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Losartan in 2025: Pharmacology, Guidelines, and Practical Prescribing

Since its approval nearly three decades ago, losartan has become a mainstay of cardiovascular and renal therapy. As the first angiotensin II receptor blocker (ARB) to enter clinical use, it helped shift hypertension management toward more targeted RAAS inhibition with improved tolerability compared to ACE inhibitors. In 2025, losartan remains a first-line antihypertensive in global guidelines and continues to play key roles in the management of heart failure, diabetic nephropathy, and high-risk cardiovascular patients.

Yet its role is not static. New formulation strategies, updated hypertension algorithms, and population-specific prescribing challenges are refining how losartan is used in everyday practice. In this review, we revisit the pharmacology, dosing principles, and evolving clinical applications of losartan with a focus on practical guidance for frontline prescribers especially in light of the 2024 ESC/ESH hypertension guidelines and renewed interest in personalized RAAS blockade.

In this review, we revisit the pharmacology, dosing principles, and evolving clinical applications of losartan with a focus on practical guidance for frontline prescribers especially in light of the 2024 ESC/ESH hypertension guidelines and renewed interest in personalized RAAS blockade.

Chemical Class & Mechanism of AT₁ Blockade

Losartan is the prototype of the angiotensin II receptor blocker (ARB) class, which was first approved in the mid-1990s and is still widely prescribed in 2025. As a selective antagonist of the angiotensin II type 1 (AT₁ receptor), losartan inhibits the key effector pathway of the renin–angiotensin–aldosterone system (RAAS). This blockade leads to vasodilation, reduced aldosterone secretion, and lower sympathetic activation, ultimately reducing blood pressure and cardiovascular stress.

Unlike ACE inhibitors, ARBs such as losartan do not affect the breakdown of bradykinin, minimizing the risk of cough and angioedema. This makes losartan an especially valuable agent in patients intolerant to ACEIs or those with higher baseline risk of bradykinin-mediated side effects (e.g., patients of African ancestry). In vascular tissue, AT₁ blockade prevents angiotensin II–induced hypertrophy and fibrosis, while in the kidneys, it attenuates glomerular hypertension and proteinuria. These effects extend beyond simple antihypertensive action, informing its use in diabetic nephropathy and heart failure.

Losartan’s development marked a pharmacologic shift from inhibiting RAAS enzymatically (via ACE) to blocking its receptor-mediated signaling, which is a strategy now central to many cardiovascular and renal therapeutic regimens.

As a selective antagonist of the angiotensin II type 1 (AT₁) receptor, losartan inhibits the key effector pathway of the renin–angiotensin–aldosterone system (RAAS).

Pharmacokinetics and Dose–Response (25–100 mg)

Losartan is well absorbed orally and metabolized in the liver to its active form, EXP3174, which has stronger and longer-lasting AT₁ blockade. The parent drug peaks in plasma within 1 hour, and the metabolite within 3–4 hours. While losartan itself has a short half-life (~2 hours), EXP3174 sustains action with a half-life of 6–9 hours, allowing for once-daily dosing in most patients.

The usual dose range is 25–100 mg/day, with 50 mg as the common starting point. Higher doses or twice-daily regimens (e.g., 50 mg BID) may enhance BP control or reduce proteinuria in selected cases. The drug’s metabolism via CYP2C9 and CYP3A4 means interactions are possible, though clinically significant effects are uncommon. Overall, losartan’s dose flexibility, renal and hepatic clearance, and predictable kinetics make it suitable for individualized titration across a broad patient spectrum.

Losartan is well absorbed orally and metabolized in the liver to its active form, EXP3174, which has stronger and longer-lasting AT₁ blockade.

Approved Indications & Off-Label Use

Losartan is approved for the treatment of hypertension in adults and children over 6 years old, and for diabetic nephropathy in patients with type 2 diabetes and proteinuria. It slows the progression of renal disease and is preferred in patients with hypertension and early signs of kidney involvement. It is also used as a substitute in heart failure with reduced ejection fraction (HFrEF) when ACE inhibitors are not tolerated due to cough or angioedema. Though not superior to ACEIs in trials, ARBs like losartan offer similar benefits in terms of mortality and hospitalization reduction when part of multi-drug regimens.

Off-label, losartan is occasionally used in Marfan syndrome to reduce aortic dilation, in migraine prophylaxis, and in post-MI LV remodeling where ACEIs are not tolerated. These uses are supported by observational studies or smaller trials but lack formal FDA or EMA indications.

Losartan is approved for the treatment of hypertension in adults and children over 6 years old, and for diabetic nephropathy in patients with type 2 diabetes and proteinuria.

2024 ESC/ESH Hypertension Algorithm Where Losartan Fits

The 2024 ESC/ESH guidelines reaffirm ARBs as first-line antihypertensives, alongside ACE inhibitors, calcium channel blockers (CCBs), and thiazide or thiazide-like diuretics. In uncomplicated cases, therapy should begin with a single-pill combination, typically an ARB plus either a CCB or diuretic. Losartan fits neatly into this framework and remains widely available as a fixed-dose combination with hydrochlorothiazide.

Unlike ACE inhibitors, which remain slightly more potent in BP reduction, ARBs such as losartan are better tolerated and particularly useful in patients who develop cough or angioedema. The guidelines now explicitly recommend ARBs in such scenarios, rather than simply discontinuing RAAS blockade altogether.

In patients with compelling comorbidities, like chronic kidney disease, diabetes, or left ventricular hypertrophy, ARBs are favored for their organ-protective effects and their additive value when paired with SGLT2 inhibitors or MRAs.

Importantly, the guidelines also endorse early combination therapy rather than stepwise monotherapy escalation. This makes losartan a highly relevant agent in initial two-drug regimens and beyond, especially in Europe where it remains a cost-effective and widely prescribed option.

The 2024 ESC/ESH guidelines reaffirm ARBs as first-line antihypertensives, alongside ACE inhibitors, calcium channel blockers (CCBs), and thiazide or thiazide-like diuretics.

Titration, Monitoring, and Common Adverse Effects

Losartan is typically initiated at 50 mg once daily, with titration to 100 mg/day based on blood pressure response and clinical context. In frail or volume-depleted patients, starting at 25 mg may be safer. Some clinicians opt for 50 mg twice daily to improve 24-hour control or proteinuria reduction, though this is off-label.

Monitoring should include blood pressure, serum potassium, and renal function, especially within 1–2 weeks of starting or adjusting the dose. Hyperkalemia is more likely in patients with CKD, diabetes, or those on potassium-sparing agents.

Common adverse effects include dizziness, fatigue, hypotension, and occasionally nasal congestion. Cough and angioedema are rare, especially compared to ACE inhibitors, and generally do not recur with losartan use.

Routine labs and clinical follow-up are critical after dose escalation, especially in polypharmacy or elderly patients, where orthostatic hypotension and drug interactions may complicate management.

Monitoring should include blood pressure, serum potassium, and renal function, especially within 1–2 weeks of starting or adjusting the dose.

Special Populations

In chronic kidney disease (CKD), losartan is often preferred for its ability to reduce proteinuria and slow progression, though caution is advised in bilateral renal artery stenosis or when eGFR declines rapidly after initiation.

In older adults, start low and titrate slowly, as risk of orthostatic hypotension and drug interactions is higher, especially with diuretics.

Pediatric use is approved for children over 6 years with hypertension; dosing is weight-based and requires close renal monitoring.

Losartan is contraindicated in pregnancy, especially in the second and third trimesters, due to risk of fetal renal injury and oligohydramnios. Safer alternatives should be used preconception or if pregnancy occurs.

Losartan is contraindicated in pregnancy, especially in the second and third trimesters, due to risk of fetal renal injury and oligohydramnios.

Future Formulation Trends

Formulation science is beginning to reshape how losartan is delivered, especially for populations with swallowing difficulties or adherence barriers. Orodispersible tablets (ODTs) are in late-stage development to aid elderly and pediatric patients, offering rapid disintegration without water and improved dosing flexibility. Meanwhile, research into nanocarrier-based delivery systems such as lipid nanoparticles and polymer-coated microspheres is underway to enhance bioavailability, improve tissue targeting, and allow lower dosing with sustained action. Though not yet commercialized, these technologies may eventually support once-weekly or depot forms.

Additionally, new fixed-dose combinations are being explored beyond thiazide diuretics, including pairing losartan with agents like neprilysin inhibitors or nonsteroidal mineralocorticoid antagonists, targeting heart failure and proteinuric kidney disease more aggressively.

These innovations aim to make losartan more precise, more convenient, and more adaptable to the evolving demands of individualized care.

Orodispersible tablets (ODTs) are in late-stage development to aid elderly and pediatric patients, offering rapid disintegration without water and improved dosing flexibility.

References

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