When to use aliskiren? A guide to its indications and place in therapy

October 9, 2025 •

4 min read

As the first and only FDA-approved direct renin inhibitor, aliskiren offers a unique mechanism for lowering blood pressure. However, understanding when to use aliskiren requires a careful evaluation of its approved indications, significant safety warnings, and a comparative analysis with other mainstay antihypertensive drug classes.

Quick Summary

This article discusses aliskiren's role in treating hypertension, focusing on its mechanism, optimal use cases, and notable contraindications, particularly dual RAAS blockade in diabetic patients.

Key Points

Approved Indication: Aliskiren is used to treat hypertension (high blood pressure) and can be prescribed as a single agent or in combination with other blood pressure medications.
Not a First-Line Therapy: It is not typically recommended as a first-line treatment option, partly due to the extensive long-term data available for other drug classes like ACE inhibitors and ARBs.
Contraindicated in Diabetes: Do not use aliskiren with ACE inhibitors or ARBs in patients with diabetes due to an increased risk of renal impairment, hyperkalemia, and hypotension.
Alternative for Intolerance: Aliskiren can be a suitable alternative for patients who require a RAAS inhibitor but cannot tolerate the persistent dry cough often caused by ACE inhibitors.
Avoid in Pregnancy: Aliskiren can cause severe harm to an unborn fetus and is contraindicated in pregnant women.
Renal Considerations: Monitor renal function in patients taking aliskiren, especially those with renal impairment or who are also on other RAAS inhibitors.
Low Bioavailability: High-fat meals can significantly decrease aliskiren's absorption, so patients should establish a consistent routine for taking it relative to food.
Combination with Diuretics: Combining aliskiren with a diuretic like hydrochlorothiazide can be effective, as aliskiren's action counteracts the compensatory RAAS activation from the diuretic.

What is aliskiren?

Aliskiren is a direct renin inhibitor, a class of medication used primarily to treat high blood pressure (hypertension). Unlike other common antihypertensives that target later stages of the renin-angiotensin-aldosterone system (RAAS), aliskiren works by directly binding to the active site of the enzyme renin. By blocking renin, aliskiren inhibits the conversion of angiotensinogen to angiotensin I, thereby preventing the entire RAAS cascade from activating. This mechanism results in a reduction of angiotensin I, angiotensin II, and aldosterone, leading to blood vessel relaxation and a decrease in blood pressure.

Approved uses for aliskiren

Aliskiren is approved for the treatment of hypertension in adults and children over 6 years of age who weigh 50 kg or more. It can be used either as a monotherapy or in combination with other antihypertensive agents. It is often reserved for specific scenarios due to its cost, limited long-term outcome data, and significant drug interaction warnings.

Aliskiren monotherapy

As a single agent, aliskiren has been shown to effectively lower blood pressure in patients with mild-to-moderate hypertension, with efficacy comparable to some angiotensin receptor blockers (ARBs). It may be considered for patients who are intolerant to other RAAS inhibitors, such as ACE inhibitors, particularly those who experience the bothersome dry cough associated with ACE inhibitors. Clinical trials have shown aliskiren to be associated with a much lower incidence of cough.

Aliskiren combination therapy

Aliskiren can be combined with other classes of antihypertensive drugs, such as diuretics (e.g., hydrochlorothiazide) or calcium channel blockers. The combination with hydrochlorothiazide is particularly well-supported, as aliskiren's action of lowering plasma renin activity counteracts the compensatory RAAS activation caused by the diuretic. Combination therapies can lead to greater blood pressure reductions than either monotherapy alone.

Important contraindications and warnings

Deciding when to use aliskiren is critically dependent on understanding its contraindications, particularly concerning dual RAAS blockade. The FDA issued a warning based on the early termination of the ALTITUDE trial, which showed increased risks in specific patient groups.

Dual RAAS blockade in diabetes: Aliskiren is contraindicated for use with ACE inhibitors or ARBs in patients with diabetes. The ALTITUDE study found that this combination in type 2 diabetes patients with renal disease or cardiovascular disease increased the risks of renal impairment, hyperkalemia, hypotension, and potentially adverse cardiovascular events.
Severe renal impairment: Combined use of aliskiren with an ACE inhibitor or ARB should be avoided in patients with moderate to severe renal impairment (creatinine clearance less than 60 mL/min).
Pregnancy: Aliskiren can cause fetal harm when used during pregnancy and should be discontinued as soon as pregnancy is detected.
Severe hypersensitivity: Patients with a history of angioedema while on aliskiren should not be readministered the drug.

Aliskiren's place in modern therapy

While aliskiren offers a unique mechanism for blood pressure reduction, its place in current hypertension management is relatively limited. The failure of large-scale outcome trials like ALTITUDE to demonstrate additional cardiovascular or renal benefits beyond standard care, combined with identified safety risks of dual blockade, has positioned it as a second-line or alternative option rather than a first-line agent.

For many patients, especially those who can tolerate ACE inhibitors or ARBs, these drug classes are the preferred RAAS inhibitors due to their extensive long-term outcome data demonstrating reduced morbidity and mortality. Aliskiren's role is most prominent in patients who require RAAS inhibition but experience unacceptable side effects, such as a severe cough, with ACE inhibitors.

Comparison of RAAS Inhibitors


Feature	Aliskiren (Direct Renin Inhibitor)	ACE Inhibitors (e.g., Lisinopril)	ARBs (e.g., Losartan)
Mechanism	Directly inhibits renin, the first step of the RAAS cascade.	Inhibits the angiotensin-converting enzyme (ACE) that converts Ang I to Ang II.	Blocks the angiotensin II type 1 (AT1) receptor.
Effect on RAAS	Decreases plasma renin activity (PRA), Ang I, and Ang II.	Increases PRA and Ang I; decreases Ang II.	Increases PRA and Ang I; blocks effects of Ang II at the AT1 receptor.
Persistent Cough	Very low incidence, similar to placebo.	Relatively high incidence, a common reason for discontinuation.	Low incidence, similar to placebo.
Angioedema Risk	Low risk, but reported; should not be re-administered to patients who experience it.	Known risk; should not be re-administered to patients who experience it.	Lower risk than ACEIs but still possible.
Dual Blockade Risk	Contraindicated with ACEIs/ARBs in diabetes due to increased risks.	Dual blockade with aliskiren contraindicated in diabetes.	Dual blockade with aliskiren contraindicated in diabetes.
Long-term Outcome Data	Lacks evidence demonstrating reduced cardiovascular morbidity/mortality.	Robust evidence for reduced cardiovascular morbidity/mortality in many populations.	Robust evidence for reduced cardiovascular morbidity/mortality.

Conclusion

Aliskiren is a potent antihypertensive agent that works by directly inhibiting renin, offering an alternative mechanism for managing hypertension. Its primary role today is for patients with uncomplicated hypertension who require a RAAS inhibitor but cannot tolerate ACE inhibitors due to adverse effects like cough. It is not a first-line treatment option, and its use is specifically contraindicated in diabetic patients also taking ACE inhibitors or ARBs due to increased risks of hyperkalemia, hypotension, and renal impairment. Its limited long-term outcome data also restricts its broader application. All patients should discuss the risks and benefits with their healthcare provider to determine the most appropriate treatment path.

FDA Drug Safety Communication: Aliskiren

U.S. Food and Drug Administration Drug Safety Communication: New warning and contraindication for blood pressure medicines containing aliskiren when used with other blood pressure medicines in patients with diabetes

Frequently Asked Questions

Aliskiren is a direct renin inhibitor used to treat hypertension. It works by blocking the enzyme renin, which is the initial and rate-limiting step in the renin-angiotensin-aldosterone system (RAAS). By inhibiting this step, it prevents the formation of angiotensin I and II, leading to blood vessel relaxation and lowered blood pressure.

Aliskiren is typically prescribed for patients with hypertension. It is often considered for those who are intolerant to other RAAS inhibitors like ACE inhibitors, particularly due to the persistent cough that can be a side effect of ACE inhibitors. It can be used alone or in combination with other antihypertensive medications.

Yes, aliskiren can be used with other blood pressure medications like diuretics. However, it is strictly contraindicated for use in combination with ACE inhibitors or angiotensin receptor blockers (ARBs) in diabetic patients due to an increased risk of severe side effects, including hyperkalemia and renal failure.

The most important contraindications for aliskiren are pregnancy, a history of angioedema related to aliskiren, and concurrent use with ACE inhibitors or ARBs in patients with diabetes. It is also advised to avoid its use with ACEIs or ARBs in patients with moderate to severe renal impairment.

No, aliskiren has a significantly lower incidence of causing a persistent dry cough compared to ACE inhibitors. This is one of the main reasons it may be chosen for patients who require RAAS inhibition but cannot tolerate an ACE inhibitor.

Common side effects of aliskiren include mild diarrhea, headache, dizziness, and fatigue. The incidence of these side effects at recommended doses is often similar to that of a placebo.

Patients should establish a routine pattern for taking aliskiren consistently with or without food. This is because high-fat meals can substantially decrease its absorption.