Clinical Insights

Telmisartan for Treating Systemic Hypertension

Renee Girens DVM, MS, University of Florida, Gainesville, Florida

Renee Girens, DVM, MS, is a rotating intern at the University of Florida. She received her DVM from the University of Missouri and her master’s degree in cell and molecular biology from Missouri State University. She will be starting a cardiology residency at the University of Florida in July.

Simon Swift MA, VetMB, CertSAC, DipECVIM-CA (Cardiology), MRCVS, University of Florida, Gainesville, Florida

After qualifying from Cambridge University, Dr. Swift spent 2 years in mixed practice before moving to a specialist small animal practice in the Northwest of England. He developed an interest in cardiology, taking the RCVS cardiology certificate in 1990. He became a partner in a large emergency and referral hospital building up the cardiology referral service until he left in 2005 to follow an alternative residency program at Liverpool University. Since becoming a European Diplomate in cardiology, he worked in a private referral hospital before moving to Florida to join the College of Veterinary Medicine as Clinical Associate Professor. He is service chief for cardiology and has recently been appointed medical director. He has been involved in breeding programs and the treatment of degenerative valvular disease especially in the cavalier King Charles spaniel having been adviser to the UK CKCS club for 20 years and more recently has helped develop advanced interventional techniques at the University of Florida.

Telmisartan for Treating  Systemic Hypertension
For cats, the telmisartan side effects reported to the FDA included vomiting, hypersalivation, weight loss, diarrhea, lethargy, among others. Photo Credit: Shutterstock

EVALUATING TELMISARTAN

The angiotensin II receptor blocker telmisartan has been primarily used in cats, although a few case reports highlight its off-label use in dogs.

Telmisartan, an angiotensin II receptor blocker (ARB), was approved by the US Food and Drug Administration in May 2018 to treat hypertension in cats. It is also used off label in dogs.

Since 1995, ARBs have been used to treat primary hypertension in humans and as adjunctive therapy for chronic renal disease and heart failure.1 Commonly used ARBs in human medicine include losartan, valsartan, and telmisartan. However, their use in veterinary medicine is currently limited. There have been few veterinary studies investigating telmisartan. Therefore, the purpose of this article is to review the mechanism of action of telmisartan and summarize published reports of its use in veterinary medicine to date.

PATHOPHYSIOLOGY OF HYPERTENSION

In dogs and cats, primary hypertension is rare and typically occurs secondary to other disease processes.2 In cats, systemic hypertension and proteinuria are common sequelae to chronic kidney disease (CKD) and untreated hyperthyroidism.3,4 In dogs, systemic hypertension and proteinuria can be secondary to CKD5 but also to other conditions, including acute kidney injury,6 hyperadrenocorticism,7 diabetes mellitus,8 and pheochromocytoma.9,10 In dogs and cats, systemic hypertension can lead to end organ damage throughout the body, resulting in, but not limited to, decreased renal function, proteinuria, retinopathy, encephalopathies, stroke, and left ventricular concentric hypertrophy.11 The degree of proteinuria is negatively associated with median survival times in dogs12 and cats13,14 with CKD.

Angiotensin II is a peptide hormone that is upregulated in certain disease processes and has multiple effects throughout the body (BOX 1).15 Angiotensin II is produced via the renin-angiotensin-aldosterone system (RAAS). In dogs and cats with CKD3 and heart disease,16 angiotensin II production is upregulated in response to chronic stimulation of the RAAS. Chronic RAAS activation ultimately increases angiotensin II and aldosterone production, which can lead to glomerular hypertension and induce glomerular hypertrophy and sclerosis.17 In addition, angiotensin II and aldosterone cause increased preload and afterload on the heart16 and induce myocardial inflammation and fibrosis,18 further exacerbating disease states.


BOX 1

Effects of Angiotensin II Throughout the Body2

  • Increased sympathetic nervous systemic activity
  • Vasoconstriction
  • Aldosterone production
  • Sodium and water retention
  • Antidiuretic hormone release
  • Increased blood pressure

Angiotensin II acts primarily on angiotensin II type 1 and 2 receptors (AT1 and AT2) throughout the body. AT1 mediates production of aldosterone and its detrimental effects.19 Activation of AT2 receptors can lead to renal and cardioprotective effects, including systemic vasodilation, natriuresis, inhibition of renin release, and renal protection from inflammation, ischemia, and fibrosis.20

Given the negative effects of AT1 and aldosterone in animals experiencing kidney disease and/or congestive heart failure, decreasing the production of angiotensin II and aldosterone is a therapeutic target.

TELMISARTAN

Pharmacology and Pharmacokinetics

Telmisartan is a selective AT1 receptor antagonist that blocks the effects of angiotensin II.21 In vitro studies have shown that telmisartan dissociates from AT1 receptors slowly, acting as an insurmountable antagonist.21 Thus, this receptor antagonism is long lasting.22

In humans, after oral administration with food, telmisartan bioavailability is decreased by 20%.23 In cats, bioavailability after oral administration is 33% and not affected by food. Plasma levels peak at approximately 20 to 30 minutes, and half-life is approximately 8 hours.24 In dogs, it is unknown whether bioavailability is affected by feeding or fasting, and absolute bioavailability is unknown. Plasma levels peak approximately 45 minutes after oral administration, and half-life is approximately 5.4 hours.25 Telmisartan is lipophilic and in dogs, more than 98% is bound to plasma proteins,26 but for cats, this information is not known. Telmisartan is metabolized via glucuronidation, which has been effective in in vitro studies using feline liver microsomes.27 It is largely excreted unchanged in the feces.

Indications and Uses

Telmisartan has been primarily used in cats, although a few case reports highlight its off-label use in dogs. It is labeled to treat systemic hypertension24,28 and proteinuria in cats29 and has been used to treat systemic hypertension and proteinuria in dogs. It can be added to the treatment regimen for chronic heart failure, especially in those animals that cannot tolerate angiotensin-converting enzyme (ACE) inhibitors. Telmisartan also has anticancer properties.30-33

Telmisartan as a 10 mg/mL oral solution was recently approved in the United States28 and European Union24 for the control of systemic hypertension in cats. In dogs and cats, ACE inhibitors have only mild hypotensive effects.34 In studies of healthy cats, telmisartan reduced systolic blood pressure.35 It blocked the systolic pressure response to exogenous angiotensin I more effectively than benazepril, irbesartan, and losartan.36 In addition, one case report highlighted the effectiveness of using telmisartan to treat systemic hypertension in a cat with gingival hyperplasia secondary to amlodipine administration.37 In dogs, telmisartan has been used in combination with amlodipine to control systemic hypertension refractory to standard hypertension therapy.38-40

The blood pressure of patients receiving telmisartan should be routinely monitored. Indeed, for patients receiving any antihypertensive medication, blood pressure should be rechecked 7 to 10 days after starting or changing the dose and routinely monitored every 1 to 4 months, depending on patient stability and severity of the hypertension.11

In addition to treating hypertension, since 2014, telmisartan as a 4 mg/mL oral solution has been approved in the European Union for the treatment of proteinuria secondary to CKD in cats.29 For dogs and cats, ACE inhibitors have been reported to decrease proteinuria but did not improve survival times.3,34,41-43 In terms of decreasing proteinuria in cats with CKD, telmisartan was not found to be less effective than benazepril.3 In one case report, refractory proteinuria in a dog initially treated with benazepril was successfully managed when telmisartan was added to the treatment regimen. The dog’s proteinuria was eventually controlled by telmisartan alone when benazepril was discontinued.44

Chronic heart failure leads to increased production of angiotensin II. Currently, enalapril is the only ACE inhibitor labeled for the treatment of heart disease in dogs.16 ACE inhibitors, but not ARBs, inhibit the breakdown of bradykinin and consequently result in vasodilation and natriuresis.45 However, ACE inhibitors may result in incomplete neuroendocrine blockade because the conversion of angiotensin I to angiotensin II can be accomplished by enzymes other than ACE.16,46 In a study of dogs receiving an ACE inhibitor for heart disease and heart failure, RAAS blockade was incomplete for approximately 30%.47 Therefore, ARBs like telmisartan may produce a more effective neuroendocrine blockade, although one study in which a small sample of healthy dogs received telmisartan showed incomplete RAAS blockade.40

In human medicine, ARBs are recommended only for patients who are intolerant to ACE inhibitors.48,49 Side effects of ACE inhibitors in humans include cough, hypotension, renal dysfunction,48 and angioedema (in up to 0.7%).50 For veterinary patients, cough is rarely reported.34 Commonly reported side effects of enalapril in dogs include gastrointestinal upset (anorexia, diarrhea, vomiting), lethargy, hypotension, renal dysfunction, and hyperkalemia.51 Therefore, telmisartan may be useful in those animals that cannot tolerate ACE inhibitors. Combination therapy with ACE inhibitors and ARBs may be beneficial for patients with proteinuria refractory to standard therapy as described above, but studies of humans found that combination therapy decreased glomerular filtration rate and was associated with hypotension, hyperkalemia, and acute renal failure.53,52 If combination therapy is indicated, routine monitoring of renal values and blood pressure is recommended.

Telmisartan may also have anticancer properties. It is a peroxisome proliferator–activated receptor-gamma (PPARγ) agonist.30 Activation of PPARγ can induce apoptosis in cancer cells.54 Telmisartan has shown anticancer properties in both in vitro31,32 and in vivo studies.33 Current information is based on human medicine; research is needed to determine the efficacy of telmisartan as an anticancer agent in veterinary medicine.

Side Effects and Precautions

For cats, the telmisartan side effects reported to the Food and Drug Administration included vomiting, hypersalivation, weight loss, diarrhea, lethargy, decreased appetite, nonregenerative anemia, dehydration, retinal lesions, and hypotension.28 Because anemia is a reported side effect, routine monitoring of hematologic parameters is recommended every 3 to 6 months, depending on baseline values. If hypotension is noted, blood pressure should be periodically monitored and dosing adjusted accordingly. In clinical studies, adverse effects of telmisartan included gastrointestinal issues (vomiting, diarrhea, regurgitation) but did not require dosage alterations or study withdrawal.3,35 Telmisartan has not been evaluated for safety and efficacy in cats younger than 6 months or in pregnant or lactating cats.24,28 Although no formal studies of safety in dogs have been conducted, no adverse reactions have been reported.38-40,44,55,56

In humans, telmisartan increases serum digoxin levels57; therefore, if these drugs are administered concurrently, serum digoxin levels should be monitored. In humans, the antihypertensive effects of telmisartan may be diminished by concurrent use of cyclooxygenase-2 (COX-2) inhibitors. Moreover, concurrent administration of COX-2 inhibitors and telmisartan to patients who are volume depleted (including those receiving diuretic therapy) and those with decreased renal function may result in further deterioration of renal function. Periodic monitoring of renal parameters is recommended for human patients58 and should also be routinely done for veterinary patients. The most serious consequence of overdosing telmisartan is hypotension, which can be managed symptomatically (fluid therapy, inotropes, vasopressors).22

SUMMARY

Telmisartan is a selective AT1 receptor antagonist21 and, as a result, may mitigate the effects of chronic RAAS activation19 while allowing angiotensin II to act on AT2 receptors to induce their renal and cardioprotective effects.20 Telmisartan effectively reduces systemic hypertension and proteinuria in cats.24,28 Isolated case reports or case series have found telmisartan to be effective at reducing proteinuria39,44 and systemic hypertension38-40 in dogs. Further research is needed to evaluate its clinical efficacy, safety, and adverse effects in dogs.

References

  1. Abraham HMA, White CM, White WB. The comparative efficacy and safety of the angiotensin receptor blockers in the management of hypertension and other cardiovascular diseases. Drug Saf 2015;38:33-54.
  2. Brown SA, Henik RA. Diagnosis and treatment of systemic hypertension. Vet Clin North Am Small Anim Pract 1998;28:1481-1494.
  3. Sent U, Gössl R, Elliott J, et al. Comparison of efficacy of long-term oral treatment with telmisartan and benazepril in cats with chronic kidney disease. J Vet Intern Med 2015;29:1479-1487.
  4. Kobayashi DL, Peterson ME, Graves TK, et al. Hypertension in cats with chronic renal failure or hyperthyroidism. J Vet Intern Med 1990;4:58-62.
  5. Bartges JW. Chronic kidney disease in dogs and cats. Vet Clin North Am Small Anim Pract 2012;42:669-692.
  6. Geigy CA, Schweighauser A, Doherr M, et al. Occurrence of systemic hypertension in dogs with acute kidney injury and treatment with amlodipine besylate. J Small Anim Pract 2011;52:340-346.
  7. Ortega TM, Feldman EC, Nelson RW, et al. Systemic arterial blood pressure and urine protein/creatinine ratio in dogs with hyperadrenocorticism. JAVMA 1996;209:1724-1729.
  8. Struble AL, Feldman EC, Nelson RW, et al. Systemic hypertension and proteinuria in dogs with diabetes mellitus. JAVMA 1998;213:822-825.
  9. Barthez PY, Marks SL, Woo J, et al. Pheochromocytoma in dogs: 61 cases (1984-1995). J Vet Intern Med 1997;11:272-278.
  10. Gilson SD, Withrow SJ, Wheeler SL, et al. Pheochromocytoma in 50 dogs. J Vet Intern Med 1994;8:228-232.
  11. Brown S, Atkins C, Bagley R, et al. Guidelines for the identification, evaluation, and management of systemic hypertension in dogs and cats. J Vet Intern Med 2007;21:542-558.
  12. Jacob F, Polzin DJ, Osborne CA, et al. Evaluation of the association between initial proteinuria and morbidity rate or death in dogs with naturally occurring chronic renal failure. JAVMA 2005;226:393-400.
  13. Jepson RE, Elliott J, Brodbelt D, et al. Effect of control of systolic blood pressure on survival in cats with systemic hypertension. J Vet Intern Med 2007;21:402-409.
  14. Syme HM, Markwell PJ, Pfeiffer D, et al. Survival of cats with naturally occurring chronic renal failure is related to severity of proteinuria. J Vet Intern Med 2006;20:528-535.
  15. Lavoie JL, Sigmund CD. Minireview: overview of the renin-angiotensin system—an endocrine and paracrine system. Endocrinology 2003;144:2179-2183.
  16. Sisson DD. Neuroendocrine evaluation of cardiac disease. Vet Clin North Am Small Anim Pract 2004;34:1105-1126.
  17. Mitani S, Yabuki A, Taniguchi K, et al. Association between the intrarenal renin-angiotensin system and renal injury in chronic kidney disease of dogs and cats. J Vet Med Sci 2013:127-133.
  18. Sciarretta S, Paneni F, Palano F, et al. Role of the renin-angiotensin-aldosterone system and inflammatory processes in the development and progression of diastolic dysfunction. Clin Sci 2009;116:467-477.
  19. Sparks MA, Crowley SD, Gurley SB, et al. Classical renin-angiotensin system in kidney physiology. Compr Physiol 2014;4:1201-1228.
  20. Padia SH, Carey RM. AT2 receptors: beneficial counter-regulatory role in cardiovascular and renal function. Pflugers Arch 2013;465:99-110.
  21. Wienen W, Hauel N, Van Meel JC, et al. Pharmacological characterization of the novel nonpeptide angiotensin II receptor antagonist, BIBR 277. Br J Pharmacol 1993;110:245-252.
  22. Boehringer Ongelheim Animal Health. Semintra 4 mg/ml oral solution for cats datasheet: further information. NOAH Compendium. noahcompendium.co.uk/?id=-447810. Accessed September 2018.
  23. Munger MA. Use of angiotensin receptor blockers in cardiovascular protection: current evidence and future directions. P T 2011;36:22-40.
  24. European Medicines Agency. CVMP assessment report for Semintra to add new strength 10 mg/ml oral solution for cats to treat systemic hypertension (EMEA/V/C/002436/X/0008). ema.europa.eu/documents/variation-report/semintra-v-c-2436-x-0008-epar-assessment-report-variation_en.pdf. Accessed September 2018.
  25. Baek I-H, Lee B-Y, Lee E-S, et al. Pharmacokinetics of angiotensin II receptor blockers in the dog following a single oral administration. Drug Res 2013;63:357-361.
  26. Wienen W, Entzeroth M, Meel JCA, et al. A review on telmisartan: a novel, long-acting angiotensin II–receptor antagonist. Cardiovasc Drug Rev 2006;18:127-154.
  27. Ebner T, SchäNzle G, Weber W, et al. In vitro glucuronidation of the angiotensin II receptor antagonist telmisartan in the cat: a comparison with other species. J Vet Pharmacol Ther 2013;36:154-160.
  28. Food and Drug Administration. NADA 141-501 Semintra (telmisartan oral solution) Oral Solution Cats. For the control of systemic hypertension in cats. https://animaldrugsatfda.fda.gov/adafda/app/search/public/document/downloadFoi/3488. Accessed September 2018
  29. European Medicines Agency. CVMP assessment report for Semintra (EMEA/V/C/002436). ema.europa.eu/documents/product-information/semintra-epar-product-information_en.pdf. Accessed September 2018.
  30. Schupp M, Janke J, Clasen R, et al. Angiotensin type 1 receptor blockers induce peroxisome proliferator–activated receptor-γ activity. Circulation 2004;109:2054-2057.
  31. Li J, Chen L, Yu P, et al. Telmisartan exerts anti-tumor effects by activating peroxisome proliferator-activated receptor-γ in human lung adenocarcinoma A549 cells. Molecules 2014;19:2862-2876.
  32. Koyama N, Nishida Y, Ishii T, et al. Telmisartan induces growth inhibition, DNA double-strand breaks and apoptosis in human endometrial cancer cells. PLoS ONE 2014;9:e93050.
  33. McKay RR, Rodriguez GE, Lin X, et al. Angiotensin system inhibitors and survival outcomes in patients with metastatic renal cell carcinoma. Clin Cancer Res 2015;21:2471-2479.
  34. Lefebvre HP, Brown SA, Chetboul V, et al. Angiotensin-converting enzyme inhibitors in veterinary medicine. Curr Pharm Des 2007;13:1347-1361.
  35. Coleman AE, Brown SA, Stark M, et al. Evaluation of orally administered telmisartan for the reduction of indirect systolic arterial blood pressure in awake, clinically normal cats. J Feline Med Surg 2018:1098612X1876143.
  36. Jenkins TL, Coleman AE, Schmiedt CW, et al. Attenuation of the pressor response to exogenous angiotensin by angiotensin receptor blockers and benazepril hydrochloride in clinically normal cats. Am J Vet Res 2015;76:807-813.
  37. Desmet L, van der Meer J. Antihypertensive treatment with telmisartan in a cat with amlodipine-induced gingival hyperplasia. J Fel Med Surg 2017;3:205511691774523.
  38. Caro-Vadillo A, Daza-González MA, Gonzalez-Alonso-Alegre E, et al. Effect of a combination of telmisartan and amlodipine in hypertensive dogs. Vet Rec Case Rep 2018;6:e000471.
  39. Kwon Y-J, Suh G-H, Kang S-S, et al. Successful management of proteinuria and systemic hypertension in a dog with renal cell carcinoma with surgery, telmisartan, and amlodipine. Can Vet J 2018;59:759-762.
  40. Konta M, Nagakawa M, Sakatani A, et al. Evaluation of the inhibitory effects of telmisartan on drug-induced renin-angiotensin-aldosterone system activation in normal dogs. J Vet Cardiol 2018; 20(5):376-383.
  41. King JN, Gunn-Moore DA, Tasker S, et al. Tolerability and efficacy of benazepril in cats with chronic kidney disease. J Vet Intern Med 2006;20:1054-1064.
  42. Mizutani H, Koyama H, Watanabe T, et al. Evaluation of the clinical efficacy of benazepril in the treatment of chronic renal insufficiency in cats. J Vet Intern Med 2006;20:1074-1079.
  43. Watanabe T, Mishina M. Effects of benazepril hydrochloride in cats with experimentally induced or spontaneously occurring chronic renal failure. J Vet Med Sci 2007;69:1015-1023.
  44. Bugbee AC, Coleman AE, Wang A, et al. Telmisartan treatment of refractory proteinuria in a dog. J Vet Intern Med 2014;28:1871-1874.
  45. Taddei S, Bortolotto L. Unraveling the pivotal role of bradykinin in ACE inhibitor activity. Am J Cardiovasc Drugs 2016;16:309-321.
  46. Aramaki Y, Uechi M, Takase K. Angiotensin converting enzyme and chymase activity in the feline heart and serum. J Vet Med Sci 2003;65:1115-1118.
  47. Ames MK, Atkins CE, Eriksson A, et al. Aldosterone breakthrough in dogs with naturally occurring myxomatous mitral valve disease. J Vet Cardiol 2017;19:218-227.
  48. Telmisartan Randomised Assessment Study in ACE intolerant subjects with cardiovascular disease (TRANSCEND) Investigators, Yusuf S, Teo K, et al. Effects of the angiotensin-receptor blocker telmisartan on cardiovascular events in high-risk patients intolerant to angiotensin-converting enzyme inhibitors: a randomised controlled trial. Lancet 2008;372:1174-1183.
  49. Ponikowski P, Voors AA, Anker SD, et al. 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail 2016;18:891-975.
  50. Banerji A, Blumenthal KG, Lai KH, et al. Epidemiology of ACE inhibitor angioedema utilizing a large electronic health record. J Allergy Clin Immunol Pract 2017;5:744-749.
  51. Sisson DD. Acute and short-term hemodynamic, echocardiography, and clinical effects of enalapril maleate in dogs with naturally acquired heart failure: results of the Invasive Multicenter PROspective Veterinary Evaluation of Enalapril Study: The IMPROVE Study Group. J Vet Intern Med 1995;9:234-242.
  52. Mann JF, Schmieder RE, McQueen M, et al. Renal outcomes with telmisartan, ramipril, or both, in people at high vascular risk (the ONTARGET study): a multicentre, randomised, double-blind, controlled trial. Lancet 2008;372:547-553.
  53. ONTARGET Investigators, Yusuf S, Teo KK, et al. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med 2008;358:1547-1559.
  54. Elrod HA, Sun S-Y. PPARgamma and apoptosis in cancer. PPAR Res 2008;2008:704165.
  55. Schierok H, Pairet M, Hauel N, et al. Effects of telmisartan on renal excretory function in conscious dogs. J Int Med Res 2001;29:131–139.
  56. Coleman AE, Schmiedt CW, Handsford CG, et al. Attenuation of the pressor response to exogenous angiotensin by angiotensin receptor blockers in normal dogs: c-10. J Vet Intern Med 2014;28:1002.
  57. Stangier J, Su CA, Hendriks MG, et al. The effect of telmisartan on the steady-state pharmacokinetics of digoxin in healthy male volunteers. J Clin Pharmacol 2000;40:1373-1379.
  58. Food and Drug Administration. Micardis (telmisartan) tablets. accessdata.fda.gov/drugsatfda_docs/label/2011/020850s032lbl.pdf. Accessed September 2018.

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