Losartan: what clinical trials show

Losartan is one of the most studied antihypertensive drugs. Over three decades it has been tested in hypertension with cardiac hypertrophy, diabetic nephropathy, heart failure, after a heart attack and even in hereditary connective tissue diseases. The editorial team has summarized the results of the key randomized trials - both the positive ones and those that did not live up to expectations.

LIFE: hypertension with left ventricular hypertrophy

The LIFE trial (Losartan Intervention For Endpoint reduction), published by Dahlof and co-authors in the Lancet in 2002, became the foundation for losartan. It included more than 9 thousand patients aged 55-80 with arterial hypertension and signs of left ventricular hypertrophy on the ECG.

Losartan was compared with the beta-blocker atenolol - at that time the standard drug. If necessary, hydrochlorothiazide and other agents were added in both groups. Follow-up lasted on average almost five years, and the blood pressure level in both groups dropped practically equally.

Despite the equal reduction in blood pressure, in the losartan group the frequency of the primary combined endpoint (cardiovascular death, heart attack, stroke) was approximately 13% lower. The advantage was provided mainly by a reduction in the number of strokes - by about a quarter. As for heart attacks, no significant difference was found.

Additionally, in the losartan group new-onset diabetes developed less often and the ECG signs of left ventricular hypertrophy decreased to a greater extent. These data supported the hypothesis that blockade of angiotensin II provides a benefit that is not reducible to lowering blood pressure alone.

At the same time, LIFE has limitations: atenolol was later recognized as not the best comparator drug, since it itself protects against stroke more weakly than other antihypertensive agents. Therefore part of losartan's advantage can be explained by the features of the comparator.

RENAAL: kidney protection in diabetes

The RENAAL trial (Brenner et al., New England Journal of Medicine, 2001) assessed losartan in more than 1500 patients with type 2 diabetes and nephropathy with marked proteinuria. Losartan or placebo was added to standard antihypertensive therapy (without ACE inhibitors and other sartans).

The primary endpoint combined a doubling of creatinine, the development of end-stage renal failure and death. In the losartan group its risk decreased by approximately 16%, and the risk of end-stage renal failure - by approximately 28%. The level of proteinuria decreased by approximately a third.

Importantly, the difference in blood pressure between the groups was small, so the nephroprotection is associated with a specific effect on intraglomerular hemodynamics - dilation of the efferent arteriole and a reduction of pressure in the glomerulus.

Together with the parallel IDNT trial with irbesartan, RENAAL established sartans as the drugs of choice for patients with diabetic kidney disease and proteinuria. This position is reflected in current hypertension guidelines.

Heart failure and heart attack: ELITE II, OPTIMAAL, HEAAL

Not all losartan trials were successful. The smaller ELITE trial showed an unexpectedly lower mortality on losartan compared with captopril in elderly patients with heart failure. To verify this, the larger ELITE II (Pitt et al., 2000) was conducted with more than 3 thousand patients.

ELITE II did not confirm the advantage: mortality on losartan was not lower than on captopril, and numerically even somewhat higher, although the difference did not reach statistical significance. On the other hand, losartan was much better tolerated - patients discontinued treatment less often due to side effects, in particular cough.

A similar result was obtained in OPTIMAAL (Dickstein, Kjekshus, 2002) in patients after acute myocardial infarction with signs of heart failure. Losartan at the dose used did not demonstrate an advantage over captopril, and overall mortality showed a trend in favor of captopril.

One of the explanations was considered to be an insufficient dose of losartan. This hypothesis was tested in HEAAL (Konstam et al., 2009): in patients with heart failure who did not tolerate ACE inhibitors, a dose of 150 mg per day was compared with 50 mg. The higher dose reduced the combined risk of death or hospitalization for heart failure by approximately 10%, at the cost of more frequent hyperkalemia, hypotension and worsening kidney function.

New indications: Marfan syndrome and others

Interest in losartan beyond hypertension arose after experiments in mice with a model of Marfan syndrome. In them, losartan, by suppressing TGF-beta signaling, prevented dilation of the aorta. This raised great hopes for a pathogenetic treatment of a hereditary disease.

The randomized Pediatric Heart Network trial (Lacro et al., 2014) with more than 600 children and young adults with Marfan syndrome compared losartan with atenolol. The rate of aortic root dilation over three years did not differ between the groups. Losartan proved to be no worse, but also no better than standard therapy.

Similarly, in animal experiments losartan improved the regeneration of skeletal muscle and reduced fibrosis (Cohn et al., 2007). However, there are no convincing clinical data on accelerating the healing of muscle injuries in humans.

Losartan has also been studied in other situations - from atrial fibrillation to liver fibrosis and COVID-19. For most of them the results are either contradictory or negative, so these uses are not among the official indications.

How to read these results

The history of losartan is a good illustration of several principles of evidence-based medicine. The first: a positive result of a small trial (such as ELITE) needs to be verified in a larger one - and it is often not confirmed.

The second: the result depends on the comparator drug and the dose. The advantage over atenolol in LIFE and the absence of an advantage over captopril in ELITE II and OPTIMAAL do not contradict each other but show that comparisons were made against different standards.

Briefly about the lessons of losartan's clinical history:

• early positive signals need confirmation in large trials;
• an advantage over one drug does not mean an advantage over all;
• the dose matters: in HEAAL the higher dose gave greater benefit and more side effects;
• results in animals do not transfer to humans automatically.

The third: a mechanism that is convincing in animals does not guarantee clinical benefit in humans, as is evident from the studies in Marfan syndrome.

Today losartan, in the ESH 2023 guidelines, is among the main classes of antihypertensive drugs, with a special place in diabetic kidney disease with proteinuria and left ventricular hypertrophy. In the treatment of heart failure with reduced ejection fraction, sartans are mainly considered as an alternative in cases of intolerance to ACE inhibitors.

Editorial conclusions

The evidence base for losartan is strongest in hypertension with left ventricular hypertrophy (LIFE) and in diabetic nephropathy (RENAAL). In these groups it reduces the frequency of strokes and slows the progression of kidney damage.

In heart failure and after a heart attack, losartan did not surpass captopril, although it was better tolerated; the benefit increases with the dose, but so do the side effects along with it.

Experimental uses, in particular for muscle regeneration, do not yet have clinical confirmation.

We also recommend reading Losartan: mechanism of action, Myths about Losartan and Telmisartan vs Losartan: what to choose and for whom.

References

1. Dahlöf B, Devereux RB, Kjeldsen SE, et al. Cardiovascular morbidity and mortality in the Losartan Intervention For Endpoint reduction in hypertension study (LIFE). Lancet. 2002;359(9311):995–1003.
2. 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 (RENAAL). N Engl J Med. 2001;345(12):861–869.
3. Pitt B, Poole-Wilson PA, Segal R, et al. Effect of losartan compared with captopril on mortality in patients with symptomatic heart failure: the Losartan Heart Failure Survival Study ELITE II. Lancet. 2000;355(9215):1582–1587.
4. Dickstein K, Kjekshus J; OPTIMAAL Steering Committee. Effects of losartan and captopril on mortality and morbidity in high-risk patients after acute myocardial infarction (OPTIMAAL). Lancet. 2002;360(9335):752–760.
5. 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). Lancet. 2009;374(9704):1840–1848.
6. 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.
7. Mancia G, Kreutz R, Brunström M, et al. 2023 ESH Guidelines for the management of arterial hypertension. J Hypertens. 2023;41(12):1874–2071.