What are the indications, dosing regimens, contraindications, adverse effects, and monitoring recommendations for losartan (angiotensin II receptor blocker) in hypertension, left‑ventricular hypertrophy, diabetic nephropathy, and heart failure?

Losartan: Comprehensive Clinical Guide

Indications

Losartan is FDA-approved for hypertension, stroke risk reduction in patients with hypertension and left ventricular hypertrophy, and diabetic nephropathy with elevated serum creatinine and proteinuria in type 2 diabetes. 1, 2

Primary Indications by Clinical Context

Hypertension:

• First-line agent for uncomplicated hypertension, equivalent in efficacy to other ARBs, ACE inhibitors, thiazide diuretics, and calcium channel blockers 1, 3
• Particularly beneficial in diabetic patients with hypertension and left ventricular hypertrophy, where losartan reduces cardiovascular endpoints by 24% and all-cause mortality by 39% compared to atenolol 4, 3

Diabetic Nephropathy:

• In type 2 diabetes with macroalbuminuria, losartan reduces progression to end-stage kidney disease by 28% (P=0.002) and the composite endpoint of doubling serum creatinine, kidney failure, or death by 20% (P=0.01) 1, 5, 6
• Reduces proteinuria by 13–18.5% independent of blood pressure lowering 1
• All patients (100%) with microalbuminuria showed improvement in urine albumin levels in clinical studies 7

Chronic Kidney Disease:

• For CKD with severely increased albuminuria without diabetes: Grade 1B recommendation to reduce risk of kidney failure and cardiovascular events 7
• For CKD with moderately increased albuminuria without diabetes: Grade 2C recommendation based on cardiovascular benefits outweighing hyperkalemia and acute kidney injury risks 7

Heart Failure with Reduced Ejection Fraction:

• Class I recommendation for patients who cannot tolerate an ACE inhibitor 1
• Target dose of 100–150 mg daily; the HEAAL trial demonstrated 150 mg was superior to 50 mg with a 10% relative risk reduction in death or heart failure hospitalization (P=0.027) 1

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Dosing Regimens

Hypertension

Start losartan 50 mg once daily and titrate to 100 mg once daily after 2–4 weeks if blood pressure remains ≥140/90 mmHg; 100 mg once daily is the maximum recommended dose for hypertension. 1, 8

• Can be administered once daily or split into 50 mg twice daily (total 100 mg/day) 1, 8
• Re-evaluate blood pressure every 2–4 weeks during titration, targeting <130/80 mmHg within three months 1
• If uncontrolled on losartan 100 mg daily, add hydrochlorothiazide 12.5–25 mg daily rather than exceeding maximum losartan dose 1
• For grade 2 hypertension (≥160/100 mmHg), initiate two agents from the outset (e.g., losartan plus thiazide or calcium channel blocker) 1

Diabetic Nephropathy

The target dose for diabetic nephropathy is 100 mg once daily. 1, 6

• Start at 50 mg once daily and titrate to 100 mg daily over 2–4 weeks 1
• Check serum creatinine/eGFR and potassium within 1–2 weeks after initiation or dose changes 1
• Continue even as eGFR declines to <30 mL/min/1.73 m² for cardiovascular benefit 1

Heart Failure with Reduced Ejection Fraction

The target dose is 100–150 mg daily; titrate no more frequently than every 2 weeks to target or maximally tolerated dose. 1

• European Society of Cardiology recommends starting at 50 mg with 150 mg as the target dose 1
• For patients with low baseline blood pressure, start at the lowest dose and up-titrate slowly with small increments every 1–2 weeks 1

Special Populations

Hepatic Impairment:

• Start at 25 mg once daily in mild-to-moderate hepatic impairment; plasma concentrations are approximately five-fold higher than in healthy individuals 1

Elderly (≥75 years):

• Initiate at a low dose to reduce risk of hypotension and renal insufficiency 1
• Increase dose more gradually (every 2–4 weeks) and monitor closely for dizziness, falls, and symptomatic hypotension 1
• Measure blood pressure in both sitting and standing positions (at 1 and 3 minutes after standing) to detect orthostatic hypotension 1

Renal Impairment:

• No dose adjustment necessary for various degrees of renal insufficiency 8
• Start at lower dose in individuals with eGFR <45 mL/min/1.73 m² 7
• Losartan is not removed during hemodialysis 8

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Contraindications

Absolute Contraindications

Pregnancy:

• Losartan is absolutely contraindicated in all trimesters due to serious fetal toxicity (renal dysfunction, oligohydramnios, skull hypoplasia, fetal death) 1
• Discontinue immediately upon pregnancy detection and switch to pregnancy-compatible antihypertensives (methyldopa, labetalol, or extended-release nifedipine) 1

Dual RAAS Blockade:

• Never combine losartan with ACE inhibitors or direct renin inhibitors (aliskiren); this increases risk of hyperkalemia, syncope, and acute kidney injury by 2–3-fold without added cardiovascular benefit 4, 1, 7
• Class III: Harm recommendation from ACC/AHA guidelines 1

History of ARB-Induced Angioedema:

• Losartan should not be used in patients with previous ARB-induced angioedema 1
• Patients with prior ACE inhibitor-induced angioedema may be started on losartan no sooner than 6 weeks after discontinuing the ACE inhibitor, with extreme caution 1

Severe Bilateral Renal Artery Stenosis:

• Use is contraindicated due to risk of acute renal failure 1, 7

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Adverse Effects

Common Adverse Effects

• Losartan is devoid of significant adverse effects and is well tolerated 8
• Dizziness, falls, and fatigue are more common in elderly patients (≥75 years) 1

Serious Adverse Effects

Hyperkalemia:

• Particularly in patients with chronic kidney disease, diabetes, or when combined with potassium-sparing agents 1
• Losartan typically increases serum potassium by approximately 1 mEq/L 7
• Halve the dose if potassium rises to >5.5 mmol/L; stop immediately if potassium ≥6.0 mmol/L 7

Acute Renal Failure:

• Can occur in severe bilateral renal artery stenosis 1
• Worsening renal function may occur due to efferent arteriolar vasodilation in patients dependent on angiotensin II for glomerular filtration 7
• A modest and transient increase in serum creatinine of 0.1–0.3 mg/dL (10–20%) is expected and hemodynamic, not indicative of kidney injury unless persistent 1, 7
• Halve the dose if creatinine rises to >220 μmol/L (2.5 mg/dL); stop immediately if creatinine rises to >310 μmol/L (3.5 mg/dL) 7

Angioedema:

• Although less frequent than with ACE inhibitors, angioedema remains possible with an incidence of approximately 0.11% 7

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Monitoring Recommendations

Initial Monitoring

Check serum creatinine/eGFR and potassium within 1–2 weeks after initiating losartan or increasing the dose, especially in patients with diabetes, chronic kidney disease, or those receiving potassium-sparing agents. 1, 7

Ongoing Monitoring

Blood Pressure:

• Re-evaluate every 2–4 weeks during titration 1
• Home blood pressure monitoring is endorsed; a home reading ≥135/85 mmHg corresponds to office hypertension ≥140/90 mmHg 1
• In elderly patients, measure blood pressure in both sitting and standing positions to detect orthostatic hypotension 1

Renal Function and Electrolytes:

• Monitor serum creatinine/eGFR and potassium at least annually during maintenance therapy 1
• In patients with CKD, diabetes, or on potassium-sparing agents, monitor more frequently (within 1–2 weeks of dose changes, then every 2–4 weeks) 1, 7

Temporary Suspension:

• Suspend losartan during interval illness, planned IV radiocontrast administration, bowel preparation for colonoscopy, or prior to major surgery 7

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Drug Interactions

Contraindicated Combinations

ACE Inhibitors and Direct Renin Inhibitors:

• Dual RAAS blockade increases adverse effects without additional benefit (Class III: Harm) 1, 7
• The VALIANT trial demonstrated increased adverse outcomes with dual blockade 1

Potassium-Sparing Diuretics and Potassium Supplements:

• Concomitant use markedly increases hyperkalemia risk, especially in chronic kidney disease 1
• Avoid combining losartan with spironolactone or other aldosterone antagonists due to compounded hyperkalemia risk 7

Clinically Significant Interactions

NSAIDs:

• May blunt losartan's antihypertensive effect and worsen renal function 1

Lithium:

• Co-administration can precipitate lithium toxicity; monitor lithium levels 1

Favorable Interaction Profile

• No clinically relevant interactions with hydrochlorothiazide, warfarin, or digoxin 8
• Overall favorable drug-drug interaction profile with CYP450 inhibitors and stimulators 8

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Combination Therapy

Preferred Combinations

Losartan + Thiazide Diuretic:

• Fixed-dose combination of losartan 50–100 mg plus hydrochlorothiazide 12.5–25 mg is guideline-endorsed first-line therapy 1
• Adding 12.5 mg HCTZ to losartan 50 mg produces a placebo-adjusted reduction of approximately 15.5 mmHg systolic / 9.2 mmHg diastolic 1
• Single-pill combination markedly improves medication adherence and persistence 1

Losartan + Calcium Channel Blocker:

• For uncontrolled hypertension on losartan plus diuretic, add a dihydropyridine calcium channel blocker (e.g., amlodipine 5–10 mg) to create triple therapy 1

Escalation Strategy for Resistant Hypertension

For resistant hypertension persisting despite triple therapy (ARB + diuretic + CCB), introduce spironolactone 25 mg daily as the preferred fourth agent. 1

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Common Pitfalls and Caveats

Underdosing

Less than 25% of patients are ever titrated to target doses in clinical practice; higher doses provide greater benefits than lower doses, with little evidence that medium-range doses approximate the benefits of target doses. 1

• For heart failure, 150 mg daily was superior to 50 mg daily with a 10% relative risk reduction 1
• For diabetic nephropathy, the target dose is 100 mg daily, not 50 mg 1, 6

Premature Discontinuation for Hyperkalemia

Implement potassium-lowering strategies before stopping losartan; do not discontinue prematurely for mild hyperkalemia. 1

• Dietary potassium restriction, discontinuation of potassium supplements, and addition of loop diuretics can manage hyperkalemia without stopping losartan 1

Misinterpreting Creatinine Elevation

A modest rise in serum creatinine (10–20%) after starting losartan is expected and hemodynamic, not indicative of kidney injury unless persistent or accompanied by acute tubular necrosis on urinalysis. 1, 7

• Differentiate expected hemodynamic rises from genuine acute tubular necrosis by using urine microscopy 1

Relying on Monotherapy Dose Escalation

Combination therapy with agents from different classes yields better blood pressure control than monotherapy dose escalation. 1

• If blood pressure remains uncontrolled on losartan 100 mg daily, add a second agent rather than exceeding the maximum dose 1

Adding Beta-Blockers Without Compelling Indication

Beta-blockers are less effective than calcium channel blockers or diuretics for stroke prevention and should not be added as second- or third-line agents unless there are compelling indications (angina, post-MI, heart failure with reduced ejection fraction, atrial fibrillation). 1

Timing of Administration

Preferential bedtime administration of losartan is not recommended; current guidelines consider both morning and evening dosing acceptable, emphasizing sustained 24-hour blood pressure control rather than specific timing. 1

• When morning hypertension persists despite once-daily morning losartan, add a complementary agent (thiazide or calcium channel blocker) instead of merely shifting dosing time 1

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Pharmacokinetics and Pharmacology

• Losartan is rapidly absorbed, reaching maximum concentrations 1–2 hours post-administration 8
• Approximately 14% is converted to the active E-3174 metabolite, which is 10- to 40-fold more potent than losartan 8
• E-3174 has an estimated terminal half-life of 6–9 hours 8
• Pharmacokinetics are linear, dose-proportional, and do not substantially change with repetitive administration 8
• No clinically significant effects of age, sex, or race on pharmacokinetics 8
• Major metabolic pathway is via CYP3A4, 2C9, and 2C10 isoenzymes 8
• Losartan is a competitive antagonist; E-3174 is a noncompetitive "insurmountable" antagonist of angiotensin II 8