Telmisartan

Telmisartan (Micardis®, Pritor®), a highly selective angiotensin II (AII) type 1 (AT₁) receptor antagonist, is approved for the treatment of hypertension, either as monotherapy or in combination with other antihypertensive agents. The long elimination half-life of telmisartan ensures the drug provides effective reductions in blood pressure (BP) across the entire 24-hour dosage interval

Extensive evidence from well designed clinical trials and the clinical practice setting indicates that telmisartan, either as monotherapy or in combination with other antihypertensive agents, provides long-term antihypertensive efficacy and is well tolerated in a broad spectrum of hypertensive patients, including the elderly and those with coexisting type 2 diabetes mellitus, metabolic syndrome and/or renal impairment. Notably, BP control is sustained throughout the 24-hour dosage interval, including during the last 6 hours of this period. Independent of its effect on BP, telmisartan displays favourable effects on insulin resistance, lipid levels, left ventricular hypertrophy (LVH) and renal function. The consistent antihypertensive efficacy during the entire 24-hour dosage interval and sustained BP-lowering effect in the long term, combined with its favourable tolerability profile, mean that telmisartan is a valuable first-line treatment option for the management of essential hypertension.

Telmisartan is a highly selective, competitive nonpeptide AT₁ receptor antagonist of AII, the primary effector of the renin-angiotensin-aldosterone system. The drug has no affinity for AT₂ or other receptors. In normotensive volunteers, once-daily telmisartan 20–80mg dose-dependently attenuated AII-induced increases in diastolic BP (DBP) and systolic BP (SBP). Maximal dose-dependent increases in plasma levels of AII and active renin were detected 4 hours after treatment. At 20–80mg doses, telmisartan inhibited the response to repeated AII challenges by >25% for 26.9–40.5 hours, respectively.

In preclinical studies, telmisartan (but not other AT₁ receptor antagonists) has been shown to act as a partial agonist of the peroxisome proliferator-activated receptor-γ at clinically relevant levels. The drug also decreased serum glucose and serum triglyceeride levels, and increased glucose uptake and GLUT4 protein expression. In patients with mild-to-moderate hypertension and impaired insulin sensitivity, telmisartan, but not losartan, significantly increased the glucose infusion rate. Telmisartan is associated with a significant reduction in left ventricular mass index, posterior and septal wall thickness, and left atrial maximal and minimal volumes in patients with essential hypertension and mild-to-moderate LVH.

Telmisartan is rapidly absorbed with a mean absolute bioavailability of approximately 50%. Peak plasma concentrations (C_max) of telmisartan are reached in 0.5–1 hour after single-dose administration and telmisartan has a half-life of ≈24 hours. Steady-state plasma concentrations are reached after 5–7 days of administration, and drug accumulation after prolonged administration appears unlikely. Following oral or intravenous administration telmisartan is excreted largely unchanged in the faeces, via biliary excretion; <1% is excreted in the urine. Studies in healthy volunteers demonstrate the low potential for drug interactions between telmisartan and simvastatin, amlodipine, glibenclamide (glyburide), ibuprofen, paracetamol (acetaminophen) and hydrochlorothiazide (HCTZ). Since median C_max and trough concentrations of digoxin are increased when the drug is coadministered with telmisartan, digoxin levels should be monitored when initiating, adjusting and discontinuing telmisartan therapy.

Extensive clinical experience gained from several well designed, large (n > 200), prospective clinical trials has firmly established the antihypertensive efficacy of telmisartan in a broad spectrum of hypertensive patients, including the elderly and those with comorbid conditions. These benefits are observed for the duration of the 24-hour dosage interval, including during the last 6 hours of the dosage interval, and are sustained in the long term. Studies based in the primary care setting confirm the antihypertensive efficacy of telmisartan.

In patients with mild-to-moderate hypertension, telmisartan monotherapy (once-daily 40 or 80mg) for 8 weeks provided better antihypertensive efficacy than monotherapy with losartan or valsartan, including during the last 6 hours of the dosage interval and, relative to valsartan, after a missed dose. Furthermore, once-daily telmisartan monotherapy (80mg) was shown to be noninferior to once-daily, fixed-dose losartan/HCTZ (50mg/12.5mg). Relative to angiotensin converting enzyme (ACE) inhibitors, once-daily telmisartan 40 or 80mg was more effective than recommended dosages of perindopril or ramipril and at least as effective as enalapril in trials of up to 26 weeks’ duration, including during the last 6 hours of the dosage interval. Telmisartan monotherapy showed similar antihypertensive efficacy to lisonopril monotherapy in a 52-week trial. In addition, telmisartan-based therapy showed similar antihypertensive efficacy to atenolol-based therapy in a 26-week study. Once-daily telmisartan also showed similar antihypertensive efficacy to once-daily amlodipine after 12 weeks’ treatment.

Combination therapy with fixed-dose telmisartan/HCTZ 80mg/25mg once daily was significantly more effective than valsartan/HCTZ 160mg/25mg or placebo once daily in lowering seated trough SBP and DBP. Once-daily, fixed-dose telmisartan/HCTZ 40mg/12.5mg and 80mg/12.5mg were also superior to once-daily fixed-dose losartan/HCTZ 50mg/12.5mg in reducing mean DBP during the last 6 hours of the dosage interval in two identically designed trials in ≈800 patients. In elderly patients with predominantly systolic hypertension, telmisartan plus HCTZ was as effective as amlodipine plus HCTZ in reducing mean SBP during the last 6 hours of the dosage interval.

Clinical trials with telmisartan have also demonstrated a beneficial effect in hypertensive patients with type 2 diabetes and/or renal impairment. Furthermore, these benefits were achieved across the entire spectrum of renal disease, including patients undergoing haemodialysis, with studies also showing improvements in renal function with telmisartan treatment. Of note, in a 5-year, double-blind study in hypertensive patients with type 2 diabetes and early nephropathy, telmisartan was shown to be noninferior to enalapril in providing renoprotection, as assessed by a fall in the rate of decline in glomerular filtration rate over this time period. In addition, in hypertensive patients with chronic nephropathy, treatment with telmisartan 80mg twice daily resulted in renoprotective effects, slowing the progression to end-stage renal disease. Telmisartan treatment, but not losartan or valsartan treatment, also resulted in improvements in lipid profiles in hypertensive patients with coexisting type 2 diabetes.

Extensive clinical experience shows that telmisartan is well tolerated, as indicated in a large-scale, 6-month, post-marketing surveillance study involving 19 870 patients with essential hypertension and concomitant diabetes (18.3%), hypercholesterolaemia (47.6%), coronary heart disease (19.9%), congestive heart failure (13.2%) or renal insufficiency (2.1%). Treatment-related adverse events were reported in <2% of patients receiving telmisartan 40–80mg once daily, with the most common being headache, dizziness and nausea. Long-term studies of up to 96 weeks’ duration support the benign tolerability profile of telmisartan.

These adverse events were similar to those observed in >6100 recipients of telmisartan in clinical trials, with the majority of treatment-related adverse events being transient and of mild intensity. The most frequently reported adverse events included headache, dizziness, fatigue, upper respiratory tract infections and nausea. In comparative trials, treatment-related adverse events occurred with a similar frequency (≤7%) in telmisartan, valsartan and losartan recipients. However, although the incidence of these adverse events was generally similar across all treatment groups, treatment-related cough appeared to occur with a higher incidence in the ACE inhibitor than the telmisartan group. Furthermore, telmisartan plus HCTZ therapy was better tolerated than amlodipine plus HCTZ therapy, with a significantly lower incidence of treatment-related adverse events and of peripheral oedema in the telmisartan group.