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HomeProductsClinically provenKrka’s telmisartans – extensive, comprehensive and publicly accessible clinical evidence

Gašper Marinšek, Breda Barbič-Žagar

Key words

telmisartan, extensive clinical evidence, comprehensive therapy, publicly accessible

Abstract

What sets telmisartan apart from other angiotensin receptor blockers (ARBs) are its advantageous pharmacological profile that enables stable 24h-blood pressure (BP) control, a favourable metabolic profile and beneficial effects beyond BP at all stages of the cardiovascular (CV) and renal continuum. Telmisartan, the most extensively studied ARB, enables effective and safe BP reduction in a broad range of hypertensive patients and is the only ARB approved for CV prevention. Nevertheless, most hypertensive patients should initially be prescribed a dual combination of a renin-angiotensin system (RAS) blocker, either with a calcium channel blocker (CCB) or a diuretic. A combination with CCB amlodipine is the optimal choice for a wide range of hypertensive patients; due to its synergistic action, it results in greater BP reduction than with respective monotherapies and enhanced cardiovascular, renal and metabolic effects. Data from several non-interventional clinical studies, which included around 24,000 hypertensive patients, demonstrated that Krka’s telmisartans (both in monotherapy and dual SPCs with HCTZ or amlodipine) represent a very comprehensive antihypertensive therapy, enabling high office and home BP control rates, effective 24h-BP control and reduced blood pressure variability (BPV), a good safety profile, advantageous metabolic effects and effects on body parameters, resulting in excellent treatment satisfaction and very high treatment adherence. In conclusion, transparent and publicly accessible extensive clinical evidence with Krka’s telmisartans is recognized and valued, making them the leading telmisartans in terms of value and volume in the markets of Central, Eastern and Southeastern Europe.

Introduction

Telmisartan has been approved for the treatment of hypertension since 1998 (1). Additionally, telmisartan is the only ARB approved for the reduction of CV morbidity in high-risk patients (patients with atherothrombotic cardiovascular disease (CVD) or diabetes mellitus with target organ damage) (2, 3). Important distinguishing features of telmisartan are its long half-life of about 24 hours (the longest among all ARBs) and slow dissociation from angiotensin II type 1 (AT1) receptor, resulting in stable 24-hour blood pressure (BP) control, including the last 6 hours before the next dose when hypertensive patients are at the greatest risk of CV and cerebrovascular events (1, 3–5). Another important feature is its favourable metabolic profile (4). Telmisartan, the most extensively studied ARB (6), was shown to offer effective and safe BP reduction in a broad range of hypertensive patients with different clinical conditions, having beneficial effects beyond BP lowering at all 4 stages of the cardiovascular and renal continuum from CV risk factor presence, subclinical organ damage, manifested disease to end-stage disease (4, 7). Compared to other ARBs, telmisartan acts as a much stronger (partial) peroxisome proliferator activated receptor-gamma (PPAR-γ) agonist, thereby improving insulin sensitivity and reducing triglycerides, which makes it a preferrable antihypertensive choice in patients with diabetes, metabolic syndrome and obesity (1, 2, 4, 8). Its involvement in the inhibition of the sympathetic nervous system (SNS) activation via an antioxidant effect is also noteworthy. This is a critical process, mainly shown in animal models (9), that is involved in obesity-related hypertension and awaits evaluation in clinical practice. Taken only once daily, together with good tolerability, telmisartan therapy positively impacts patient adherence (1), which is one of the key factors in achieving better BP control rates (10). With all these attributes, telmisartan can be considered one of the preferred options for the treatment of hypertension (4).

At least 3 out of 4 patients with hypertension require combination therapy to achieve BP targets (2). According to 2023 ESH Guidelines for the Management of Arterial Hypertension most patients should initially be treated with a dual combination of a renin-angiotensin system (RAS) blocker (angiotensin-converting enzyme inhibitor (ACEi) or an angiotensin receptor blocker (ARB)) with a CCB or a diuretic. Using the dual combination in a fully tolerated dose should enable BP control in around 60% of hypertensive patients (10). According to guideline recommendations, RAS blocker combination with a CCB is the preferred option for hypertensive patients with concomitant lipid disorders, coronary artery disease (CAD) with angina pectoris, stage 4–5 chronic kidney disease (CKD), asthma, gout and rheumatoid arthritis. Conversely, RAS blocker combination with a diuretic is more appropriate for hypertensive patients with heart failure with a reduced ejection fraction (HFrEF), psychiatric diseases and in the case of pre-existing leg edema (10–11). Telmisartan SPCs with amlodipine (T/A) or HCTZ (T/HCTZ) provide better BP efficacy than respective monotherapies at all stages of hypertension (4), with T/A being the preferred choice for a wide range of hypertensive patients due to enhanced cardiovascular, renal and metabolic effects (4, 12–14).

Krka’s telmisartans are available as a monotherapy (Tolura, since 2010) in dual SPCs with HCTZ (Tolucombi, since 2013) and amlodipine (Teldipin, since 2017), with nine different dosages for treatment tailored to individual patient’s needs (15). Krka’s telmisartans have extensive clinical evidence, which is derived from several different non-interventional clinical studies at both general practitioner (GP) and specialist levels, and expands every year. Krka’s telmisartans were shown to enable high office and home BP control rates, a good safety profile and neutral metabolic effects, resulting in excellent treatment satisfaction and very high treatment adherence (16–22). Extensive clinical evidence was further expanded by the latest Krka clinical study Telmistar III, which evaluated telmisartan and T/A in almost 400 Slovakian patients, confirming all these benefits and adding crucial new information (21). Krka’s telmisartan and T/A provided effective 24-hour BP control and reduced BP variability (BPV), which may contribute to optimal CV protection – the ultimate goal of antihypertensive treatment (23–25). Clinical evidence for Krka’s telmisartans is described in more detail in sections below.

Clinically proven in various groups of hypertensive patients

Clinical studies with Krka’s telmisartans included around 24,000 naïve or previously treated hypertensive patients, representative of real-clinical practice: patients with all stages of hypertension, including isolated systolic hypertension (ISH), patients of all CV risk categories, with different risk factors (e.g. smoking, obesity, dyslipidemia) and comorbidities (e.g. diabetes, metabolic syndrome, CAD, CKD). Lasting 2 to 6 months, the studies assessed BP efficacy (office and home BP, 24h BP, including BPV), safety, effects on body parameters and metabolic effects, satisfaction with treatment by doctors and patients and treatment adherence (16–22) (Table 1).

Table 1: List of Krka’s clinical studies with telmisartan and its combinations.

Table 1: List of Krka’s clinical studies with telmisartan and its combinations.

In the Tandem study, treatment with Krka’s telmisartan and T/HCTZ enabled office BP control (< 140/90 mmHg) in more than 60% of patients with different stages of hypertension (16). The TellME study showed even greater office BP control with Krka’s T/A, namely in over 85% of patients. Office BP control was confirmed simultaneously also by home BP measurement (HBPM) (20), which is known to be superior to office BP measurements in predicting CV events, with its prognostic ability similar to 24h ambulatory BP measurement (ABPM) (26). In the Telmistar II study, effective office BP control rates were observed across different patient groups with risk factors and comorbidities constantly exceeding 60% (19). The SMART24 study showed very high BP control (in around 90% of patients), both in patients without and with the metabolic syndrome (22).

As for optimal BP (130/80 mmHg or lower for patients up to 80 years old), Krka’s T/A in the TellME study enabled 1 out of 3 patients to achieve it. While this proportion may seem low, it was still a significant increase from baseline (only 1 out of 20 patients) (20), and could have been substantially higher if more than just 3% of patients had had a dose up-titration. In the SMART24 study with Krka’s T/HCTZ and T/A, optimal BP was achieved in around 1 out of 2 patients (22).

Effective 24h-BP control and reduced BPV

The results from the Telmistar III study on 24h-ambulatory BP measurement (ABPM), which is viewed as an important complementary BP measurement method for both diagnostic and treatment decisions and should be used whenever possible (10, 27), showed that Krka’s telmisartan and T/A effectively reduced 24h-BP values and BPV. Both SBP and DBP values were mainly within target levels at all time periods: < 135/85 mmHg during the day, < 120/70 mmHg during the night and < 130/80 mmHg during the whole 24 hours.

Single ABPM patient data provided extensive information on 24h-BP profile and BPV patterns. The most clinically relevant is nocturnal BP reduction, because it predicts CV events better than daytime BP. Nocturnal BP reduction is normally about 10–20% (i.e. “normal dipping”) of the daytime average BP. Hypertensive phenotypes are characterized by either “non-dipping” (BP reduction is <10%) or “rising/reverse dipping” (BP increases during the night) (10). Another BPV parameter is BP increase during the first hours of the morning, also called “morning surge”. This parameter, however, is not characterized by any numerical thresholds (27–29). As shown in Figures 1 and 2, patients, after being treated with T and T/A, reversed from “rising/reverse dipping” profile to “normal dipping”, while they also had restored normal “morning surge”.

Figure 1: 24h-BP profile before and after treatment with telmisartan.

Figure 1: 24h-BP profile before and after treatment with telmisartan.

Figure 2: 24h-BP profile before and after treatment with telmisartan/amlodipine.

Figure 2: 24h-BP profile before and after treatment with telmisartan/amlodipine.

The antihypertensive drug effect over 24 hours is evaluated with the help of the smoothness index (SI) (30). SI was expectedly greater for Krka’s T/A than telmisartan (SI SBP: 1.11 vs 0.79) (21). The SI for T/A surpassed the desirable value of >1, indicating a large and consistent BPV reduction (25). Krka’s telmisartan and T/A were also shown to improve other important 24h-BP parameters that refine patients’ CV risk – they reduced both 24h mean arterial pressure (MAP) and 24h pulse pressure (PP) (21).

Good safety profile

Krka’s telmisartan in a monotherapy and SPC with HCTZ or amlodipine were very well tolerated in different studies. Adverse event (AE) incidence was low, with only 3% or less patients experiencing AEs (16–22). In the Tandem study, treatment discontinuation because of treatment-related adverse events was very low (1.2% of patients with Krka’s telmisartan and T/HCTZ) (16).

Great clinical efficacy

Clinical efficacy (i.e. a combination of BP lowering and occurrence of AEs) for Krka’s telmisartan and T/HCTZ (evaluated by the Tandem study), was very good or excellent in 93.5% of patients. Their BP was either < 140/90 mmHg (diabetic patients < 140/85 mmHg) and they reported no AEs or only mild ones; or their BP was < 150/95 mmHg (diabetic patients < 150/90 mmHg) and they reported no AEs (16).

Neutral metabolic effects

In the Telmistar I, II and III studies, Krka’s telmisartan and T/A demonstrated (at least) neutral effects on metabolic parameters, including blood glucose, lipids (total cholesterol, LDL-C, nonHDL-C, and triglycerides), uric acid and creatinine (17–19, 21), confirming Krka’s telmisartan and T/A are suitable choices for patients with metabolic conditions and renal impairment.

Beneficial effects on body parameters

A positive metabolic effect of Krka’s T/HCTZ or T/A was additionally shown in the SMART24 study in HT patients with metabolic syndrome, as treatment with both resulted in reduced waist circumference, hip circumference and body mass index (BMI). These effects were observed already after 12 weeks of treatment (22).

Excellent treatment satisfaction

In the Telmistar II and III studies, both patients and doctors (GPs and specialists) were highly satisfied with the treatment with Krka’s telmisartan and T/A. More than 90% of patients and doctors were satisfied with treatment, rating treatment satisfaction with either 1 or 2 on the 1–5 scale, where 1 stood for “the best possible satisfaction” and 5 “the worst” (19, 21). Similar results were obtained also in the SMART24 study, which additionally showed that 99% of patients were completely satisfied or satisfied with the ease of using marked blisters (22).

High treatment adherence

Patients treated with either T/HCTZ or T/A in the SMART24 study were highly adherent, with over 85% of patients taking the prescribed antihypertensive every day or forgetting to take it less than once per week. Such high adherence was observed regardless of presence or absence of the metabolic syndrome (22).

Conclusion

Extensive clinical evidence from different non-interventional clinical studies, which included around 24,000 hypertensive patients, showed that Krka’s telmisartans, both in monotherapy and SPCs with amlodipine or HCTZ, represent a very comprehensive antihypertensive therapy. Krka’s telmisartans enable high office and home BP control rates, effective 24h-BP control and reduced BPV, a good safety profile, great clinical efficacy, neutral metabolic effects and beneficial effects on body parameters, resulting in excellent treatment satisfaction and very high treatment adherence (16–22). Furthermore, Krka’s telmisartans also possess additional added values. Firstly, they are available in 9 different dosages (31) for treatment tailored to individual patient’s needs. Secondly, their high quality having an environmentally-friendly impact has been demonstrated by several certificates, awards and patents: EDQM Certificate of Suitability (CoS) by the European Directorate for the Quality of Medicines (32), Golden Award for innovative analytical methods (33), Silver Award for innovative, environmentally sound and cost-efficient solutions in the synthesis (34) awarded by the Slovenian Chamber of Commerce, and patents for innovative synthesis and formulation, driven by the need for fast accessibility of medications (granted patents for the process of Tolura preparation and Tolucombi and Teldipin formulation) (35). Last, but not least, Krka’s telmisartans come in the form of user-friendly blisters with marked days for better adherence that patients are (very) satisfied with (22, 30, 36). In conclusion, extensive clinical evidence is publicly available for Krka’s telmisartans, which makes them, together with other benefits, the leading telmisartans in terms of value and volume in the markets of Central, Eastern and Southeastern Europe (37).

References

  1. Destro M, Cagnoni F, Dognini GP, et al. Telmisartan: just an antihypertensive agent? A literature review. Expert Opin Pharmacother. 2011 Dec; 12(17): 2719–35.
  2. Segura J, Ruilope LM. A review of the benefits of early treatment initiation with single-pill combinations of telmisartan with amlodipine or hydrochlorothiazide. Vasc Health Risk Manag. 2013; 9: 521–8.
  3. Akhrass PR, McFarlane SI. Telmisartan and cardioprotection. Vasc Health Risk Manag. 2011; 7: 677–83.
  4. Galzerano D, Capogrosso C, Di Michele S, et al. New standards in hypertension and cardiovascular risk management: focus on telmisartan. Vasc Health Risk Manag. 2010 Mar 24; 6:113–33.
  5. Lacourcière Y, et al. A prospective, randomized investigation of the safety and efficacy of telmisartan vs ramipril in mild-to-moderate hypertensives using ambulatory blood pressure monitoring. Am J Hypertens 2006; 19: 104–12.
  6. Wang JG, Pimenta E, Chwallek F. Comparative review of the blood pressure-lowering and cardiovascular benefits of telmisartan and perindopril. Vasc Health Risk Manag. 2014; 10: 189–200.
  7. Patel, P. Telmisartan: clinical evidence across the cardiovascular and renal disease continuum. Drugs Ther Perspect. 2017; 33: 77–87.
  8. Dézsi CA. The Different Therapeutic Choices with ARBs. Which One to Give? When? Why? Am J Cardiovasc Drugs. 2016 Aug; 16(4): 255–66.
  9. Konno S, Hirooka Y, Kishi T, Sunagawa K. Sympathoinhibitory effects of telmisartan through the reduction of oxidative stress in the rostral ventrolateral medulla of obesity-induced hypertensive rats. J Hypertens. 2012 Oct; 30(10): 1992–9.
  10. Mancia G, Kreutz R, Brunström M, et al. 2023 ESH Guidelines for the management of arterial hypertension The Task Force for the management of arterial hypertension of the European Society of Hypertension: Endorsed by the International Society of Hypertension (ISH) and the European Renal Association (ERA). J Hypertens. 2023; 41(12): 1874–2071.
  11. Ungar T, Borghi C, Charchar F et al. 2020 International Society of Hypertension Global Hypertension Practice Guidelines. Hypertension 2020; 75(6): 1334–57.
  12. Fares H, DiNicolantonio JJ, O’Keefe JH, Lavie CJ. Amlodipine in hypertension: a first-line agent with efficacy for improving blood pressure and patient outcomes. Open Heart. 2016 Sep 28; 3(2): e000473.
  13. Lee SA, Choi HM, Park HJ, Ko SK, Lee HY. Amlodipine and cardiovascular outcomes in hypertensive patients: meta-analysis comparing amlodipine-based versus other antihypertensive therapy. Korean J Intern Med 2014; 29: 315–24.
  14. Abraham G, Almeida A, Gaurav K et al. Reno protective role of amlodipine in patients with hypertensive chronic kidney disease. World J Nephrol. 2022 May 25; 11(3): 86–95.
  15. Krka Annual Report 2017. [internet]. [cited May 2020]. Available at: https://www.krka.biz/media/doc/en/for_investors/2018/Annual_Report_2017.pdf
  16. Zaletel A, Knavs Vrhunec P, Barbič Žagar B. Achieving Blood Pressure Control with Telmisartan and Fixed Dose Combination of Telmisartan and Hydrochlorothiazide. Cardiologia Croatica 2016; 11 (10-11): 598–601.
  17. Čaprnda M, Novodomska K, Farkašovsky J et al. Čaprnda M, Novodomska K, Farkašovsky J et al. The TELMISTAR I project – “Monitoring the Effect of Telmisartan and the Fixed Combination of Telmisartan + Amlodipine on the Achievement of Target Values of Systolic and Diastolic Blood Pressure in Slovakia by Specialist Physicians. Kardiol Prax 2019; 17 (3): 169–75.
  18. Čaprnda M, Novodomska K, Farkašovsky J et al. Project TELMISTAR I – Effect of telmisartan on selected metabolic and biochemic parameters in patients with arterial hypertension. Kardiol Prax 2020; 18 (3): 118–28.
  19. Čaprnda M, Barbič Žagar B, Marinšek G. Effectiveness and safety of telmisartan and telmisartan/amlodipine single-pill combination in the treatment of essential hypertension in Slovakian patients treated by general practitioners – the TELMISTAR II study. Krka Med Farm [internet]. 2022. [cited 2022 September 19]. Available from: https://www.krka.biz/en/for-professional-public/kmf/prescriptionpharmaceuticals/cardiovascular-diseases/telmisartan/
  20. Járai Z, Ámon T, Baracsi-Botos V, Mészáros. Telmisartan/amlodipine single-pill combination therapy to achieve blood pressure goal values in hypertensive patients in GPS` practice – an observational study. Journal of Hypertension. 2022; 40(1): 9 e303.
  21. Final report of epidemiological study TELMISTAR III. Effectiveness of telmisartan and telmisartan/amlodipine single-pill combination in the treatment of essential hypertension. Data on file, 2023, Krka, d.d., Novo mesto.
  22. Napalkov DA. Effectiveness and tolerability of fixed-dose combinations of telmisartan in patients with hypertension with metabolic syndrome and without metabolic changes. Consilium Medicum. 2023; 25(10): 709–14.
  23. Elliott HL. 24-hour blood pressure control: its relevance to cardiovascular outcomes and the importance of long-acting antihypertensive drugs. J Hum Hypertens. 2004 Aug; 18(8): 539–43.
  24. Schutte AE, Kollias A, Stergiou GS. Blood pressure and its variability: classic and novel measurement techniques.Nature Reviews Cardiology. 2022; 19: 643–54.
  25. Antonakoudis G, Poulimenos I, Kifnidis K et al. Blood pressure control and cardiovascular risk reduction. Hippokratia. 2007; 11(39: 114–9.
  26. Kollias A, Kyriakoulis KG, Komnianou A, Stathopoulou P, Stergiou GS. Prognostic value of home versus ambulatory blood pressure monitoring: a systematic review and meta-analysis of outcome studies. J Hypertens. 2024 Mar 1; 42(3): 385–392.
  27. Parati G, Stergiou GS, Dolan E, Bilo G. Blood pressure variability: clinical relevance and application. J Clin Hypertens (Greenwich). 2018 Jul;20(7): 1133–7.
  28. Stergiou GS, Palatini P, Parati G, et al. 2021 European Society of Hypertension practice guidelines for office and out-of-office blood pressure measurement. J Hypertens. 2021 Jul 1; 39(7): 1293–302.
  29. Rosei EA, Chiarini G, Rizzoni D. How important is blood pressure variability? Eur Heart J Suppl. 2020 Jun;22(Suppl E):E1–E6.
  30. Parati G, Omboni S, Rizzoni D, et al. The smoothness index: a new, reproducible and clinically relevant measure of the homogeneity of the blood pressure reduction with treatment for hypertension. J Hypertens. 1998 Nov; 16(11): 1685–91.
  31. SmPC Tolura, Tolucombi, Teldipin
  32. European Directorate for the Quality of Medicines, Strasbourg. [internet]. [cited Oct 2022]. Available at: http://www.edqm.eu.
  33. Slovenian chamber of commerce: The Chamber of Commerce of Dolenjska and Bela krajina. [internet]. [cited Oct 2022]. Available at: https://www.gzdbk.si/media/GZDBK_Katalog_Inovacije_2022_Pop.pdf
  34. Annual Report 2019. Krka, d. d., Novo mesto, 2022 [cited Oct 2022]. Available from: https://www.krka.biz/media/doc/en/for_investors/2020/KRKA_2019%20Annual%20Report%20digital.pdf
  35. European Patent Office (EPO), Munich. [internet]. [cited Feb 2024]. Available at: http://ep.espacenet.com
  36. Laufs U, Rettig-Ewen V, Böhm M. Strategies to improve drug adherence. Eur Heart J 2011; 32 (3): 264–8.
  37. APTEEKIDE INF. (Medicube), CEGEDIM, INTELLIX, IQVIA, PROXIMA (PHARMSTANDART), SITEMICS (ePharma Market), Softdent 1–12 2023.

Author

  1. Gašper Marinšek, mag. biokem., Krka d. d., gasper.marinsek@krka.biz
  2. Breda Barbič-Žagar, dr. med., Krka d. d., breda.zagar@krka.biz

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We have compiled a collection of scientific papers in which we present the rich experience obtained from the clinical studies with Krka’s medicines.

Published: July, 2024