Telmisartan – antihypertensive with cardioprotective effects

Introduction

Chronic activation of RAAS plays an important role in the pathogenesis of atherosclerosis, arterial hypertension, left ventricular hypertrophy, myocardial infarction, and heart failure. Effective inhibition of the RAAS can be achieved by administering angiotensin-converting enzyme inhibitors (ACEi) or sartans.

Both groups of drugs have demonstrated significant efficacy in the therapy of arterial hypertension, and the administration of ACEis has also been associated with reduced mortality and cardiovascular risk in high-risk cardiovascular patients. However, a disadvantage of ACEis is their side effects, such as a bothersome dry cough, which leads to intolerance in a significant portion of patients.

A similar cardioprotective effect has also been confirmed for drugs from the group of direct angiotensin receptor inhibitors − sartans. These are already an established group of drugs in the therapy of hypertension and heart failure after myocardial infarction. However, telmisartan was the first drug from this group to also demonstrate a cardioprotective effect in several cardiovascular parameters.

Reduction of Albuminuria

Proteinuria is an important cardiovascular risk factor. In the HOPE study, which included 9043 patients, a correlation between cardiovascular risk and the severity of proteinuria was demonstrated. After adjusting for other risk factors, this study documented an association between the risk of major cardiovascular events and microalbuminuria (relative risk [RR] 1.83; 95% confidence interval [CI] 1.64–2.05).

ACE inhibitors and sartans exhibit renoprotective effects such as reducing microalbuminuria and improving renal function. The DETAIL study demonstrated the non-inferiority of telmisartan compared to enalapril in preventing the progression of renal dysfunction in patients with diabetes. In the INNOVATION study, 527 patients with diabetes were assigned to telmisartan therapy at daily doses of 80 mg and 40 mg or to a placebo, regardless of the presence of hypertension. The progression to overt diabetic nephropathy during 30 months of treatment was significantly lower in patients on telmisartan compared to placebo. Dose dependence was also observed (16.7 and 22.6 vs. 49.9%; p < 0.0001). The benefit of telmisartan was also observed in patients without arterial hypertension, indicating that this effect is independent of blood pressure levels.

Prevention of Cardiovascular Diseases

Several randomized controlled clinical studies have also demonstrated reduced mortality and hospitalization rates in heart failure patients treated with sartans. One groundbreaking study in this regard is ONTARGET. It included 25,260 patients with coronary, peripheral, or cerebrovascular atherosclerosis or diabetes with target organ damage. Patients with heart failure were excluded. They were randomized to therapy with ramipril at a daily dose of 10 mg, telmisartan at a dose of 80 mg, or a combination of both. The primary composite outcome included death from cardiovascular causes, acute myocardial infarction, stroke, or hospitalization for heart failure. The follow-up period was 56 months. The reduction in the occurrence of the primary composite outcome was comparable between telmisartan and ramipril treatment (16.7 vs. 16.5%; RR 1.01; 95% CI 0.94–1.09). Telmisartan was associated with a lower incidence of cough (1.1 vs. 4.2%; p < 0.001) and angioedema (0.1 vs. 0.3%; p = 0.01). Combined therapy did not lead to an improvement in the primary outcome and increased the incidence of adverse events and the proportion of patients discontinuing therapy.

The TRANSCEND study included 5962 patients at high cardiovascular risk and intolerant to ACEis. The population characteristics were otherwise similar to the ONTARGET study, and the primary composite outcome was the same. Patients were randomized to telmisartan therapy at a daily dose of 80 mg or placebo. After 56 months, no significant difference in the primary outcome was observed between active treatment and placebo. However, telmisartan significantly reduced the incidence of the secondary composite outcome comprising cardiovascular mortality, acute myocardial infarction, and stroke (13 vs. 14.8%; odds ratio [OR] 0.86; 95% CI 0.74–1.00; p = 0.045).

Reduction of Left Ventricular Mass

In subsequent analyses of the ONTARGET and TRANSCEND studies, a reduction in left ventricular hypertrophy prevalence was observed with telmisartan treatment. For example, in the TRANSCEND study, left ventricular hypertrophy was present in 12.7% of patients at baseline and in 9.9% of patients on telmisartan after 5 years of therapy compared to 12.8% on placebo (OR 0.79; 95% CI 0.68–0.91; p = 0.0017). Compared to placebo, telmisartan reduced the risk of developing left ventricular hypertrophy by 37%. The ONTARGET study observed a comparable reduction in left ventricular hypertrophy prevalence between telmisartan and ramipril.

Prevention of Atrial Fibrillation

A metaanalysis of 23 clinical studies confirmed the efficacy of RAAS blockade in reducing the incidence of atrial fibrillation by 33% (p < 0.00001). The benefit was observed in primary prevention in patients with heart failure, hypertension, and left ventricular hypertrophy (but not after myocardial infarction), as well as in secondary prevention when RAAS blockers were added to antiarrhythmics. The ONTARGET study found comparable prevention of atrial fibrillation with telmisartan and ramipril.

Favorable Metabolic Effects

Finally, the potential effect of telmisartan on metabolic diseases is noteworthy. In the TRANSCEND study, patients on telmisartan had a lower risk of developing diabetes compared to placebo (hazard ratio [HR] 0.85; 95% CI 0.71–1.02; p = 0.081). Wang et al. published a metaanalysis of 21 clinical studies showing that telmisartan administration, compared to other sartans, leads to reduced insulin resistance and decreased fasting blood glucose and insulin levels in patients with obesity, diabetes, impaired glucose tolerance, or metabolic syndrome. The positive effect of telmisartan on metabolism is likely due to its partial agonism on the PPAR-γ receptor. Numerous experimental studies have shown that this receptor plays an important role in the development of dyslipidemia, metabolic syndrome, and vascular diseases.

Conclusion

The results of numerous studies suggest that telmisartan is not only an effective and safe antihypertensive but also exhibits complex favorable effects on the cardiovascular and metabolic systems.

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Sources:
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2. Ayza M. A., Zewdie K. A., Tesfaye B. A. et al. Anti-diabetic effect of telmisartan through its partial PPARγ-agonistic activity. Diabetes Metab Syndr Obes 2020; 13: 3627–3635. doi: 10.2147/DMSO.S265399.
3. Wang Y., Qiao S., Han D. W. et al. Telmisartan improves insulin resistance: a meta-analysis. Am J Ther 2018; 25 (6): e642–e651. doi: 10.1097/MJT.0000000000000733.