Effect of telmisartan, angiotensin‐converting enzyme inhibition, or both, on proteinuria and blood pressure in dogs

Abstract Background The use of telmisartan (TEL), an angiotensin‐receptor blocker, for the control of systemic hypertension and proteinuria in dogs has not been reported extensively in a clinical setting. Objectives To determine the effects of an angiotensin‐converting enzyme inhibitor (ACEi) alone, ACEi in combination with TEL, or TEL alone on systolic blood pressure and proteinuria in dogs with protein losing nephropathy (PLN). Animals Forty‐two client‐owned dogs being treated for PLN. Methods Retrospective observational study of medical records of dogs at a university teaching hospital from 2012 to 2018 with the use of benazepril or enalapril alone, TEL alone, or both modalities for the management of PLN. Noninvasive blood pressure and urine protein to creatinine ratio (UPC) were compared among the treatment groups over time. A multivariable mixed‐effects linear regression model followed by post hoc analysis was used to estimate the marginal means and differences between the treatment groups. Results In comparison to group ACEi alone, combination treatment of an ACEi with TEL significantly reduced (P = .007) systolic blood pressure by 13 mm Hg (95% confidence interval [95% CI]: 4‐22 mm Hg). Angiotensin‐converting enzyme inhibitor + TEL in comparison to ACEi alone showed significant (P = .01) reduction in UPC of 2.5 (95% CI: 0.6‐4.4). The UPC of group ACEi + TEL was significantly lower (P = .01) in comparison to TEL alone by 3.8 (95% CI: 0.8‐6.8). Conclusions and Clinical Importance Telmisartan can be used to treat systemic hypertension and proteinuria in dogs.

consensus that attention must be given to the detection, evaluation, treatment, and monitoring of proteinuria in dogs to improve outcomes in dogs with CKD and in protein losing nephropathy (PLN) of other origin. 2 Dogs with CKD can also develop systemic hypertension, which has a multifactorial pathogenesis. In humans, hypertension because of renal disease is attributed to impaired renal sodium handling, excessive activation of the renin-angiotensin-aldosterone system (RAAS), sympathetic nervous system hyperactivity, and endothelial factors. 3 The major target system for medically reducing proteinuria and controlling blood pressure is the RAAS, with the most common medication used in dogs being an angiotensin-converting enzyme inhibitor (ACEi). However, the production of angiotensin-II (AT-II) can occur through non-ACE pathways, which are left unaffected by ACE inhibition. 4,5 Telmisartan (TEL) is a selective angiotensin receptor antagonist, and blocks the AT-II type I receptor with a high affinity. 4,5 Because TEL acts directly on the AT-II receptor rather than preventing the production of AT-II itself, it can block AT-II independent of the pathway by which it is produced. 5 In 2013, the first approved angiotensin receptor blocker (ARB), TEL (Semintra, Boehringer Ingelheim Vetmedica GmbH, 4 mg/mL), became available for use in cats with CKD in the European Union (EU). 6 A large prospective multicenter controlled clinical trial evaluated the effect of TEL on proteinuria in cats compared to benazepril. 7 The results showed that cats in the TEL group had a significantly decreased urine protein to creatinine ratio (UPC) when compared to baseline, whereas these changes were not observed in the benazepril group. 7 Prospective placebo-controlled studies in cats and 1 case report have also demonstrated a significant reduction in systolic blood pressure with TEL compared to placebo. 8,9,10 The veterinary literature is sparse regarding the use of TEL in dogs. A study evaluating the effect of TEL on renal excretory function in conscious healthy dogs concluded that TEL promoted the excretion of water, sodium, and chloride without influencing potassium or creatinine excretion. 11 The only clinical report of the utility of TEL in a dog is a case report detailing refractory proteinuria in a middle-aged Beagle dog, which resolved with the use of TEL. 12 The paucity of information for the role of TEL in the management of proteinuria and systemic hypertension in dogs led to the main study aims: to describe a study sample of dogs treated for PLN with an ACEi alone, ACEi with the addition of TEL, and with TEL alone; and to determine if there was a significant difference in systolic blood pressure or proteinuria among dogs in these same groups. It was hypothesized that dogs treated with TEL alone or in combination with an ACEi would have a significantly lower systolic blood pressure and UPC compared to those treated with ACEi alone. Lastly, we aimed to assess changes in clinicopathologic variables including potassium, phosphorus, blood urea nitrogen (BUN), and creatinine amongst treatment groups.

| MATERIALS AND METHODS
A retrospective observational study for dogs with PLN was performed. All medical records were initially screened to identify dogs with suspect renal proteinuria. Three study samples were created for evaluation and review. Group ACEi dogs received benazepril or enalapril as the primary medical treatment to reduce proteinuria. Group ACEi + TEL dogs received TEL in addition to benazepril or enalapril.
Group TEL dogs received TEL and no ACEi.
Group ACEi served as the control treatment group for the study.
Once all TEL cases were identified and reviewed (either group ACEi + TEL or group TEL), additional medical records of dogs prescribed an Because of the nature of the study, a washout period was not performed when transitioning dogs from 1 group to the next. were removed from the study as they were lost to follow-up, could no longer tolerate the medication, or were euthanized.

| Statistical analyses
Inference statistical analysis was conducted in 2 steps. First, univariate linear regression was used to identify statistically significant confounders associated (P < .20) with the main outcomes (BUN, creatinine, potassium, phosphorus, blood pressure, and UPC). 15 Variables examined as possible confounders were age, sex, and reproductive status. Second and final, a multivariable mixed-effects linear regression model was used that included the fixed effects of treatment and the interaction between treatment and observation sample as categorical variables and any confounders identified in the previous steps.

Mixed-effects linear regression was chosen because of large numbers
of missing values in the dataset, subjects moving from 1 group to another, repeated measures over time, and departures from normality of the outcome. The random effects were set on the level of the individual animal. Robust estimation of the variance was used to adjust for any possible departures from the normality of the outcome. Post hoc analysis was used to estimate the marginal means and 95% confidence intervals (95% CIs) and differences between the treatment groups. Least Significant Difference method was used to adjust for multiple comparisons. When using statistical models with 2 or more independent variables (fixed or random-effects or any statistical interaction between them) to explain a given outcome (dependent variable), the marginal means for a given outcome in respect to 1 of the independent variables are the means of the dependent variable averaged across all levels of the other independent variables. 16 3 | RESULTS One dog was transitioned from group ACEi + TEL to group ACEi at visit 5. One dog was represented in all 3 groups, and 1 dog started in group ACEi + TEL, was transitioned to group TEL, and shortly after transitioned back to group ACEi + TEL.

| Study demographics
At entry into the study, 31 dogs were identified to have hypertension (systolic blood pressure >150 mm Hg), and 22 of those dogs were subsequently treated with amlodipine. Out of the dogs with hypertension where amlodipine was not used the median blood pressure was 170 mm Hg (range, 155-226 mm Hg).

| Drug doses
The median dose of enalapril or benazepril used for dogs in the ACEi

| Telmisartan effect on blood pressure and proteinuria
Besides the time of observation, the univariate analysis showed that systolic blood pressure was dependent on reproductive status, whereas there was no effect of sex or age on blood pressure. Hence, the mixed-effects linear regression model included this significant confounder. When analyzing all dogs within each group over time, the marginal mean systolic blood pressure in the ACEi + TEL group (Table 2) was significantly lower (P = .007) than the marginal mean blood pressure in the ACEi group by 13 mm Hg (95% CI: 4-22 mm Hg). The marginal mean systolic blood pressure in the TEL group was lower than in the ACEi group, but did not reach significance (P = .31; Table 2). There was no difference in marginal mean systolic blood pressure between the TEL group and the ACEi + TEL group (Table 2).
When adjusted for time, the marginal mean UPC was significantly lower in the ACEi + TEL group (P = .01; Table 2) compared to the ACEi group by 2.5 (95% CI: 0.6-4.4). There was no difference in the marginal mean UPC of the TEL group and the ACEi group (P = .40; Table 2). The TEL group had a significantly higher (P = .01) marginal mean UPC over time (Table 2) compared to the ACEi + TEL group by 3.8 (95% CI: 0.8-6.8).

| DISCUSSION
This study describes and compares a sample of dogs medically treated for proteinuria with an ACEi, TEL, or a combination of ACEi and TEL over time. Findings show that the marginal mean systolic blood pressure is significantly lower in dogs treated with both an ACEi and TEL compared to dogs treated with an ACEi alone. This finding suggests that TEL can be considered for treatment of hypertension in dogs.
This study also found that the UPC was lower in dogs receiving combination treatment with an ACEi and TEL compared to ACEi alone.
These data support the continued use of TEL in the management of proteinuria in dogs.
Looking further at the effects of TEL use and proteinuria, the marginal mean UPC was significantly higher for dogs in the TEL group over time compared to the marginal mean UPC for dogs in the ACEi + TEL group over time. This unexpected finding might be explained with the consideration that these dogs had more advanced disease. In current clinical settings, many clinicians do not prescribe TEL for proteinuria treatment unless the dogs have developed progressive proteinuria in the face of ACEi treatment or experienced an adverse effect prohibiting future use (ie, acute kidney injury, a rise in potassium, gastrointestinal adverse effects). Based on current practices, it is most likely that dogs transitioned to the TEL group had higher starting UPC measurements than dogs in the ACEi group and the ACEi + TEL group. Therefore, based on our statistical evaluation of marginal means at the group level, the comparison reflects that the overall marginal mean was higher for dogs in group TEL compared to group ACEi + TEL. It is also possible that the ACEi + TEL combination is a superior form of treatment for proteinuria than TEL alone. Future prospective studies should be performed with dogs that are matched for starting UPC measurements and randomly allocated to receive each treatment. These treatment groups can be analyzed at the individual level, and considerations can also be made to assess the percent decrease in UPC over time.
When evaluating the effects of TEL on blood pressure, the results of this study suggest an additive effect of ACE inhibition and TEL.
Telmisartan is an approved drug to treat systemic hypertension in cats, and it is important to be aware of this effect when using TEL to treat proteinuria in dogs. Further prospective studies are warranted to evaluate the effect of TEL alone or in combination treatment on blood pressure in dogs.
Although it did not reach significance, the blood pressure was higher for dogs in the TEL group compared to the ACEi + TEL group.
This could be reflective of more advanced disease in dogs treated with TEL alone. In addition, many dogs were added to the TEL group or transitioned into the TEL group toward the end of the study window and had fewer visits to evaluate. The median number of days from enrollment for dogs in the TEL group was smaller compared to the median number of days from enrollment for dogs in the ACEi + TEL group. It is possible that the blood pressure would have continued to decrease with more time after implementation of the TEL treatment as a sole agent.
One concern with the use of TEL in dogs is the risk for hyper- Another consideration when reviewing the study results is that several dogs had concurrent diseases and were receiving additional medications which could have affected blood pressure, clinicopathologic variables, and confounded treatment decisions regarding ACEi or TEL use (amlodipine, 22; prednisone, 4; trilostane, 2; omega-3 fatty acids, 23).
Given that both dogs with Cushing's disease were treated with trilostane, the contribution of proteinuria from hyperadrenocorticism should be minimal. Out of the 4 dogs treated with prednisone, 3 of them were short tapering courses, decreasing the likelihood for any significant lasting impact on proteinuria. Lastly, the sample size was small, dictated by the total use of TEL at the University of Pennsylvania School of Veterinary Medicine within the study window.