Recent advances in treatment of Hypertension

- Dr. Chandini Rao Moderator: Dr. Nicole Pereira

Introduction Drug therapy for HTN• Drugs acting on RAAS - DRIs - ACEIs - ARBs - Vasoactive peptides - Vaccines against RAAS• CCBs• Diuretics• Beta blockers• Misc drugs

Combination Rx Rx of Resistant HTN

Contents

Intro -• Hypertension is the most common modifiable risk factor for

cardiovascular events.

• 50% of global adult population (60-69 yrs)

• Prevalence further increased beyond age 70

• Major risk factor for stroke, MI, heart failure, CKD etc

• Sustained increase in BP >/= 140/90 mmHg, based on an average

>/= 2 seated BP readings during each of >/= 2 OPD visits

JNC criteria for diagnosis of HTN

• Essential hypertension – no known cause (>90%) – hereditary component

• Secondary hypertension – secondary to an underlying cause (<10%) - chronic kidney disease, endocrine disorders, drugs, diet etc

• Control of BP leads to a reduction in events – Approximately 50% reduction in heart failure – Approximately 40% reduction in stroke – Approximately 20-25% reduction in MI

• Persistent/untreated HTN LVH, coronary artery disease, HF, atrial fibrillation, renal insufficiency etc.

Treatment

Life style modification - 1st line

salt restriction - DASH diet (Dietary Approaches to Stop Hypertension) smoking cessation weight loss physical exercise relaxation techniques limited alcohol consumption

DASH diet• 2000-calorie-a-day diet: Daily & weekly eating plan goals

Low in Na+: Standard DASH diet – upto 2300mg/day Lower Na+ DASH diet – upto 1500mg/day

Eating vegetables, fruits, and whole grains Including fat-free or low-fat dairy products, fish (salmon,

tuna), poultry, nuts & vegetable oils. (high saturated fatty foods to be avoided) Limiting sugar-sweetened beverages and sweets. Limiting caffeine & alcohol

• Prevention of osteoporosis, cancer, stroke, diabetes

Drug therapy

Anti-hypertensives –

1. Drugs acting on RAAS2. Calcium channel blockers3. Diuretics4. Sympatholytics5. Adrenergic blockers6. Vasodilators

Resistant HTN – - 10-15% of general hypertensive population - Uncontrolled BP on >/= 3 antihypertensive drugs of different classes, including a non-potassium sparing diuretic, at optimal doses, OR requiring >/= 4 drugs to achieve control

Refractory HTN –• 0.5% of hypertensive patients• Uncontrolled BP on >/= 5 drugs

Newer therapies – high-risk patients - treat HTN & co-morbidities

Drugs inhibiting RAAS

Direct Renin inhibitorsDRI

1st generation

Peptide analogues of renin

2nd generationPeptide mimetics – CGP2928RemikirenEnalkirenZankiren

3rd generation

Aliskiren

Current status

• Aliskiren – as effective as ACEI/ARBs in lowering BP (ALLAY, ALOFT & AVOID trials).

• FDA – Combinations of aliskiren with ACEI/ARBs to be avoided in diabetic patients with renal impairment

- combination with hydrochlorothiazide approved

SPP635 – completed Phase IIa

SPP676SPP1148

SPP1234 SPP800

Phase I

Pre-clinical phases

ACE inhibitors

Current status

• Stage 1: w/o comorbidities – 1st line drugs (if thiazides are not being used) DOC for HTN a/w DM, LVH, CCF, post-MI, CAD, CKD, CVA• Stage 2 : in combination with thiazides

Drugs of the future:

MC-4232 –• combination of MC-1 and lisinopril• MC-1: naturally occurring metabolite of vitamin B6 damage

to the heart caused by ischemia• Phase II trial (MATCHED) promising safety & efficacy

profile (co-existing T2 DM & HTN)• Phase III trial

Angiotensin Receptor Blockers

Current status

- Similar to ACEIs

- As an alternative to ACEIs – intolerance to ACEIs

- Important option in patients with concurrent disorders – heart failure, stroke, DM

Losartan

Candesartan

Irbesartan

Valsartan

Telmisartan

Eprosartan

Olmesartan medoxomil

Newer drugsAzilsartan medoxomil• Developed by Takeda – ‘Edarbi’

• Prodrug Azilsartan

• Approved by FDA (Feb’11) - treatment of essential HTN in adults. Approved in India in 2017.

• 3 major trials (24 wks duration) – @20, 40 or 80 mg doses BP, with OD administration - better anti-hypertensive efficacy than olmesartan & valsartan - well-tolerated; headache & dizziness - better patient compliance

• Further studies required

Dual ACE/NEP Inhibitors• Neural endopeptidase (NEP) or Neprilysin - therapeutic target for HTN & other forms of CVD - degrades Natriuretic peptides (ANP, BNP), Angiotensin I, II endothelin, bradykinin etc

• Potentiation of ANP + attenuation of angiotensin II (NEP inhibition) (ACE inhibition)

Natriuresis, Vasodilation, RAAS inhibition, Reduced sympathetic drive, Antiproliferative and antihypertrophic effects on the heart and vessels

Control of BP

Vasoactive peptides

Dual ACE/NEP inhibitors

Sampatril - Halted in Phase II Omapatril (OCTAVE, OVERTURE trials) – failed in Phase III Gemopatril – preclinical Mixanpril – preclinical Fasidotril – Phase III CGS30440 – preclinical Ilepatril – Phase IIb RAVEL – 1 trial

Dual ARB/ NEP inhibitor• LCZ696 (Entresto) – AHU377 (Sacubitril) + Valsartan (1:1)

• Currently approved for Rx of HF, not yet approved for HTN (off label)

PARAMOUNT (Phase II trial)

LCZ696 vs Valsartan

Greater in SBP than valsartan

PARADIGM ( Phase III trial)

LCZ696 vs Enalapril

Greater in symptoms, physical limitations & cardiac death due to HF

PARAMETER LCZ696 vs Olmesartan

Greater in BP, pulse pressure & arterial stiffness in elderly

Dual Angiotensin (AT1) receptor/Endothelin inhibition & NEP/Endothelin Converting Enzyme (ECE) inhibition

Big ET-1 (39 AA precursor)

Endothelin (ET-1)

Endothelin-converting enzyme (ECE)Ang IIADHThrombinCKs etc

• Most potent vasoconstrictor• Vascular diseases of several organ systems• Antagonists - Rx of PAH ( Ambrisentan & Macitentan – recently approved)• Rx of Sys HTN? (Darusentan, TBC3711 trials)

ET-1 antagonism in Rx of Systemic HTN

ET-1 R antagonist + ARB ECE inhibitor + NEP inhibitor

Dual ET-1 R/ARB blocker

PS433540 (Sparsentan) – Phase II trial for stage 1-2 HTN (200, 400 & 800mg) - BP compared to placebo & also to Irbesartan (in Phase III trial for Rx of FSGS)

Dual ECE/NEP inhibitor (only preclinical data available)

Daglutril (SLV-306) – • prodrug

• oral administration KC-12615 (active metabolite)

• Diabetic rat - BP, proteinuria & prevent nephrosclerosis as effectively as the captopril.

- safe & well-tolerated

• Heart failure patients (multicentre RCT) - pulmonary and right atrial pressures without affecting systemic arterial pressure, cardiac output, or heart rate

Others - SLV336 and SLV338

Aldosterone• Mineralocorticoid Receptor (MR) - principal effector - Cortical collecting duct

• Na+ & water reabsorption & K+ loss BP

• MRs in extra-adrenal tissues (heart & blood vessels) HTN & CVD

• Aldosterone inhibition additive effect to Ang II inhibition

Anti-Aldosterone agentsMechanism of action:

MR antagonistsSpironolactone• 1st MR antagonist• Current status – Add-on drug in Resistant HTN - Rx of HF - Primary & Secondary aldosteronism• Lack of specificity (also binds to progesterone & androgen Rs) - not well toleratedEplerenone - more selective, but less potent with short T1/2Canerenone – active metabolite of spironolactone, limited use

Non-steroidal MR antagonists • Finerenone (BAY94-8662) – more selective to MR - greater in BP vs Eplerenone - under phase III trials for Rx of CHF & CKD

Aldosterone Synthase Inhibitors• Aldosterone synthase – - catalyses the final three rate-limiting steps of aldosterone synthesis - CYP11B2 gene

• Preclinical studies of aldosterone synthase inhibition – Fadrozole & FAD286

– tested preclinically in rats - inhibit aldosterone synthase & BP - urine & plasma aldosterone levels (FAD286) - atherosclerosis - lack specificity; also inhibits 11-β-hydroxylase inhibition of cortisol synthesis

Clinical studies of aldosterone synthase inhibition –LCI699 – • Greater selectivity for inhibition of CYP11B2 (> CYP11B1) - less influence on cortisol• 1st orally active aldosterone synthase inhibitor tested in

humans.• 4 Phase II trials -

Lack of selectivity @ higher doses (>3mg) – unlikely to supplant MR blockers clinically.

Pyridyl- or isoquinolinyl-substituted indolines and indoles

- recently synthesized - More selective than LCI699 for CYP11B2 - currently tested as Rx for mineralocorticoid-dependent CVD & renal disease

Disadv of aldosterone synthase inhibitors - hyperkalemia and hyponatraemia. - long-term effect on kidney function is not known.

Current status of Aldosterone blockers –

- Rx of HTN: used less in most countries- 4th/5th line therapy in resistant HTN- More selective agents are required

Drugs activating Counter-regulatory RAAS pathwayAT2 R agonistsACE 2 activatorsAng (1-7) analogsNonpeptide activators of the Mas RAlamandine

(complexed with cyclodextrin)

AT2 R• Vasodilatation• Antiproliferative

action• Fetal tissue

development• Apoptosis

AT2 Receptor agonists

• Compound 21 (C21) – - 1st orally available, specific, and selective AT2 R agonist - Anti-inflammatory, antifibrotic and antiapoptotic properties - Anti-inflammatory Rx & TGF-β guided immunosuppression innovative strategy for the Rx of high BP - Effect on the vascular wall C21 + ARB in HTN rats collagen content in vessels & improved their elastic properties (w/o additional effect on BP) - also improved MI - Other effects: Renoprotective Neuroprotective - Preclinical phase

ACE2 agonists• XNT & DIZE – small molecule ACE2 activators - BP, improve myocardial function, and reverse myocardial and perivascular fibrosis in the SHR

• Recomb human ACE2 (rhACE2) - BP in SHR - slow the progression of diabetic nephropathy - Phase I study – suppression of circulating Ang II levels after a single iv injection of rhACE2 with no effect on BP (& no major a/e)

Ang (1-7) analogues• Peptide analogues - NorLeu3-Ang 1–7, CGEN-856 Cyclic analogue – PanCyte

• CGEN-856 - BP in SHR

• Other peptide analogues – tested for pulmonary hypertension and pulmonary diseases

• Encapsulated Ang (1–7) – - hydroxyl-propyl‑β-cyclodextrin encapsulation - BP, HR & myocardial hypertrophy in SHR - inflammation in carotid atherosclerotic plaques - ameliorated type 2 diabetes - expected to enter the clinical phase of development soon

Non-peptide Mas Receptor agonist

AVE-0991- Very promising experimental data

- only available nonpeptide Mas receptor agonist

- Besides blood pressure-lowering effects, AVE-0991 seems to exert blood pressure-independent renoprotective effects as well

- Preclinical phase

Alamandine (complexed with cyclodextrin)

• Ala1-Ang(1–7) - novel member of the Ang peptide family

• Isolated from human plasma and rat heart

• Alamandine is similar in structure to Ang(1–7) 

• Antihypertensive, antifibrotic, and central cardiovascular effects

• Mas-related G-protein-coupled receptor

• Alamandine/HPβCD – Alamandine/β-cyclodextrin inclusion complex

Centrally acting Aminopeptidase Inhibitiors

APA inhibitor RB150

Crosses BBB

Block Ang III formation

Diuresis & sympathetic tone

BP

• Combination with systemic RAAS inhibitor (ACEI) potentiated RB-150 induced BP & CVD disease risk.• Phase I

Vaccines against RAAS

• AngQb x Ang II derived peptide - Phase 1a: Ang II–specific antibodies in all subjects - Phase IIa: 2 doses of AngQb significantly mean ambulatory daytime & early morning BP (high-dose group) - mild a/e - T1/2: 4 months• need for daily dosing of anti-htn medications - adherence.• ATRQB-001 & ATR12181 - x AT1 R

Calcium channel blockers

• 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

Clevidipine (Cleviprex)

• 3rd gen (L-type) CCB • Approved as IV infusion for acute pre-op & post-op HTN in

adult cardiac surgery patients.• Easily titratable – rapid onset & short duration of action• 3 large Phase III: - more effective than NTG or sodium nitroprusside (peri-op) & as effective as IV Nicardipine (post-op) - acute severe HTN• Safe & well-tolerated in cardiac surgery

Combined L-type & T-type Ca+ channel blocking action

• Newly developed DHP CCBs - Manidipine, Nilvadipine, Benidipine, Efonidipine & Benzimidazole mibefradil

• Greater efficacy than classical L-type CCBs in controlling BP• Adv – vasodilatory properties - minimum reflex tachycardia - renal protection - very less risk of edema ( compared to L-type CCBs) Mibefradil • More desirable profile - as part of combination therapy• Further study required to asses risk/benefit ratio

Ca2+

NE

Pure L-type Ca2+

channel blockers like nifedipine,

amlodipine

Ca2+

Vessels Vessels Heart Kidneyα1 adrenoceptors

β1 adrenoceptors

α1 & β1 adrenoceptors

•Vasoconstriction

Vasoconstriction

•↑ Cardiac contraction•↑ Heart rate

• ↓ Renal blood flow• Renin secretion

L-type Ca2+

channels

N-type Ca2+ channelsCilnidipine

Norepinephrine

Combined L- & N-type calcium channel blocking action:Cilnidipine (4th gen CCB)

ACHIEVE ONE CLEAREDCARTER

Cilnidipine od 24 hr BP controlAs effective as traditional CCBs

Indian studyESC 2014

Cilnidipine vs Amlodipine

Cilnidipine – greater in BP & prevention of ankle edema

CLEARED Cilnidipine Reno protective effects in DM

proteinuria in DM patients (compared to Amlodipine)

Current status• 1st line drug for HTN (as alt to Thiazides) • Combination therapy

Diuretics

LOOP DIURETICSTHIAZIDESTHIAZIDE-LIKE AGENTSPOTASSIUM-SPARING DIURETICS

LOOP DIURETICS –FurosemideBumetanideTorsemideEthacrynic acid

THIAZIDE DIURETICS –HydrochlorothiazideChlorthiazideTrichlormethiazideBenzthiazideHydroflumethiazideEpitizideMethychlorthiazideBendroflumethazidePolythiazide

THIAZIDE-LIKE DIURETICS –ChlorthalidoneIndapamideMetolazoneXipamide

POTASSIUM-SPARING DIURETICS –SpironolactoneAmilorideTriamtereneEplerenone

Current status

Thiazides Loop K+ - sparing1st choice in Rx of essential HTN (esp in elderly)

Severe HTN associated with CRF, CCF

Used with thiazides to prevent K+ loss

• Most of the outcome trials favour CTD over HCTZ (HDFP, MRFIT, SHEP, ALLHAT) – 1st line drug in resistant HTN

• Indapamide – best thiazide-type diuretic to be considered for HTN

• Spironolactone most effective add-on drug for resistant HTN.

β blockers

Newer generation beta blockers(3rd gen beta blockers)

• Vasodilating effects• Carvedilol – most evidence for morbidity & mortality in HF & acute MI patients• Adv – better tolerated - do not risk of DM, atherogenic dylipidemia or weight gain

Nebivolol –- Recently approved β1 selective blocker with NO enhancing effects- Superior therapeutic profile- formation of atherosclerosis – benefit in HF- SENIORS trial (in HF Rx) - mortality & morbidity irrespective of LVEF

Natriuretic Peptide Receptor Agonists• ANP & BNP Natriuretic, vasodilatant, and antiproliferative

effects via NPR-A• Rx of HTN, heart failure, stroke• PL3994, MK-7145 & MK-8150 - clinical phase of development for HTN

PL3994- Phase I trial: single SC dose natriuresis & diuresis in BP (compared to placebo)- Phase II trial (≥1 antihypertensive medications): synergistic action with ACEI as an adjunct to standard therapy in patients with refractory or resistant HTN or HF

Vasoactive Intestinal Peptide Receptor Agonist• VIP - neuropeptide with vasodilator and positive inotropic / chronotropic properties - mediated via the VPAC1 and VPAC 2

• Vasomera (PB1046) - a stable long-acting form of VIP, selective for VPAC2 - BP and improves inotropic and lusitropic properties of the heart in animal models - safe and well-tolerated after single SC or IV injections (Phase I) - SC Vasomera: once weekly dosing regimen chronic use in the home setting. - Phase II

Intestinal Na+/H+ exchanger 3 inhibitor

• Na+/H+ exchangers – NHE2, NHE3, and NHE8 - apical regions of the enterocyte - transport Na+ from the intestinal lumen into enterocytes

• Tenapanor - selectively inhibits NHE3 - BP & urinary sodium excretion in rat models. - may be a useful alternative or adjunct to dietary Na+ reduction or diuretics in the Rx of HTN - Phase I

Dopamine β-hydroxylase inhibitor • DβH - catalyzes hydroxylation of dopamine noradrenaline sympathetic activation BP

• 1st, 2nd & early 3rd generations DβH inhibitors (Disulfiram, Fusaric acid, and Nepicastat) CNS a/e not clinically used

• Etamicastat (BIA 5–453) - potent and reversible inhibitor of DβH - selective for peripheral DβH (orally) - BP & prolonged survival in animal models - significantly lowered 24-hr ambulatory BP in HTN patients

Soluble epoxide hydrolase inhibitors• Soluble epoxide hydrolase (s-EH) – catalyzes the conversion of multiple lipid epoxides to the corresponding dihydroxy lipids.

• Inhibitors of s-EH BP, cardiac hypertrophy prevent atherosclerosis & aneurysm insulin resistance, in animal models

• AR9281 – potent & selective inhibitor of s-EH - BP improve vascular function, renal damage & improve glycemic parameters in rat models - RCT in healthy volunteers: BP (further studies needed)

Phosphodiesterase inhibitors

• Rx of PAH for years - PDE-3 I (Cilostazol) PDE-5I (Sildenafil, vardenalfil, tadalafil)

• Not shown significant results in improving sys HTN

• Tadalafil - Pleiotropic CV effects - under trial for exceptional cases of resistant hypertension

• KD027 (PDE-5 I) - Phase II studies for hypertension treatment

Drugs under trial for HTN

Class Drug PhaseDRI SPP636 IIa

ACEI MC-4232 III

Dual ACE/NEP inhibitor FasidotrilIlepatril

IIIIIb

Dual ARB/NEP inhibitor LCZ696 (Entresto) III

Dual ET-1/NEP inhibitor PS433540 (Sparsentan) II

Dual ECE/NEP inhibitor Daglutril (SLV-306) II

Anti-aldosterone agents Finerenone III

AT2 R agonist C21 Preclinical

ACE2 agonists XNT & DIZErhACE2

PreclinicalPhase I

Ang(1-7) analogues CGEN-856Encapsulated Ang (1–7)

PreclinicalPreclinical

Drugs under trial (contd)

Class Drug PhaseNon-peptide Mas Receptor agonist AVE-0991 Preclinical

Alamandine Alamandine/HPβCD Preclinical

APA inhibitor RB 150 Preclinical

Natriuretic Peptide Receptor Agonists PL-3994 II

VIP R agonist Vasomera II

Intestinal Na+/H+ exchanger 3 inhibitor Tenapanor I Dopamine β-hydroxylase inhibitor Etamicastat I

PDE inhibitors TadalafilKD027 II

Vaccines x Ang II: x AT1 R:

AngQbATRQB-001 & ATR12181

IIPreclinical

Newly approved drugs

Class Drug

DRI Akiskiren

ARB Azilsartan medoxomil

CCBs: L-type blockersCombined L- & T- type blockers

Combined L- & N-type blockers

ClevidipineManidipine, Nilvadipine, Benidipine, Efonidipine & Benzimidazole mibefradilCilnidipine

Β blockers: 3rd gen Carvedilol & Nebivolol

Combination RxDual combinations• Preferred - ACEI or ARB + DHP CCB ACEI or ARB + diuretic

• Recently approved – RAAS inhibitor + CCB Olmesartan + Amlodipine (Azor) RAAS inhibitor + Diuretic Azilsartan + Chlorthalidone (Edarbycyclor)

Triple combinations – VAL+AML+HCTZ OM+AML+HCTZ (TRINITY trial) ALI+AML+HCTZ

blocker + diureticMetoprolol + HCTZ(Lopressor HCTZ)Thiazide + K-sparing diureticHCTZ + Triamterene (Maxzide)

Rx of Resistant HTN• Patients already on 3 anti-htn drugs: ACEI/ARBs + CCB + Thiazide diuretic

• Chlorthalidone (twice as potent as HCTZ) - initial Rx

• Add-on drugs: MR antagonists – Spironolactone (4th agent) - if serum K+ level </= 4.5 mmol/L

• BP still high – Vasodilating β blockers (5th agent) sympatholytics or direct vasodilators

• Newer drug Rx - under trial

Interventional treatments

1. Renal denervation2. Baroreflex activation Rx3. Carotid body ablation4. A-V fistula5. Neurovascular decompression6. Renal artery stenting

References1) Goodman & Gilman2) Progress in medicine – Pritam Gupta3) New Approaches in the Treatment of Hypertension - Suzanne Oparil, Roland

E. Schmieder. Circulation research http://circres.ahajournals.org4) Aldosterone synthase inhibitors in hypertension: current status and future

possibilities – Milan Hargovan & Albert Ferro. JRSM Cardiovascular disease www.ncbi.nlm.nih.gov/pmc/articles/PMC3930157/5) ACE Inhibitors: A Comprehensive Review – Pradeep K Arora, Ashish Chauhan https://www.researchgate.net/publication/2368750206) New Developments in the Pharmacological Treatment of Hypertension: Dead- End or a Glimmer at the Horizon? – Ludovit, Romana, Fedor. Current Hypertension reports.www.ncbi.nlm.nih.gov/pmc/articles/PMC4412646/7) Current perspectives on combination therapy in the management of hypertension – Samir, Houssam, Bassem. Integrated blood pressure control.www.ncbi.nlm.nih.gov/pmc/articles/PMC3699293/