Amanda Coleman, University of Georgia, Athens, GA, USA
Jonathan Elliott, Royal Veterinary College, London, UK
Jonathan Elliott, Royal Veterinary College, London, UK
The renin-angiotensin-aldosterone system (RAAS) is important in the physiology of blood pressure regulation and in the adaptation of the kidney to the loss of functioning nephrons, as occurs in chronic kidney disease (CKD). Hyperfiltration driven by RAAS activation is a maladaptive mechanism that exacerbates proteinuria, the severity of which is linked to progressive loss of functioning nephrons and to poorer patient outcomes.1-3 In addition, the hyperfiltration and accompanying proteinuria of CKD may be exacerbated by systemic arterial hypertension (HT), which, in turn, may hasten the decline of renal function and aggravate glomerulosclerosis.4,5 Dysfunction of the RAAS is implicated in the pathophysiology 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 CKD patients. While these drugs demonstrably decrease glomerular hypertension, systemic arterial blood pressure, and proteinuria, the concept of blocking the RAAS by reducing the formation of angiotensin II (and as a consequence, decreasing a major stimulus for excess aldosterone secretion) may be too simplistic. Indeed, the use of ACE-i as single agent to control HT has proven disappointing in both dogs and cats. In addition, despite their benefit in lowering proteinuria within populations, ACE-i are not universally successful, with degree of antiproteinuric effect varying considerably on a patient-to-patient basis. For example, in a clinical trial designed to evaluate the efficacy of enalapril as a treatment for naturally occurring proteinuria, a clinically significant (i.e., 50%) reduction in proteinuria was noted in only 9/14 (64%) subjects, with 3/14 (22%) experiencing an increase in proteinuria despite therapy with enalapril.6 However, there are relatively few published randomized controlled clinical trials examining the antiproteinuric effect of ACE-i in dogs with CKD, in which large enough group sizes and different dose rates have been examined to be sure of the true efficacy of this group of drugs.
Selective and tight-binding inhibition of the angiotensin II, subtype 1 (AT1) receptor is a relatively new approach to interfering with the RAAS system that may have some advantages over ACE inhibition. First, this approach preserves the potentially beneficial effects associated with stimulation of the angiotensin II, subtype 2 (AT2) receptor. Expression of the AT2 receptor appears to be upregulated in times of stress, and activation of these receptors seems to counter-balance the detrimental consequences of AT1 receptor activation by antiproliferative, vasodilatory, antifibrotic and natriuretic effects. In addition, AT2 receptor activation seems to restore endothelial cell function. Selective AT1 receptor inhibition leaves the AT2 receptors free to interact with angiotensin II, which may favorably rebalance angiotensin II's downstream effects 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, its blockade is associated with increased angiotensin II levels, which are available to interact with the unopposed AT2 receptors, potentially amplifying their beneficial effects. How much this rebalancing effect 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.
Specificity for the AT1 receptor also allows ARBs to antagonize the detrimental effects of angiotensin II independent of the latter's source, circumventing ACE-independent proteolytic pathways that are known to contribute to angiotensin II production. The well-described phenomenon of aldosterone breakthrough is thought to be explained, at least in part, by upregulation, or lack of blockade, of non-ACE pathways, which lead to the continued formation of angiotensin II, restoring plasma aldosterone concentrations to pre-treatment levels. Aldosterone breakthrough has been documented in dogs with experimental RAAS activation7,8 and naturally occurring myxomatous mitral valve disease,9 all treated with ACE-i. In people, aldosterone breakthrough is a well-recognized phenomenon not only in patients treated with an ACE-i, but also in those receiving an ARB, suggesting that persistence of angiotensin II production (i.e., angiotensin II breakthrough) is only part of the 'story'.10 Recently, aldosterone breakthrough was documented in 2 of 5 healthy, telmisartan-treated dogs undergoing pharmacologic RAAS activation,11 and evaluation of this phenomenon's incidence in dogs treated with an ARB is an area of ongoing investigation. Aldosterone break through has been demonstrated to occur in human patients receiving ARBs to a similar extent as those receiving ACE-i. Nonetheless, focus on aldosterone as a marker of RAAS activation should not under estimate the multitude of additional, non-aldosterone-mediated, detrimental effects of AT1 receptor activation, which are mitigated during treatment with ARBs.
Finally, in addition to theoretical advantages over ACE-i, ARBs may also have advantages when compared to other antihypertensive agents. For example, differences between the effects on the renal microvasculature of these drugs as compared to the dihydropyridine calcium channel blocker, amlodipine, may translate to differences in these drugs' renoprotective effects. Amlodipine causes preferential dilation of the afferent renal arteriole, which may exacerbate glomerular hypertension and promote progressive renal injury, especially if systemic arterial blood pressure is not effectively decreased during its administration. In contrast, through preferential dilation of the efferent renal arteriole, RAAS-blocking agents (both ACE-i and ARB) reduce intraglomerular pressure, mitigating glomerular hypertension and proteinuria, if present. However, the clinical significance imparted by these theoretical differences is not known.
Using relatively new equilibrium analysis techniques, the comprehensive measurement of the range of angiotensin peptides in clinical patients, before and after institution of RAAS inhibitory therapies, is now possible and seems to hold great promise in unravelling the mysteries of this complex system in dogs and cats. Although publications to date involve small numbers of patients and have focused on those with heart disease 12,13, it is likely that the application of this technology to CKD patients with proteinuria and hypertension at diagnosis and whilst on treatment with ARBs and ACE-I drugs will increase our knowledge in this area.
Losartan, the first ARB with oral bioavailability, was approved for clinical use in people in 1995. Since then, a total of nine ARB have completed clinical development, making this class the most rapidly-growing of the antihypertensives. Likely due to its relative affordability, compared to other available ARBs, losartan has received the most attention from veterinary clinicians, particularly in the USA, with anecdotal reports of success in the treatment of proteinuria in dogs.14 However, in preclinical studies of healthy cats15 and dogs,16 losartan was no better than placebo in attenuating the angiotensin I-induced rise in systolic arterial blood pressure (SBP) when administered at a dosage of 2.5 mg/kg q24h (i.e., 2.5 times the maximum anecdotally recommended dosage14). The failure of 4 mg of losartan/kg to reduce SBP significantly in cats with experimentally-induced hypertensive renal insufficiency supports these findings.17 It is noteworthy that the dog forms little of the active metabolite of losartan (EXP 3174), which is largely responsible for the antihypertensive effects of the drug.18 While it is not known whether cats are similarly incapable of forming EXP 3174, this may explain the poor performance of losartan in these preclinical studies.
In the studies referenced above, the ARB telmisartan was found to attenuate 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 the treatment of cardiovascular and renal diseases in these species.15,16 In a separate study, telmisartan treatment was associated with measurable reductions in indirectly measured SBP in awake, unstimulated cats.19 Results from these studies, among others, revealed the potential utility of telmisartan for RAAS blockade in dogs and cats. As such, to date, telmisartan is the ARB that has been evaluated with the greatest rigor in companion animals.
A veterinary specific 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 PO once daily) was shown to be non-inferior to benazepril (0.5-1.0 mg/kg PO once daily) for the reduction of time-averaged urinary protein-to-creatinine ratio (UPC), when administered for 3-6 months.20 Blood pressure was not assessed in this study.
Two recent, prospective, multicenter, double-blinded, placebo-controlled clinical trials - one conducted at 51 European centers,21 and the other carried out at 33 primary care facilities in the United States and Canada22 - have evaluated the antihypertensive efficacy and safety of telmisartan oral solution when administered to a combined total of 483 spontaneously hypertensive cats with SBP of 160-200 mmHg. In both studies, compared to placebo, treatment with telmisartan oral solution was associated with both a statistically significant and clinically relevant decrease in SBP relative to baseline. On average, telmisartan resulted in mean SBP decreases of 19-23 mmHg by day 14 of treatment, whereas mean SBP reductions of 7-9 mmHg were noted in placebo-treated cats over the same time period. The telmisartan-induced decrease in SBP was sustained throughout a 4- or 6-month dosing period in both studies, with mean SBP reductions of 28-31 mmHg documented at study end. These data support the efficacy of telmisartan for the treatment of feline systemic hypertension, although the utility of this drug in cats with SBP >200 mmHg, evidence of severe target organ damage, severe azotemia, or a combination of these, remains untested. Furthermore, the optimal SBP to protect the kidneys and how this is influenced by the level of proteinuria in the individual patient remains to be investigated in veterinary medicine.
The results of a prospective, randomised, double-masked, controlled clinical trial, comparing the short-term efficacy of telmisartan with a standard dose of compounded enalapril suspension in the management of persistent renal proteinuria in dogs with CKD, have recently been published 23. This study also examined the effect of dose escalation of both drugs in dogs that proved resistant to the standard dose and examined the safety of combining the two therapies. This was a single centre study in which 39 dogs with CKD (azotaemic or non-azotaemic) and persistent proteinuria (i.e., urinary protein-to-creatinine ratio [UPC] > 0.5 [if azotemic] or ≥ 1.0 [if nonazotemic] were block randomised according to the presence or absence of azotemia and systemic arterial hypertension (i.e, systolic BP [SBP] >150 mmHg). Dogs from each group were allocated to receive telmisartan (1mg/kg once daily) or enalapril (0.5 mg/kg q 12 h) in a 1:1 ratio. Enalapril was formulated by the hospital pharmacy into a liquid form to facilitate investigator and owner blinding.
The first phase of this study lasted 30 days. Hypertensive dogs with SBP >180 mmHg were also treated with amlodipine (0.1 mg/kg once daily, with weekly dosage adjustments to a maximum dosage of 0.3 mg/kg q12h performed as needed to target SBP between 100 and 180 mmHg). On day 30 of the study (beginning of phase 2), UPC was reassessed. Dogs with UPC <0.5 remained on their original treatment allocation and were not re-evaluated until day 120 of treatment, while those with UPC > 0.5 underwent up-titration of their allocated medication dosage on day 30 (i.e., doubling of the allocated dose) and 60 (i.e., tripling of the allocated dose), and addition of the standard dosage of the other study drug (i.e., telmisartan [1 mg/kg daily] or enalapril [0.5 mg/kg q 12 h]) on day 90, if UPC > 0.5 was noted at these visits. All dogs were re-evaluated after 120 days of therapy. Thus, phase 2 examined the efficacy and safety of dose escalation and drug combination for dogs with persistent proteinuria on standard treatment.
The main conclusions of this study were that at the standard dose rates (Phase 1), telmisartan treatment was associated with a greater median (range) percentage reduction in UPC than enalapril ((–65% [–95% to 104%]) vs (–35% [–74% to 87%]). Interpretation of the dose escalation phase (phase 2) requires caution because of the small group sizes of persistently proteinuric dogs (i.e., those with UPC >0.5) at each time point; nonetheless, telmisartan remained superior to enalapril at treatment days 60 and 90. Median time to 50% reduction in UPC was significantly shorter for the telmisartan group versus the enalapril group. No difference in percentage change in UPC between study groups was observed at day 120, when combination therapy was allowed. Combination therapy resulted in clinically relevant worsening of azotaemia in 4 (31%) of the 13 dogs so treated, and was therefore not recommended by the authors.
The study was not designed to assess the antihypertensive efficacy of the two drugs, and 10 dogs were concurrently treated with amlodipine during the study. However, in those not treated with amlodipine, mean percentage reduction in SBP was significantly greater in telmisartan-versus enalapril-treated dogs at most time points assessed. Clinically relevant hypotension was not observed in any patient. A limitation of the study was the use of a compounded liquid formulation of enalapril and associated uncertainty over batch-to-batch quality and bioequivalence with the approved formulation. Nonetheless, the conclusions of this study and the magnitude of the effects seen are supported by two uncontrolled retrospective studies of the efficacy of telmisartan in proteinuric canine patients 24, 25.
Angiotensin receptor blockers offer several theoretical advantages over ACE-i when used for the treatment of patients with cardiovascular and renal diseases. Pre-clinical 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. The incidence of aldosterone breakthrough in patients treated with ARB remains to be elucidated.
Clinical trials in cats with naturally occurring CKD and systemic arterial hypertension have demonstrated the safety and efficacy of telmisartan for proteinuria and SBP reduction, although the drug's performance in the setting of severe systemic hypertension (i.e., SBP >200 mmHg) and severe renal azotemia requires further study. Whether telmisartan can be used safely in combination with amlodipine to achieve lower target SBPs in cats, and if using it in this manner leads to enhanced renoprotection, remains to be determined.
Finally, whether ARBs have utility for delaying the progression of CKD in cats and dogs, and for the treatment of other cardiovascular conditions, represent important questions that are in need of further investigation.
Both authors have acted as paid consultants to Boehringer Ingelheim Ltd, the company that holds the product authorization for telmisartan as an antihypertensive agent for use in cats.
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