Losartan: What the Clinical Trials Show
Losartan was the first angiotensin II receptor blocker to reach the market, and it has been tested in some of the largest cardiovascular trials ever run. The results were not uniformly positive. Looking at where losartan succeeded and where it fell short explains how it is used today and why doctors sometimes choose alternatives.
Background: the first sartan
ACE inhibitors transformed cardiovascular medicine in the 1980s, but a dry cough affects a notable proportion of users. Blocking the angiotensin II type 1 receptor directly was expected to deliver similar benefits without the cough, because ARBs do not affect bradykinin breakdown in the same way.
Losartan was approved in the mid-1990s. Its manufacturer then funded a series of large outcome trials to test whether lowering blood pressure through this route also protected the heart, brain and kidneys.
Unlike surrogate studies that look only at blood pressure readings, outcome trials count real events: strokes, heart attacks, hospital admissions, dialysis and deaths. That is why they carry most weight in guidelines.
In the UK losartan is a widely used generic prescription medicine. The trials below explain why it appears in NICE pathways for hypertension and diabetic kidney disease.
Hypertension and stroke: the LIFE trial
The Losartan Intervention For Endpoint reduction in hypertension (LIFE) study enrolled over 9,000 people aged 55–80 with hypertension and left ventricular hypertrophy on ECG. They were randomised to losartan-based or atenolol-based treatment and followed for at least four years.
Blood pressure fell by similar amounts in both groups. Even so, the losartan group had a lower rate of the primary composite outcome of cardiovascular death, stroke and heart attack. The difference was driven mainly by a reduction in stroke.
LIFE also found less new-onset diabetes and greater regression of left ventricular hypertrophy with losartan. These findings contributed to a shift away from beta-blockers as first-line treatment for uncomplicated hypertension, reflected in later UK guidance.
The trial did not show reduced heart attacks or total mortality in the overall population, and its comparison with atenolol, a drug later regarded as relatively weak for stroke prevention, is sometimes criticised.
| Trial | Population | Comparison | Headline result |
|---|---|---|---|
| LIFE (2002) | Hypertension with LVH | Losartan vs atenolol | Fewer strokes; similar BP |
| RENAAL (2001) | Type 2 diabetes with nephropathy | Losartan vs placebo (plus usual care) | Slower progression to kidney failure |
| ELITE II (2000) | Heart failure | Losartan vs captopril | Not superior to captopril |
| OPTIMAAL (2002) | High-risk after myocardial infarction | Losartan vs captopril | No advantage; trend favoured captopril |
| HEAAL (2009) | Heart failure, ACE-intolerant | Losartan 150 mg vs 50 mg | Higher dose reduced death or HF admission |
Kidney protection in diabetes: RENAAL
The Reduction of Endpoints in NIDDM with the Angiotensin II Antagonist Losartan (RENAAL) trial included over 1,500 people with type 2 diabetes and established nephropathy with proteinuria. Losartan or placebo was added to conventional blood pressure treatment.
Brenner and colleagues reported that losartan reduced the combined risk of doubling of serum creatinine, end-stage kidney disease or death. The benefit on end-stage kidney disease was particularly clear. Proteinuria fell substantially in the losartan group.
RENAAL, together with a parallel trial of irbesartan, established ARBs as a standard of care for diabetic kidney disease with albuminuria. NICE guidance for type 2 diabetes and chronic kidney disease reflects this role.
Because ARBs can raise potassium and initially reduce kidney filtration slightly, blood tests are checked after starting treatment. A small early rise in creatinine is expected and does not usually mean the drug should be stopped.
Heart failure and after a heart attack
In heart failure, losartan was compared directly with the ACE inhibitor captopril. ELITE II, published by Pitt and colleagues in 2000, found that losartan was not superior to captopril in reducing mortality, although it was better tolerated.
OPTIMAAL, reported by Dickstein and Kjekshus in 2002, compared the two drugs in high-risk patients after a myocardial infarction. Again losartan did not outperform captopril, and the trend favoured the ACE inhibitor. These trials used losartan 50 mg daily, a dose later suspected to be too low for heart failure.
HEAAL tested that hypothesis. Konstam and colleagues compared losartan 150 mg with 50 mg in patients with heart failure who could not tolerate ACE inhibitors. The higher dose reduced the composite of death or admission for heart failure, at the cost of more kidney impairment, high potassium and low blood pressure.
Taken together, these results explain why ACE inhibitors remain the first choice in heart failure and after myocardial infarction, with ARBs as an alternative for those who cannot tolerate them. Newer agents have since changed the landscape further.
Marfan syndrome and other investigations
Mouse studies suggested that losartan could slow aortic dilatation in Marfan syndrome by reducing TGF-beta signalling. This generated great hope. Lacro and colleagues tested losartan against atenolol in over 600 children and young adults with Marfan syndrome.
The rate of aortic root enlargement did not differ significantly between the two drugs over three years. Losartan is still used as an option in Marfan syndrome, but not as the breakthrough the animal studies had suggested.
Other areas of study have included:
- effects on uric acid, as losartan has a modest uricosuric effect that may help some people with gout;
- muscle regeneration and fibrosis, studied mainly in animals;
- various inflammatory and fibrotic conditions, with inconsistent results.
For athletes, the most practical lesson from this research is that losartan's benefits are established for specific medical conditions. There is no trial evidence of performance or recovery benefits in healthy people.
Conclusions of the editorial team
Losartan's strongest evidence comes from LIFE, where it reduced strokes in hypertension with left ventricular hypertrophy, and RENAAL, where it slowed kidney disease in type 2 diabetes.
In heart failure and after heart attack, it did not beat captopril at the doses tested, although higher doses performed better than lower ones in HEAAL.
The hope that losartan would transform Marfan syndrome was not confirmed in a large human trial. We also recommend our articles on myths about losartan, on atorvastatin clinical trials, and on how ezetimibe interacts with other medicines.
References
- Dahlöf B, Devereux RB, Kjeldsen SE, et al. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE): a randomised trial against atenolol. Lancet. 2002;359(9311):995–1003.
- Brenner BM, Cooper ME, de Zeeuw D, et al. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med. 2001;345(12):861–869.
- Pitt B, Poole-Wilson PA, Segal R, et al. Effect of losartan compared with captopril on mortality in patients with symptomatic heart failure: randomised trial — the Losartan Heart Failure Survival Study ELITE II. Lancet. 2000;355(9215):1582–1587.
- Dickstein K, Kjekshus J; OPTIMAAL Steering Committee. Effects of losartan and captopril on mortality and morbidity in high-risk patients after acute myocardial infarction: the OPTIMAAL randomised trial. Lancet. 2002;360(9335):752–760.
- Konstam MA, Neaton JD, Dickstein K, et al. Effects of high-dose versus low-dose losartan on clinical outcomes in patients with heart failure (HEAAL study): a randomised, double-blind trial. Lancet. 2009;374(9704):1840–1848.
- Lacro RV, Dietz HC, Sleeper LA, et al. Atenolol versus losartan in children and young adults with Marfan's syndrome. N Engl J Med. 2014;371(22):2061–2071.
