What are examples of direct renin inhibitors?

Direct Renin Inhibitors: Clinical Examples

Aliskiren is currently the only direct renin inhibitor available for clinical use in the treatment of hypertension. 1, 2

Available Agent

• Aliskiren is the sole FDA-approved direct renin inhibitor, available as oral tablets in 150 mg and 300 mg strengths for once-daily administration 2, 3
• Aliskiren works by directly inhibiting renin at its activation site, blocking the conversion of angiotensinogen to angiotensin I, thereby reducing angiotensin II formation 1, 2
• The drug is approved for use as monotherapy or in combination with other antihypertensive agents (thiazide diuretics, calcium channel blockers) in appropriate patient populations 1, 2

Mechanism and Pharmacology

• Unlike ACE inhibitors and ARBs which reactively increase plasma renin activity, aliskiren suppresses renin effects and reduces plasma renin activity by 50-80% 2, 3
• Aliskiren has poor oral bioavailability (approximately 2.5%) and reaches steady state in 7-8 days with an accumulation half-life of 24 hours 2
• The drug is primarily metabolized by CYP3A4, with about one-fourth of the absorbed dose excreted unchanged in urine 2

Critical Safety Considerations and Contraindications

• Combination therapy with aliskiren plus an ACE inhibitor or ARB is contraindicated in patients with diabetes mellitus due to increased risk of renal complications, hyperkalaemia, and hypotension 1
• The ALTITUDE trial was stopped early due to higher incidence of adverse events including end-stage renal disease, renal death, hyperkalaemia, and hypotension when aliskiren was added to other RAAS blockers in diabetic patients 1
• Aliskiren should be avoided in bilateral renal artery stenosis as it may precipitate acute renal failure 4
• Triple RAAS blockade (ACE inhibitor + ARB + renin inhibitor) combined with mineralocorticoid antagonists is not recommended due to risk of renal dysfunction and hyperkalaemia 1

Clinical Efficacy Profile

• Aliskiren lowers systolic blood pressure by 12-16 mm Hg and diastolic blood pressure by 2-12 mm Hg at approved doses 5
• Efficacy is comparable to ARBs (losartan 100 mg, irbesartan 150 mg, valsartan 80-320 mg) in clinical trials 5
• No trials have demonstrated beneficial effects of aliskiren on cardiovascular or renal morbidity and mortality endpoints in hypertension 1
• The APOLLO trial evaluating aliskiren for major cardiovascular events in elderly patients was stopped, and no aliskiren-based trials with hard endpoints are expected in the near future 1

Common Pitfalls to Avoid

• Do not use aliskiren as a first-line agent when ACE inhibitors or ARBs with proven mortality benefits are appropriate 1
• Avoid prescribing aliskiren in combination with ACE inhibitors or ARBs in diabetic patients, particularly those with renal impairment 1, 6
• Do not assume aliskiren provides end-organ protection equivalent to ACE inhibitors or ARBs, as long-term outcome data are lacking 1, 5
• Monitor for hyperkalaemia when using aliskiren, particularly in patients with renal impairment or those on other potassium-retaining medications 1

Current Clinical Role

• Aliskiren may be considered as an alternative agent for mild-to-moderate hypertension in patients who are intolerant of first-line therapies (ACE inhibitors, ARBs, calcium channel blockers, thiazide diuretics) 3, 5
• The drug is not recommended as an alternative to ACE inhibitors or ARBs in heart failure management 1
• Aliskiren can be combined with thiazide diuretics or calcium channel blockers for additional blood pressure reduction in appropriate patients without diabetes or advanced renal disease 1, 2