Inhibition of the Renin-Angiotensin-Aldosterone System in Cats and Dogs: The Emerging Role of Angiotensin II Receptor Blockers

Adapted from the IRIS education article by Amanda Coleman (University of Georgia, Athens, GA, USA) and Jonathan Elliott (Royal Veterinary College, London, UK), 2018.

The Renin-Angiotensin-Aldosterone System and Angiotensin Receptor Blockers

The renin-angiotensin-aldosterone system (RAAS) is important in the regulation of blood pressure and in the kidney's adaptation to the loss of functioning nephrons, as occurs in chronic kidney disease (CKD). Hyperfiltration driven by RAAS activation is a maladaptive mechanism that worsens proteinuria, the severity of which is linked to the progressive loss of functioning nephrons and to poorer patient outcomes (references 1 to 3). In addition, the hyperfiltration and proteinuria of CKD may be worsened by systemic arterial hypertension (HT), which in turn may hasten the decline of kidney function and aggravate glomerulosclerosis (references 4 and 5). Dysfunction of the RAAS is implicated in the development of HT in many species.

In veterinary medicine, angiotensin-converting enzyme inhibitors (ACE-i) have been used since the 1980s to treat heart disease, and since the early 2000s to manage proteinuria in patients with CKD. Although these drugs clearly decrease glomerular hypertension, systemic arterial blood pressure, and proteinuria, the idea of blocking the RAAS by reducing the formation of angiotensin II, and so removing a major stimulus for excess aldosterone secretion, may be too simplistic. Indeed, ACE-i used as single agents to control HT have proven disappointing in both dogs and cats. And despite their benefit in lowering proteinuria across populations, ACE-i are not universally successful, and the size of their antiproteinuric effect varies considerably from patient to patient. For example, in a clinical trial of enalapril for naturally occurring proteinuria, a clinically significant (50%) reduction in proteinuria was seen in only 9 of 14 dogs (64%), and 3 of 14 (21%) had an increase in proteinuria despite enalapril treatment (reference 6). However, there are relatively few published randomized controlled trials of the antiproteinuric effect of ACE-i in dogs with CKD with large enough groups, and with different dose rates examined, to be sure of the true efficacy of this group of drugs.

Selective, tight-binding inhibition of the angiotensin II subtype 1 (AT1) receptor is a relatively new approach to blocking the RAAS that may have some advantages over ACE inhibition. First, it preserves the potentially beneficial effects of stimulating the angiotensin II subtype 2 (AT2) receptor. Expression of the AT2 receptor appears to increase at times of stress, and activation of these receptors seems to counterbalance the harmful consequences of AT1 receptor activation through antiproliferative, vasodilatory, antifibrotic, and natriuretic effects. AT2 receptor activation also seems to restore endothelial cell function. Selective AT1 receptor inhibition leaves the AT2 receptors free to interact with angiotensin II, which may favorably rebalance the downstream effects of angiotensin II in patients with kidney disease, heart failure, HT, or a combination of these. In addition, because the AT1 receptor mediates feedback inhibition of renin release, blocking it increases angiotensin II concentrations, which are then available to act on the unopposed AT2 receptors, potentially amplifying their beneficial effects. How much this rebalancing contributes to the antihypertensive action of an AT1 receptor blocker (ARB) is unclear, but AT2 receptor activation is likely to be at least somewhat beneficial.

Their specificity for the AT1 receptor also allows ARBs to block the harmful effects of angiotensin II whatever its source, getting around the ACE-independent pathways known to contribute to angiotensin II production. The well-described phenomenon of aldosterone breakthrough is thought to be explained, at least in part, by increased activity, or lack of blockade, of these non-ACE pathways, which allows angiotensin II to continue to be formed and plasma aldosterone concentrations to return to pre-treatment levels. Aldosterone breakthrough has been documented in dogs treated with ACE-i, both with experimental RAAS activation (references 7 and 8) and with naturally occurring myxomatous mitral valve disease (reference 9). In people, aldosterone breakthrough is well recognized not only in patients treated with an ACE-i but also in those receiving an ARB, to a similar extent, which suggests that the persistence of angiotensin II production (angiotensin II breakthrough) is only part of the story (reference 10). Aldosterone breakthrough was documented in 2 of 5 healthy dogs treated with telmisartan during pharmacological RAAS activation (reference 11), and how often it occurs in dogs treated with an ARB is being investigated. Nonetheless, a focus on aldosterone as a marker of RAAS activation should not lead us to underestimate the many other, non-aldosterone-mediated, harmful effects of AT1 receptor activation, which are reduced by ARB treatment.

Finally, as well as their theoretical advantages over ACE-i, ARBs may have advantages over other antihypertensive drugs. For example, differences between their effects on the kidney's small blood vessels and those of the dihydropyridine calcium channel blocker amlodipine may translate into differences in how well they protect the kidneys. Amlodipine preferentially dilates the afferent renal arteriole, which may worsen glomerular hypertension and promote progressive kidney injury, especially if systemic blood pressure is not effectively lowered. In contrast, RAAS-blocking drugs, both ACE-i and ARBs, preferentially dilate the efferent renal arteriole and so reduce intraglomerular pressure, lessening glomerular hypertension and any proteinuria. However, the clinical significance of these theoretical differences is not known.

With relatively new equilibrium analysis techniques, it is now possible to measure the full range of angiotensin peptides in clinical patients before and after starting RAAS-inhibiting treatment, and this seems to hold great promise for unraveling this complex system in dogs and cats. Publications to date involve small numbers of patients and have focused on heart disease (references 12 and 13), but applying this technology to patients with CKD, proteinuria, and hypertension, at diagnosis and during treatment with ARBs and ACE-i, is likely to increase our knowledge in this area.

Angiotensin II Subtype 1 Receptor Blockers in Veterinary Medicine

Losartan, the first orally bioavailable ARB, was approved for clinical use in people in 1995. Since then, a total of nine ARBs have completed clinical development, making this class the most rapidly growing group of antihypertensive drugs. Probably because it is more affordable than other ARBs, losartan has received the most attention from veterinary clinicians, particularly in the USA, with anecdotal reports of success in treating proteinuria in dogs (reference 14). However, in preclinical studies in healthy cats (reference 15) and dogs (reference 16), losartan was no better than placebo at blunting the rise in systolic arterial blood pressure (SBP) caused by angiotensin I, when given at 2.5 mg/kg once daily, which is 2.5 times the maximum anecdotally recommended dosage (reference 14). The failure of losartan at 4 mg/kg to reduce SBP significantly in cats with experimentally induced hypertensive renal insufficiency supports these findings (reference 17). Notably, dogs form little of losartan's active metabolite, EXP 3174, which is largely responsible for the drug's antihypertensive effects (reference 18). It is not known whether cats are similarly unable to form EXP 3174, but this may explain the poor performance of losartan in these preclinical studies.

In the same studies, the ARB telmisartan blunted the angiotensin I-induced rise in SBP more effectively than benazepril (in cats), enalapril (in dogs), losartan (in cats and dogs), irbesartan (in cats), and placebo, suggesting a potential advantage of this drug for treating cardiovascular and kidney diseases in these species (references 15 and 16). In a separate study, telmisartan treatment produced measurable reductions in indirectly measured SBP in awake, unstimulated cats (reference 19). These and other results showed the potential usefulness of telmisartan for RAAS blockade in dogs and cats, and telmisartan is now the ARB that has been evaluated most rigorously in companion animals.

Telmisartan in Cats

A veterinary formulation of telmisartan was first licensed in Europe in 2013 for the treatment of proteinuria in cats with CKD. In a prospective, randomized, investigator-blinded clinical trial of 224 cats with naturally occurring CKD, telmisartan (1 mg/kg by mouth once daily) was shown to be non-inferior to benazepril (0.5 to 1.0 mg/kg by mouth once daily) for reducing the time-averaged urine protein-to-creatinine ratio (UPC) over 3 to 6 months of treatment (reference 20). Blood pressure was not assessed in this study.

Two prospective, multicenter, double-blinded, placebo-controlled clinical trials, one at 51 European centers (reference 21) and the other at 33 primary care practices in the United States and Canada (reference 22), evaluated the antihypertensive efficacy and safety of telmisartan oral solution in a combined total of 483 cats with spontaneous hypertension and an SBP of 160 to 200 mmHg. In both studies, telmisartan was associated with a statistically significant and clinically relevant decrease in SBP from baseline compared with placebo. On average, telmisartan reduced mean SBP by 19 to 23 mmHg by day 14 of treatment, compared with reductions of 7 to 9 mmHg in placebo-treated cats over the same period. The decrease was sustained throughout 4 or 6 months of treatment in both studies, with mean SBP reductions of 28 to 31 mmHg at the end of the studies. These data support the efficacy of telmisartan for treating hypertension in cats, although its usefulness in cats with an SBP above 200 mmHg, severe target organ damage, severe azotemia, or a combination of these remains untested. The optimal SBP for protecting the kidneys, and how it is influenced by the level of proteinuria in the individual patient, also remain to be investigated in veterinary medicine.

Telmisartan in Dogs

The results of a prospective, randomized, double-masked, controlled clinical trial comparing the short-term efficacy of telmisartan with a standard dose of compounded enalapril suspension for persistent renal proteinuria in dogs with CKD have been published (reference 23). The study also examined dose escalation of both drugs in dogs that did not respond to the standard dose, and the safety of combining the two treatments. In this single-center study, 39 dogs with CKD (azotemic or non-azotemic) and persistent proteinuria (a UPC above 0.5 if azotemic, or 1.0 or higher if non-azotemic) were block-randomized according to the presence or absence of azotemia and systemic hypertension (SBP above 150 mmHg). Dogs in each group were allocated in a 1:1 ratio to telmisartan (1 mg/kg once daily) or enalapril (0.5 mg/kg every 12 hours). Enalapril was formulated by the hospital pharmacy into a liquid to allow investigators and owners to be blinded.

The first phase of the study lasted 30 days. Hypertensive dogs with an SBP above 180 mmHg were also treated with amlodipine (0.1 mg/kg once daily, adjusted weekly as needed up to a maximum of 0.3 mg/kg every 12 hours, to target an SBP between 100 and 180 mmHg). On day 30, the start of phase 2, the UPC was reassessed. Dogs with a UPC below 0.5 continued their original treatment and were not re-evaluated until day 120. Dogs with a UPC above 0.5 had the dose of their allocated drug increased on day 30 (doubled) and on day 60 (tripled), and the standard dose of the other study drug (telmisartan 1 mg/kg daily, or enalapril 0.5 mg/kg every 12 hours) was added on day 90, if the UPC was still above 0.5 at those visits. All dogs were re-evaluated after 120 days of treatment. Phase 2 therefore examined the efficacy and safety of dose escalation and combination treatment in dogs with persistent proteinuria on standard treatment.

The main conclusion was that, at the standard doses (phase 1), telmisartan was associated with a greater median percentage reduction in UPC than enalapril: −65% (range −95% to +104%) versus −35% (range −74% to +87%). The dose escalation results (phase 2) must be interpreted with caution because of the small numbers of persistently proteinuric dogs at each time point, but telmisartan remained superior to enalapril on days 60 and 90. The median time to a 50% reduction in UPC was significantly shorter with telmisartan than with enalapril. There was no difference in the percentage change in UPC between the groups on day 120, when combination treatment was allowed. Combination treatment caused clinically relevant worsening of azotemia in 4 of the 13 dogs (31%) that received it, and the authors therefore did not recommend it.

The study was not designed to assess the antihypertensive efficacy of the two drugs, and 10 dogs were also treated with amlodipine. However, in dogs not treated with amlodipine, the mean percentage reduction in SBP was significantly greater with telmisartan than with enalapril at most time points. Clinically relevant hypotension was not seen in any dog. A limitation of the study was the use of a compounded liquid enalapril, with uncertainty about batch-to-batch quality and bioequivalence with the approved formulation. Nonetheless, the conclusions of this study, and the size of the effects seen, are supported by two uncontrolled retrospective studies of telmisartan in proteinuric dogs (references 24 and 25).

Conclusions and Future Directions

Angiotensin receptor blockers offer several theoretical advantages over ACE-i for treating patients with cardiovascular and kidney diseases. Preclinical work in normal cats and dogs supports the superiority of these drugs, in particular telmisartan, over ACE-i for more effective RAAS blockade, with the benefit of once-daily dosing. How often aldosterone breakthrough occurs in patients treated with ARBs remains to be established.

Clinical trials in cats with naturally occurring CKD and systemic hypertension have demonstrated the safety and efficacy of telmisartan for reducing proteinuria and SBP, although its performance in severe hypertension (SBP above 200 mmHg) and severe renal azotemia needs further study. Whether telmisartan can be used safely with amlodipine to reach lower target SBPs in cats, and whether doing so gives better protection to the kidneys, remains to be determined. In dogs with proteinuric CKD, a randomized trial found telmisartan more effective than enalapril at reducing proteinuria at standard doses, while combining the two drugs worsened azotemia in some dogs.

Finally, whether ARBs can delay the progression of CKD in cats and dogs, and whether they are useful for other cardiovascular conditions, are important questions in need of further investigation.

Author Conflicts of Interest

Both authors have acted as paid consultants to Boehringer Ingelheim, the company that holds the product authorization for telmisartan as an antihypertensive agent for use in cats.

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