of Azelnidipine Guided by Self-Measured Morning and Evening Home Blood Pressure: Subgroup Analysis of the At-HOME Study At-HOME study conducted in Japan Objective: To evaluate the sustained BP lowering effect of Azelnidipine , using mean morning and evening systolic BP [ME average] and morning systolic BP minus evening systolic BP (ME difference). Efficacy analysis- N = 4852 Safety analysis- N = 5265 18 Drugs R D (2013) 13:75–85

19. Clinical Improvement From Baseline 19 Changes in a morning and evening home blood pressure (BP) Changes in morning and evening home pulse rates after Azelnidipine treatment *p\0.0001 vs. baseline, according to Dunnett’s test. DBP diastolic blood pressure, SBP systolic blood pressure Changes in morning & evening SBP (ME average) & morning SBP minus evening SBP (ME difference) following Azelnidipine treatment Drugs R D (2013) 13:75–85

20. Improvement in Patient Distribution Drugs R D (2013) 13:75–85 20 Changes in patient distribution according to morning and evening systolic blood pressure (ME average) and morning systolic blood pressure minus evening systolic blood pressure (ME difference) [n = 2,101; p\0.0001 vs. baseline according to the McNemar test]. Significant reduction in home SBP and DBP BP-lowering effect lasted till next day morning Useful for patients with morning hypertension, who are at high risk of cardiovascular events, especially stroke.

21. Study 2: Inhibitory Effects of Azelnidipine Tablets on Morning Hypertension Treatment: Azlenidipine 8/16 mg once daily for 16 weeks 21 Drugs R D (2013) 13:63–73 Objective: To determine the BP- and pulse rate-lowering effects of Azelnidipine , administered once daily in the morning. N=5433 Hypertensive patients Azelnidipine offered significant reduction in morning BP and heart rate within 4 weeks

22. Study 3: Azelnidipine and Amlodipine: A Comparison of their Pharmacokinetics and Effects on ABPM To compare the effects of Azelnidipine and Amlodipine on 24-h blood pressure A randomized, double-blind Study in Hypertensive patients Azelnidipine 16 mg (23 patients) or amlodipine 5 mg (23 patients) was administered once daily for 6 weeks 22 Hypertens Res. 2003 Mar;26(3):201-8.

23. 23 Hypertens Res. 2003 Mar;26(3):201-8. Differences of Blood Pressure (BP) and Pulse Rate (PR) from the Baseline Values after 6 Weeks of Treatment with Azelnidipine or Amlodipine Both drugs offered 24h BP reduction and have similar antihypertensive effect Azelnidipine decrease pulse rate Amlodipine significantly increased pulse rate

24. Study 4: Azelnidipine and Amlodipine: A Comparison of Their Effects and Safety in a Randomized Double-Blinded Clinical Trial in Chinese Essential Hypertensive Patients N=220 Treatment Azelnidipine 8 and 16 mg. Amlodipine 2.5 and 5 mg Duration: 8 Weeks ABPM was monitored at baseline and at 8 weeks (N=40) 24 Clinical and Experimental Hypertension , 32(6): 372–376, (2010) Changes of blood pressure and pulse rate in azelnidipine or amlodipine group

25. Conclusion Azelnidipine significantly reduced BP, and was greater than amlodipine. 25 Clinical and Experimental Hypertension , 32(6): 372–376, (2010) Differences of Δ BP after treatment with Azelnidipine or Amlodipine

26. Study 5: Clinical use of Azelnidipine in Treatment of Hypertension in Chinese Patients Relevant literature identified by from PubMed and CNKI (China National Knowledge Infrastructure) Total of 23 articles selected from 54 articles 26 Therapeutics and Clinical Risk Management 2015:11 Azelnidipine and BP Reduction Significant reduction in BP mild-to moderate hypertension, similar to amlodipine and nifedipine Showed CV protective effects, anti-oxidative action, reduction in heart rate and improved systolic and diastolic function Well tolerated and no severe adverse events were observed

27. Study 6: Impact of Azelnidipine and Amlodipine on Left Ventricular Mass & Longitudinal Function in Hypertensive Patients with LVH The study conducted to compare the effects of Azelnidipine & amlodipine on LV function N= 32 hypertensive patients Intervention- 5 mg of amlodipine/day and16 mg of Azelnidipine /day. LV function and morphology was examined by conventional and speckle tracking echocardiography at baseline and at 1, 3, 6,and 12 months after treatment initiation 27 DOI: 10.1111/echo.12548 Echocardiography

28. 28 DOI: 10.1111/echo.12548 Echocardiography Serial Changes in Global Longitudinal Left Ventricular (LV) Strain With CCBs Global longitudinal strain had improved by 3 months of treatment, further regression of LVH observed at 12 months.

29. Study 7: Effects Of Azelnidipine Plus Olmesartan Vs Amlodipine Plus Olmesartan on Central BP and LVMI: The AORTA Study Effects of olmesartan combined with either Azelnidipine or amlodipine on central blood pressure (CBP) and left ventricular mass index (LVMI) in hypertensive patients was tested. Patients with SBP > 140 mmHg and/or DBP >90 mmHg received olmesartan monotherapy (20 mg daily) for 12 weeks. The patients were then randomly assigned to fixed-dose add-on therapy with Azelnidipine (16 mg daily) or amlodipine (5 mg daily) (25 patients/group) for a further 24 weeks. CBP and LVMI were measured at baseline and at the end of study 29 Vascular Health and Risk Management 2011:7

30. Changes in CBP and LVMI 30 Vascular Health and Risk Management 2011:7 AIx@75: Heart Rate-corrected Augmentation Index 24 weeks of combination therapy, olmesartan / Azelnidipine showed significantly greater decreases in CBP than olmesartan /amlodipine HR showed significantly greater reduction with olmesartan / Azelnidipine than with olmesartan /amlodipine.

31. Study 8: Effects of Azelnidipine on Reflex Tachycardia 95 patients with mild-to-moderate hypertension were treated with Azelnidipine for 1 year 31 Drugs. 2003;63(23):2613-21; discussion 2623-4. Azelnidipine significantly reduced BP Its use was not associated with reflex tachycardia

32. 32 90 Clinical Evidences Azelnidipine and Kidney Protection

33. Azelnidipine Reduces Urinary Protein Excretion and Urinary Liver-Type Fatty Acid Binding Protein in Patients with Hypertensive Chronic Kidney Disease A randomized study N= 30 Hypertensive CKD patients Azelnidipine 16 mg once daily or amlodipine 5 mg once daily Duration 6 months Endpoints: Change in BP and HR Urinary protein excretion and urinary levels of 8-OHdG and urinary L-FABP measured before 3 and 6 months post treatment 33 Am J Med Sci 2007;333(6):321–326.

34. Effects of Azelnidipine and Amlodipine on BP Both drugs exhibited similar effects on systolic and diastolic blood pressure. Azelnidipine exhibited reduction in HR 34 Am J Med Sci 2007;333(6):321–326

35. Effects of Azelnidipine and Amlodipine on Urinary Protein Excretion (UPE) 35 Azelnidipine offered significant reduction in urinary protein excretion, amlodipine was ineffective in reducing UPE Am J Med Sci 2007;333(6):321–326.

36. Effects of  Azelnidipine  on Uric Acid  Metabolism  in Patients with Essential Hypertension N= 72 Azelnidipine 8 or 16 mg In 22 cases out of the 72 patients, a different CCB was switched to Azelnidipine BP measured and biochemical parameters of blood and urine were evaluated before and 2–3 months after the administration 36 Clin Exp Hypertens , 2014; 36(7): 447–453

37. Effects of  Azelnidipine  on Uric Acid Metabolism  in patients with Essential Hypertension 37 Clin Exp Hypertens , 2014; 36(7): 447–453 SBP: systolic blood pressure, DBP: diastolic blood pressure, Cr: creatinine, eGFR : estimated glomerular filtration rate, LDL: low density lipoprotein, HDL: high-density lipoprotein

38. 1 Azelnidipine Diabetic Perspective

39. Azelnidipine and Amlodipine on Glucose Tolerance and Endothelial function (AGENT Trial) N=17 non-diabetic patients with essential hypertension, controlled BP with amlodipine (5 mg/day) were enrolled Either Azelnidipine (16 mg/day) or amlodipine (5 mg/day) was administered in a crossover design for 12-weeks At baseline and the end of each CCB therapy, OGTT was performed 39 Cardiovascular Diabetology 2011 10:79.

40. Comparison of Laboratory Data and PAT Ratio Between Treatment with Azelnidipine and Amlodipine Cardiovascular Diabetology 2011 10:79. 40 Data are mean ± SD. TC; total cholesterol, LDL-C; low-density lipoprotein cholesterol, HDL-C; high-density lipoprotein cholesterol, Hb ; hemoglobin , hs -CRP; high sensitivity C-reactive protein, BNP; brain natriuretic peptide, eGFR ; estimated glomerular filtration ratio, GFR(ml/min/1.73 m2) L-FABP, L-type fatty acid binding protein, alb ; albuminuria, U- Cre ; urine creatinine, HPC; hematopoietic progenitor cell, PAT: peripheral arterial tonometry. * P < 0.05 vs. baseline. ** Azelnidipine vs. amlodipine. Azelnidipine treatment have beneficial effects against glucose intolerance, insulin sensitivity, inflammatory state in non-diabetic patients with hypertension.

41. Azelnidipine , but not amlodipine, reduces urinary albumin excretion and carotid atherosclerosis in subjects with type 2 diabetes: blood pressure control with olmesartan and azelnidipine in Type 2 diabetes (BOAT2 study) To evaluate the efficacy of Azelnidipine and amlodipine on diabetic nephropathy and atherosclerosis A prospective, two-arm, randomized controlled clinical study 38 hypertensive subjects with type 2 diabetes Treatment: Azelnidipine 16 mg/day or amlodipine 5mg/day for 32 weeks Endpoints: Change in BP and heart rate 41 Diabetol Metab Syndr. 2015; 7: 80.

42. BOAT2 Study- Efficacy in Reduction of BP and HR 42 Reduction in BP was similar between both groups Azelnidipine offered significant reduction in HR than Amlodipine ( p < 0.05) Diabetol Metab Syndr. 2015; 7: 80.

43. BOAT2 Study- Efficacy In Urinary Albumin Excretion 43 Azelnidipine offered significant reduction in Urinary albumin excretion (p < 0.05), amlodipine was not effective Urinary albumin excretion in Azelnidipine group was significantly lowered compared to amlodipine group (p < 0.05) Diabetol Metab Syndr. 2015; 7: 80.

44. BOAT2 Study- Carotid Intima Media Thickness And Inflammatory Markers IMT: Carotid intima-media thickness MCP -1: monocyte chemoattractant protein 1 (type of cytokine) TNF: Tumor necrosis factor 44 Azelnidipine offered significant reduction in Max IMT, MCP-1and TNF - α compared to amlodipine Azelnidipine but not amlodipine, delayed the progression of urinary albumin excretion and carotid atherosclerosis ( p < 0.05) ( p < 0.05) ( p =0.05)

45. Changes in Left Ventricular Relaxation After Azelnidipine Treatment in Hypertensive Patients With Diabetes: Sub Analysis of Prospective Single-arm Multicentre Study 45 BMJ Open 2014;4:e006136 The e-velocity is a marker of the function of the left ventricle of the heart. Sub analysis of a prospective single-arm multicentre study 228 hypertensive patients with normal ejection fraction and impaired left ventricular relaxation (septal e-velocity <8 cm/s on echocardiography) enrolled for CALVLOC trial. They were divided into two groups based on presence or absence of diabetes. Administered Administration of 16 mg of Azelnidipine for 8 months Septal e-velocity before and at the end of the study.

46. Changes in LV Relaxation After Azelnidipine Treatment in Hypertensive Patients With Diabetes Whereas patients with diabetes (n=53, 23.2%) had lower SBP than Patients without diabetes (155±17 vs 161±16 mm Hg, p=0.03). They had lower e’ velocity (5.7±1.5 vs 6.1±1.4 cm/s, p=0.04) at baseline. Azelnidipine decreased BP and heart rate, and increased e’ velocity similarly in patients with diabetes (5.7±1.5 to .3±1.5 cm/s, p=0.0003) and without diabetes (6.1±1.4 to 6.9 ±1.4 cm/s, p<0.0001). LV relaxation was more impaired in hypertensive patients with diabetes than in those without diabetes . Azelnidipine improved LV relaxation in both groups to the same degree 46 BMJ Open 2014;4:e006136

47. Salient Features Azelnidipine offers 24 hr smooth BP control including double digit BP control Superior sympathetic nerve activity reduction compared to amlodipine – sympathomodulating CCB Reduces proteinuria, reduces glomerular hypertension Exhibits anti oxidant property, improves endothelial function and arterial stiffness Reduction in B type natriuretic peptide, can be beneficial in improving prognosis of HF patients Preserves insulin signaling Reduces serum uric acid in hypertensive patients with hyperuricemia Exhibits -Cardio-protection, Neuro-protection and renal protection & Lesser incidences of pedal edema Well tolerated 47

48. Thank You 48