Direct Renin Inhibitors

Direct renin inhibitors block the first and rate-limiting step of the renin-angiotensin system by binding the active site of renin. Aliskiren is the only agent in clinical use. It lowers blood pressure but has no proven benefit on cardiovascular outcomes, and its role is limited.

Mechanism. Aliskiren is a transition-state mimic of angiotensinogen that blocks cleavage to angiotensin I. Plasma renin activity, angiotensin I, angiotensin II and aldosterone fall. Renin concentration rises because feedback is lost, but its activity stays suppressed.

Pharmacokinetics. Oral bioavailability is only about 2.5% and is further reduced by a high-fat meal, so it should be taken consistently with or without food. The half-life is about 24 to 40 hours, so it is given once daily. It is a substrate of P-glycoprotein and a minor substrate of CYP3A4, and is eliminated mainly unchanged in faeces.

Outcome evidence. A large outcomes study in type 2 diabetes with kidney disease was stopped early when aliskiren added to an ACE inhibitor or angiotensin receptor blocker raised the risk of non-fatal stroke, renal complications, hyperkalaemia and hypotension, with no benefit.

Pregnancy risk. Foetal toxicity as with other renin-angiotensin blockers.

• Aliskiren: the only marketed agent. Blood pressure reduction is similar to that of ACE inhibitors and angiotensin receptor blockers. Fixed combinations with hydrochlorothiazide or amlodipine exist in some markets.
• Other agents: earlier compounds (remikiren, enalkiren) were not developed because of poor bioavailability.

• Hypertension: aliskiren 150 mg orally once daily, increased to 300 mg after 2 to 4 weeks. Full effect takes up to 4 weeks.
• Place in therapy: a later option for patients intolerant of ACE inhibitors and angiotensin receptor blockers, or as an add-on to a thiazide-like diuretic or calcium channel blocker. It is not first line.
• Not advised: in combination with an ACE inhibitor, angiotensin receptor blocker or sacubitril-valsartan, particularly in diabetes or with eGFR under 60 mL/min/1.73 m2, where it is contraindicated.
• Heart failure and kidney disease: no outcome benefit shown, so other agents are preferred.

Contraindications. Pregnancy, previous aliskiren angioedema, use with ciclosporin or itraconazole, and use with an ACE inhibitor or angiotensin receptor blocker in diabetes or with eGFR under 60 mL/min/1.73 m2.

Adverse effects. Dose-related diarrhoea, hyperkalaemia, hypotension, acute kidney injury, cough (less than with ACE inhibitors), rash, rare angioedema, and raised uric acid and creatine kinase.

Interactions. Ciclosporin and itraconazole raise aliskiren levels markedly. Ketoconazole, verapamil and other P-glycoprotein inhibitors increase exposure. Furosemide levels fall. NSAIDs reduce effect and raise kidney injury risk. Potassium-sparing drugs raise potassium.

Monitoring. Blood pressure, potassium and creatinine at baseline, 1 to 2 weeks after starting or increasing, then yearly.

Referral and escalation. Throat or facial swelling needs emergency care and permanent discontinuation.

Special groups. Pregnancy: stop. Renal impairment: no dose change in mild to moderate disease, but monitor potassium. Children: not used. Older adults: start at the usual dose with monitoring. Breastfeeding: avoid because of limited data.