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Comparing long term treatment of Chronic Kidney Disease with telmisartan and benazepril in cats

Sent U, Gössl R, Elliott J, Syme HM, Zimmering T. Comparison of Efficacy of Long-term Oral Treatment with Telmisartan and Benazepril in Cats with Chronic Kidney Disease. J Vet Intern Med. 2015 Nov;29(6):1479-87. PubMed PMID: 26474314.

Chronic renal disease (CRD) is one of the most common conditions recognized in the geriatric cat population. This progressive disease is associated with increased urination, loss of body condition, lack of appetite, and is eventually fatal. While no cure exists for chronic renal disease in cats, there are many therapies in place to manage the clinical signs and keep cats’ quality of life acceptable.

Two conditions commonly linked to chronic renal disease are hypertension (increased blood pressure) and  proteinuria (the presence of protein in the urine). While high blood pressure develops as a response of the body to decreased renal blood flow, it is ultimately damaging to multiple organs and may accelerate the course of renal disease and cause other issues, such as retinal detachment or strokes.

Proteinuria has been associated with a negative prognosis ion cats with CRD. Animals with a larger protein concentration in the urine has been shown to have significantly lower survival times. While it has never been demonstrated that proteinuria causes decreased survival or is simply associated with it, there is evidence that protein molecules crossing the glomerulus may accelerate kidney damage.

In cats, dogs, and humans, the key to reducing proteinuria has long been a class of drugs called “Angiotensin Converting Enzyme Inhibitors” (ACEIs). These drugs block a step in hormone production that prevents the formation of the hormone Angiotensin II. Decreased angiotensin II production lowers blood pressure and prevents the release of aldosterone. Lower aldosterone further decreased blood pressure and also decreased the amount of protein leaving the blood into the urine. The most significant ACEI in veterinary medicine has been for many years Benazepril.

Two major concerns exist with benazepril and other ACEIs. One is that they are non specific and block all of the effects of Angiotensin II. Some of these are mediated by the reception AT1 and are considered negative effects. Others, (mediated by AT2) are more positive and may actually protect the kidney. ACEIs block both of these receptors. The other concern is the phenomenon known as “ACE Escape” whereby, after a period of time on an ACEI, alternative biochemical pathways are found to produce angiotensin II and the drugs become ineffective

Recently, a new class of drug has entered the veterinary market from the human world known as “Angiotensin Receptor Blockers” (ARBs). ARBs directly block AT1, thereby removing concerns with AT2 blockade. They are also not susceptible to ACE Escape and as such may be useful for longer periods of treatment. The most significant entry to the veterinary market is the drug “telmisartan”.

While telmisartan has been shown to be effective at reducing proteinuria and blood pressure in cats with CRD, no studies have looked at long term comparisons. The standard measure for proteinurea is the “UP/C” or “Urien Protein to Creatinine Ratio”.

The purpose of the study was to establish if telmisartan is non-inferior to benazepril after long term administration, and also to evaluate any potential side effects of the medication. 224 cats were include from 48 centers across Europe (out of over 2000 cats screened for eligibility). Efforts were taken to ensure the study design matched the design of a previous study on benazapril efficacy compared to placebo. 112 cats were randomized to be placed on either benazepril or telmisartan. Inclusion criteria were cats diagnosed with clinically stable IRIS stage 2–3 CRD. Diagnosis of CKD was based on history, physical exam and lab findings. Lab criteria included: creatinine concentration ≥1.6 and <5.0 mg/dL, urine specific gravity <1.035, UP/C ≥ 0.2 and <2.0, plasma or serum T4 concentrations ≤3.1 μg/dL, and systolic blood pressure (SBP) ≤170 mmHg. Cats with SBP > 170–<180 mmHg were eligible if they had been stable on amlodipine treatment for ≥4 weeks.

The study was designed as a prospective, randomized, investigator-blinded, positive-controlled, parallel group trial.  Cats were treated with telmisartan or benazepril daily for a 180 day period and hematologic and biochemical variable measured

At the end of 180 days, urine protein: creatinine ratio was measured and compared to baseline. While both groups had decreased, only the telmisartan group was statistically significant. Further, only 30.8% of benazapril treated cats had changed form proteinuric to borderline or non-proteinuric, while 57.2% of telmisartan treated cats had changed.

Side effects of medications were comparable in both groups and were mild, often attributable to the underlying disease process. 15% of telmisartan cats dropped out of the study compared to 19.8% of benazapril cats.

From this study, it is evident that telmisartan is non-inferior to benazapril at treated CKD. Evidence suggests, in fact, that it may have greater ability to reduce proteinuria over a longer period of time. It also demonstrated that the risk of adverse events with either treatment is very low. Significant theoretical advantages exist for telmisartan over benazapril, however these have not all been conclusively demonstrated in vivo.  (MRK)

See also:
Jenkins TL, Coleman AE. 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 Sept; 76(9):807-813.

Syme HM, Markwell PJ, et al. (2006), Survival of Cats with Naturally Occurring Chronic Renal Failure Is Related to Severity of Proteinuria. J Vet Intern Med. 2006 May- June; 20: 528–535.  (Free article)