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- Keating, G.M. Drugs (2009) 69: 1239. doi:10.2165/00003495-200969090-00008
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Losartan/hydrochlorothiazide (HCTZ) [Hyzaar®] is a fixed-dose combination of the angiotensin II receptor antagonist (angiotensin receptor blocker [ARB]) losartan and the thiazide diuretic HCTZ. It is indicated for the treatment of hypertension (including as initial therapy in severe hypertension) and for stroke risk reduction in patients with hypertension and left ventricular hypertrophy (LVH).
Losartan/HCTZ is an effective combination therapy, lowering blood pressure (BP) to a greater extent than losartan or HCTZ alone in patients with hypertension. Other ARB/HCTZ fixed-dose combinations generally lowered BP to a greater extent than losartan/HCTZ in patients with hypertension, although whether this translates into improvements in cardiovascular outcomes is not known. In the LIFE study, losartan-based therapy was associated with a lower incidence of cardiovascular morbidity and mortality than atenolol-based therapy, mainly as a result of a reduced risk of stroke; the incidence of new-onset diabetes mellitus was also lower with losartan- based therapy. Losartan/HCTZ is a well tolerated combination therapy. Thus, losartan/HCTZ remains an important option in the treatment of hypertension, as well as being indicated to reduce stroke risk in patients with hypertension and LVH.
Losartan is a reversible, selective, competitive inhibitor of the angiotensin II type 1 (AT1) receptor; E3174, the active metabolite of losartan, is more potent than the parent drug. HCTZ acts directly on the kidney, ultimately increasing the urinary excretion of sodium and reducing the extracellular fluid volume and peripheral resistance, which leads to activation of the renin-angiotensin and sympathetic nervous systems, thereby increasing the sensitivity of the AT1 receptor and enhancing the response to ARBs.
Combination therapy with losartan and HCTZ achieved greater reductions in BP than those seen with either drug alone. Losartan alone and in combination with HCTZ maintained BP control over the entire 24-hour period in patients with essential hypertension, with no significant change in heart rate.
Significantly greater regression of electrocardiographic (ECG) LVH occurred with losartan-than with atenolol-based therapy in patients with hypertension and LVH in the LIFE study. Losartan ameliorated structural abnormalities and endothelial dysfunction in resistance arteries in patients with essential hypertension. In LIFE substudies, regression of carotid artery hypertrophy was seen with losartan- but not atenolol-based therapy, although there was no significant between-group difference in carotid artery plaque development. Losartan-based therapy reduced albuminuria to a significantly greater extent than atenolol-based therapy in patients with hypertension and LVH in a LIFE substudy. Losartan may ameliorate some of the deleterious metabolic effects of HCTZ. For example, losartan attenuated the increase in serum uric acid levels and the potassium loss associated with HCTZ therapy. In addition, losartan reduced serum levels of natriuretic peptides and inhibited platelet aggregation.
Oral losartan tablets have a bioavailability of 33% and oral HCTZ has a bioavailability of ≈60–80%. Losartan undergoes extensive first-pass metabolism by the cytochrome P450 (CYP) isozymes CYP3A4 and CYP2C9, whereas HCTZ is not metabolized and is mainly eliminated unchanged in the urine.
Three dose-ranging trials revealed that once-daily losartan 50 mg in combination with HCTZ 12.5 or 25 mg once daily (but not 6.25 mg once daily) was consistently more effective than losartan or HCTZ alone in patients with essential hypertension. The fixed-dose combination of losartan/HCTZ was effective in patients with essential hypertension in another three trials, reducing trough sitting systolic BP (SiSBP)/sitting diastolic BP (SiDBP) to a significantly greater extent than placebo or losartan monotherapy, and achieving significantly higher response rates. In four trials in Black, Chinese, Japanese and obese patients with hypertension, losartan/HCTZ consistently showed significantly greater antihypertensive efficacy than monotherapy with losartan or HCTZ or than placebo.
Comparisons of losartan/HCTZ with other ARB/HCTZ combination therapies in patients with essential hypertension revealed significantly greater BP reductions with telmisartan/HCTZ than with losartan/HCTZ in two trials assessing the reduction in ambulatory BP during the last 6 hours of the dosing interval, with candesartan cilexetil/HCTZ than with losartan/HCTZ in two trials assessing trough SiSBP/SiDBP, and with irbesartan/HCTZ than with losartan/HCTZ in one trial assessing 24-hour ambulatory mean DBP. In terms of response rates, significant between-group differences favouring the comparator ARB/HCTZ were seen in the candesartan/cilexetil trials and in patients receiving the higher telmisartan/HCTZ dosage in one of the telmisartan/HCTZ trials. The reduction in trough SiDBP did not significantly differ between losartan/HCTZ and olmesartan medoxomil/HCTZ recipients in one trial, although the reduction in trough SiSBP and the response rate significantly favoured olmesartan medoxomil/HCTZ.
In two trials, losartan/HCTZ had similar efficacy to captopril/HCTZ or enalapril/HCTZ in patients with essential hypertension, in terms of reductions from baseline in trough SiSBP/SiDBP and response rates.
In the LIFE study in patients with hypertension and LVH, recipients of losartan-based therapy were significantly less likely than those receiving atenolol-based therapy to experience cardiovascular mortality, stroke or myocardial infarction (MI) [primary composite endpoint]. When considered separately, the risk of stroke was significantly lower with losartan- than with atenolol-based therapy, although there were no significant between-group differences in the risk of cardiovascular mortality or MI. The significant effect of losartan-based therapy on stroke was found to be independent of its effects on regression of ECG LVH or BP. New-onset diabetes occurred in significantly fewer patients receiving losartan- versus atenolol-based therapy.
The risk of cardiovascular mortality, stroke or MI was significantly lower in most patient subgroups, including patients with no clinically evident vascular disease, patients with isolated systolic hypertension, patients with diabetes, women, patients with a history of atrial fibrillation and patients considered higher risk. However, Black patients who received losartan-based therapy were significantly more likely than those receiving atenolol-based therapy to experience the composite endpoint of cardiovascular mortality, stroke or MI.
Losartan-based therapy was a cost-effective alternative to atenolol-based therapy in patients with hypertension and LVH, according to the results of cost-effectiveness analyses that were conducted from healthcare payer and/or societal perspectives (and based on the findings of the LIFE study).
Losartan/HCTZ was well tolerated in patients with essential hypertension or hypertension and LVH; adverse events were usually transient and of mild severity. According to a pooled analysis of data from patients with essential hypertension, adverse events reported in >1% of losartan/HCTZ recipients and in numerically more losartan/HCTZ than placebo recipients included upper respiratory tract infection, dizziness, cough, back pain, rash, palpitations, oedema/swelling, abdominal pain and sinusitis. The adverse events seen with losartan/HCTZ were consistent with those seen with losartan or HCTZ monotherapy, and losartan/HCTZ and other ARB/HCTZ combination therapies had generally similar tolerability profiles. In general, losartan/HCTZ was better tolerated than captopril/HCTZ or enalapril/HCTZ in patients with essential hypertension (e.g. a lower incidence of cough).
Losartan-based therapy was generally better tolerated than atenolol-based therapy in patients with hypertension and LVH in the LIFE study. For example, hypotension was the only prespecified adverse event that occurred in significantly more recipients of losartan- versus atenolol-based therapy, whereas bradycardia, cold extremities and sexual dysfunction occurred in significantly more patients receiving atenolol-than losartan-based therapy.