Telmisartan

A Review of its Use in Hypertension

Summary

Abstract

Telmisartan is an angiotensin II receptor antagonist that is highly selective for type 1 angiotensin II receptors. It was significantly more effective than placebo in large (n >100), double-blind, randomised, multicentre clinical trials in patients with mild to moderate hypertension. Telmisartan 20 to 160mg once daily produced mean reductions in supine trough systolic blood pressure and diastolic blood pressure of up to 15.5 and 10.5mm Hg, respectively. Maximum blood pressure reduction occurred with a dosage of 40 to 80 mg/day.

Telmisartan 40 to 120 mg/day was as effective as amlodipine 5 to 10 mg/day or atenolol 50 to 100 mg/day in dose-titration studies. Telmisartan 20 to 160 mg/day was generally similar in efficacy to enalapril 5 to 20 mg/day or lisinopril 10 to 40 mg/day in both titration-to-response and other studies. Hydrochlorothiazide was coadministered in most of the titration-to-response studies if patients remained hypertensive.

Telmisartan 80 mg/day was more effective than submaximal dosages of losartan (50 mg/day) or valsartan (80 mg/day) and was as effective as a fixed-dose combination of losartan 50mg plus hydrochlorothiazide 12.5mg over the last 6 hours of the dosage interval and the whole 24-hour postdose interval. In patients with severe hypertension, telmisartan 80 to 160 mg/day was as effective as enalapril 20 to 40 mg/day (both agents could be titrated and combined sequentially with hydrochlorothiazide 25mg and amlodipine 5mg).

The addition of hydrochlorothiazide to telmisartan was more effective than each agent alone at lowering blood pressure in patients with hypertension.

Telmisartan was well tolerated in patients with mild to moderate hypertension and was significantly less likely to cause persistent, dry cough than lisinopril.

Conclusion: Telmisartan is an effective antihypertensive agent with a tolerability profile similar to that of placebo. Comparative data have shown telmisartan to be as effective as other major classes of antihypertensive agents at lowering blood pressure. Compared with lisinopril, telmisartan is associated with a significantly lower incidence of dry, persistent cough. Therefore, telmisartan is a useful therapeutic option in the management of patients with hypertension.

Pharmacodynamic Properties

Telmisartan is an angiotensin II (AII) receptor antagonist that is highly selective for type 1 AII (AT1) receptors.

In normotensive male volunteers enrolled in a randomised, double-blind, placebo-controlled study, telmisartan 20 to 80mg dose-dependently attenuated AII-induced increases in diastolic blood pressure (DBP), systolic blood pressure (SBP) and heart rate (HR). Single doses of telmisartan 20 to 80mg inhibited AII-induced increase in DBP by >25% within 0.3 to 1.1 hours when administered 30 minutes after intravenous administration of AII (the dose of AII was that which produced maximal increases in SBP). During repeated challenges, AII-induced increases in blood pressure were inhibited by >25% for 26.9, 35.4 and 40.5 hours among those randomised to telmisartan 20, 40 and 80mg, respectively. Plasma levels of AII and active renin increased to maxima within 4 hours of treatment. In concert with these neurohormonal changes, urinary flow and sodium and potassium excretion were significantly and dose-dependently increased in the first 3 hours after administration of telmisartan 20 to 80mg.

In untreated patients with hypertension telmisartan had a significant natriuretic effect during the first 3 days of treatment. Urinary sodium excretion was significantly greater in recipients of telmisartan 80 mg/day than in those randomised to telmisartan 40 mg/day or placebo. The differences between groups were no longer significant after 15 days of treatment, although a trend toward greater total daily sodium excretion was apparent in recipients of the higher telmisartan dosage.

Significant increases in plasma renin activity and AII levels occurred in patients treated with telmisartan 40 to 120 mg/day in a randomised, placebo-controlled 4-week study.

Telmisartan has a potassium-sparing effect in patients with hypertension that attenuated the kaliuretic effect of hydrochlorothiazide when the 2 drugs were coadministered.

Systemic vascular resistance was reduced and systemic vascular and brachial artery compliance increased in patients with hypertension during treatment with telmisartan 40 mg/day. Telmisartan 40 mg/day reduced arterial stiffness in patients with type 2 diabetes mellitus and hypertension in a randomised, double-blind, placebo-controlled, 3-week, crossover study.

During 9 months of treatment with telmisartan 40 or 80 mg/day, blood pressure and left ventricular (LV) mass index were significantly reduced compared with baseline in patients with hypertension and mild to moderate LV hypertrophy. When introduced 7 days after the withdrawal of ACE inhibitors, single doses of telmisartan 10 to 80mg improved haemodynamic variables in patients with stable mild to moderate congestive heart failure enrolled in a multicentre, randomised, double-blind, placebo-controlled study.

In patients with mild to moderate congestive heart failure, no significant change in exercise capacity, ejection fraction, New York Heart Association class or health-related quality of life score occurred when enalapril 10mg twice daily as replaced with telmisartan 10 to 40 mg/day in a 12 week, randomised, double-blind, multicentre trial.

Pharmacokinetic Properties

There is a high degree of interindividual variability in the plasma concentration profile of telmisartan. As a result of saturable first-pass metabolism, the oral bioavailability of telmisartan is dose dependent (42.4% after a single 40mg oral dose) and maximum plasma concentrations (Cmax) increase disproportionately after oral administration. Administration with food reduced the bioavailability of a 40mg dose by 6%, thus telmisartan may be taken with or without food. Steady-state plasma concentrations were achieved after approximately 5 to 7 days. The area under the plasma concentration-time curve (AUC) of telmisartan was 1.2-fold greater in elderly females than males after administration of 120 mg/day for 7 days.

Telmisartan is extensively distributed to tissues (mean apparent volume of distribution at steady state was 460 to 510L in healthy male volunteers) and is highly bound (99.5%) to plasma proteins, including albumin, α-1-acid glycoprotein, γ-globulin and lipoproteins.

A pharmacologically inactive acylglucuronide conjugate, which comprised 16% of the drug in circulation after a single 40mg dose, is the only metabolite of telmisartan. Biliary-faecal excretion is the primary route of elimination of telmisartan and its metabolite. The mean terminal elimination half-life of the drug was ≈24 hours in healthy volunteers and patients with hypertension.

Cmax, AUC0–24 and AUC0–∞ of telmisartan were markedly reduced and the mean free fraction of the drug in plasma was approximately doubled in patients undergoing dialysis compared with healthy volunteers.

The absolute bioavailability of telmisartan was increased in patients with hepatic impairment (to 97.2%) and the Cmax and AUC0–∞ of telmisartan were approximately 3-fold greater in hepatically-impaired patients compared with healthy controls.

In healthy male volunteers, telmisartan had a small effect on plasma warfarin concentrations, but there was no change in the international normalised ratio.

AUC, Cmax and minimum plasma concentrations of digoxin increased during coadministration with telmisartan in healthy male volunteers. The increase in Cmin did not exceed the predefined range for a lack of interaction, but serum digoxin concentrations should be monitored during concomitant therapy with telmisartan.

Telmisartan had no effect on the pharmacokinetics of amlodipine, glibenclamide (glyburide), hydrochlorothiazide, ibuprofen, paracetamol (acetaminophen) or simvastatin.

Therapeutic Efficacy

Placebo-Controlled and Dose-Finding Studies

Oral telmisartan 20 to 160mg once daily consistently reduced supine SBP and DBP (primary end-point) to a significantly (p ≤ 0.05) greater extent than placebo at trough or throughout the 24-hour dosage interval in randomised, double-blind, multicentre studies in patients with mild to moderate hypertension or isolated systolic hypertension.

Generally, telmisartan 20 to 160 mg/day did not show a significant dose-response relationship with the exception of 1 study, where a statistically significant linear dose-response relationship for SBP was observed. Dosages above 80mg once daily did not result in further blood pressure reduction in patients with mild to moderate hypertension. The drug was generally more effective in White than in Black patients, although Black patients still experienced clinically meaningful reductions in blood pressure with telmisartan.

Comparisons with Other Antihypertensive Agents

Telmisartan 40mg titrated to 80 or 120mg once daily produced similar anti-hypertensive effects, as assessed by primary end-points, to amlodipine 5mg titrated to 10mg once daily or atenolol 50mg titrated to 100mg once daily (with or without the addition of hydrochlorothiazide if patients remained hypertensive) in 232 to 533 patients with mild to moderate hypertension in randomised, double-blind, multicentre, titration-to-response trials. Ambulatory blood pressure monitoring (ABPM) has shown that telmisartan 40mg titrated to 120mg provides better blood pressure control during night-time and in the last 4 hours of the dosage interval than amlodipine 5mg titrated to 10mg.

In randomised, double-blind studies of 4 to 52 weeks’ duration in patients with mild to moderate hypertension, telmisartan 20mg once daily titrated to 80 or 160mg (when patients remained hypertensive) was similar in efficacy to enalapril 5mg once daily titrated to 20mg or lisinopril 10mg once daily titrated to 40mg (hydrochlorothiazide was also added when patients remained hypertensive in these studies) and telmisartan 40 to 160mg once daily was at least as effective at reducing blood pressure as enalapril 20mg once daily and similar in efficacy to lisinopril 20mg once daily. Telmisartan 40 mg/day titrated to 80mg and enalapril 10 mg/day titrated to 20mg [with furosemide (frusemide) if patients remained hypertensive] appeared to reduce blood pressure to a similar extent in patients with mild to moderate hypertension and moderate renal failure.

Telmisartan 80mg once daily was more effective at reducing blood pressure measured by ABPM over the 18- to 24-hour postdose interval or the whole 24-hour postdose interval than submaximal dosages of losartan (50mg once daily) or valsartan (80mg once daily) and was as effective as the fixed-dose combination of losartan 50mg plus hydrochlorothiazide 12.5mg once daily. These randomised trials were conducted in patients with mild to moderate hypertension; 2 trials were nonblind, 1 was double-blind.

In patients with severe hypertension, telmisartan 80 mg/day titrated to 160 mg/day reduced blood pressure as effectively as enalapril 20 mg/day titrated to 40 mg/day (in patients who remained hypertensive on monotherapy, hydrochlorothiazide 25 mg/day and amlodipine 5 mg/day were added sequentially) in a randomised, nonblind, multicentre study.

In Combination and in Comparison with Hydrochlorothiazide

In randomised, double-blind trials, the combination of telmisartan 40 or 80 mg/day and hydrochlorothiazide 12.5 mg/day (as a fixed-dose combination in some trials) was more effective than each agent alone in patients with mild to moderate hypertension. Telmisartan monotherapy was generally more effective than hydrochlorothiazide monotherapy at lowering blood pressure in a similar patient group, but these agents were similar in efficacy in patients with isolated systolic hypertension. Telmisartan 40 or 80mg once daily administered alone or in combination with other antihypertensive agents produced a sustained antihypertensive effect for up to 1 (≈64% of patients) or >3 years (≈84% of patients) in 2 noncomparative extension studies.

Tolerability

According to pooled tolerability data, adverse events reported by >5300 patients who received telmisartan (including 1758 patients in placebo-controlled studies) were generally mild and transient and occurred at a similar incidence as those reported by placebo recipients. The only adverse events occurring at a markedly higher incidence with telmisartan than placebo were back pain (2.6 vs 0.9%), diarrhoea (2.8 vs 1.1%) and upper respiratory tract infection (6.7 vs 5.1%), although headache was much more common with placebo than telmisartan (7.1 vs 15.1%) [statistical analysis not reported]. 2.8% of patients who received telmisartan and 6.1% of placebo recipients discontinued treatment because of adverse events.

In randomised, double-blind or nonblind, comparative trials, telmisartan had a similar tolerability profile to amlodipine or atenolol (with or without hydrochlorothiazide), other AII receptor antagonists (valsartan and losartan) and hydrochlorothiazide alone or telmisartan in combination with hydrochlorothiazide (including telmisartan 40 or 80mg with hydrochlorothiazide as a fixed-dose combination), although oedema was more common with amlodipine than telmisartan.

Telmisartan was also at least as well tolerated as the ACE inhibitors lisinopril and enalapril. Furthermore, telmisartan produced a significantly lower incidence of dry cough than lisinopril in patients with a history of ACE inhibitor-related cough in a study for which this parameter was the primary end-point (15.6 vs 60%; p = 0.001). Telmisartan and enalapril, both in combination with hydrochlorothiazide and amlodipine, were similarly tolerated in patients with severe hypertension.

Dosage and Administration

Telmisartan, alone and in combination with other antihypertensive agents, is indicated for the treatment of hypertension. The usual recommended dosage is 40mg once daily. Some patients may experience benefit at a dosage of 20 mg/day. In patients in whom a satisfactory blood pressure response is not achieved, the dosage may be increased to a maximum of 80mg once daily. The maximum antihypertensive effect is generally attained 4 to 8 weeks after the start of treatment. As hydrochlorothiazide complements the blood pressure-lowering effect of telmisartan, the combination of telmisartan and a thiazide diuretic may be appropriate in some patients. Telmisartan may be given with or without food.

Dosage adjustments are not required on the basis of age, gender or renal dysfunction. The manufacturer recommends that telmisartan be used with caution in patients with hepatic impairment, in whom the dosage should not exceed 40 mg/day, and those with depleted intravascular volume.

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Notes

  1. 1.

    The dose of AII that produced the maximal increase in SBP (≈30mm Hg) was determined the day prior to the study for each individual and ranged from 2 to 5μg. AII challenges were repeated for 48 hours after administration of telmisartan or placebo.

  2. 2.

    In Canada the recommended dosage is 80 mg/day.[79]

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Correspondence to Miriam Sharpe.

Additional information

Various sections of the manuscript reviewed by: R.W. Bilous, James Cook University Hospital, Middlesbrough, England; L. Brown, Department of Physiology and Pharmacology, University of Queensland, Brisbane, Queensland, Australia; R.R. Castillo, Manila Doctors Hospital, Manila, The Philippines; L. de Angelis, Dipartimento di Scienze Biomediche, Università degli Studi di Trieste, Trieste, Italy; P.A. Meredith, Department of Medicine and Therapeutics, Gardiner Institute, Western Infirmary, Glasgow, Scotland; M. Tan, Mount Elizabeth Medical Centre, Singapore; M.H. Weinberger, Hypertension Research Center, Indiana University School of Medicine, Indianapolis, Indiana, USA.

Data Selection

Sources: Medical literature published in any language since 1966 on telmisartan, identified using Medline and EMBASE, supplemented by AdisBase (a proprietary database of Adis International). Additional references were identified from the reference lists of published articles. Bibliographical information, including contributory unpublished data, was also requested from the company developing the drug.

Search strategy: Medline search terms were ‘telmisartan’ or ‘BIBR 277’. EMBASE search terms were ‘telmisartan’ or ‘BIBR 0277’ or ‘BIBR 277’. AdisBase search terms were ‘telmisartan’ or ‘BIBR 277’. Searches were last updated 23 July, 2001.

Selection: Studies in patients with hypertension who received telmisartan. Inclusion of studies was based mainly on the methods section of the trials. When available, large, well controlled trials with appropriate statistical methodology were preferred. Relevant pharmacodynamic and pharmacokinetic data are also included.

Index terms: Hypertension, telmisartan, pharmacodynamics, pharmacokinetics, therapeutic use.

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Sharpe, M., Jarvis, B. & Goa, K.L. Telmisartan. Drugs 61, 1501–1529 (2001). https://doi.org/10.2165/00003495-200161100-00009

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Keywords

  • Diastolic Blood Pressure
  • Enalapril
  • Losartan
  • Amlodipine
  • Hydrochlorothiazide