Clinician's Forum: Expert Views from a Roundtable on Endocrine Disease (Part 2)

Brought to you by Dechra Veterinary Products

Participants

• Patty Lathan, VMD, MS, DACVIM (Small Animal) Associate Professor, Small Animal Internal Medicine, Mississippi State University

• Christopher Byers, DVM, DACVECC, CVJ, DACVIM (Small Animal), CriticalCareDVM.com

• Brett Wasik, DVM, DACVIM (SAIM), Internal Medicine & Endocrinology Consultant, Veterinary Information Network Internal Medicine Consultant, Antech Diagnostics

Moderator

• Nancy Zimmerman, DVM, Dechra Veterinary Products

Managing Canine Hyperadrenocorticism

Once hyperadrenocorticism (HAC) is diagnosed, focus should turn to management. Client education and communication are vital, as clients must monitor for certain clinical signs at home. Successful management often requires a substantial time and financial commitment from clients; however, a decrease in signs can be seen in as little as a few weeks. The following discussion highlights tips for discussing treatment with clients and managing this lifelong endocrinopathy.

Dr. Zimmerman: How do you approach the subject of treatment with clients?

Dr. Lathan: It’s important to emphasize that the goals of treatment for Cushing’s are to control the clinical signs and to prevent negative side effects. I talk to clients about how they are in charge of monitoring their pet and reporting in their journal how the pet is doing at home. Then when they come to see us, we’ll assess that and run tests, mostly to tell us whether the current dose is safe and efficacious or whether we need to adjust it.

Dr. Byers: I usually tell owners there are a lot of therapies available or that have been tried anecdotally, but right now there is only one drug for both pituitary and adrenal-dependent hyperadrenocorticism that has gone through the extensive FDA approval process, and that is VETORYL Capsules. For the vast majority of patients, that is the drug that I recommend as initial therapy. Where my therapy may change from the labeled q24h dosing in the morning to a lower dose q12h is, for example, when I encounter diabetes in a patient. We’ll discuss that it is an off-label use as well as the benefits and potential risks. But, without question, we start with the FDA-approved drug, VETORYL Capsules.

Dr. Lathan: I don’t really discuss mitotane with owners much anymore, primarily because I think that a major benefit of the FDA-approved drug is that it’s a lot easier for clients and referring veterinarians to understand how to use it and monitor the pet. It doesn’t require teaching about how to break therapy into induction and maintenance phases. 

Dr. Wasik: I think veterinarians overall feel more comfortable and safe with trilostane.

Dr. Lathan: Once we have established VETORYL Capsules as the drug of choice, I talk to clients first about dosing. Although the label states starting with once-daily dosing, I feel dogs exhibit regulation more quickly when I start with dosing twice a day. I begin at around 1 mg/kg twice a day. I recognize that the cost of the pills increases when using the drug twice a day: 2 30-mg capsules cost more than one 60-mg capsule. But in the long-term, you’re probably changing the dose less, pursuing less testing, and probably seeing a cost advantage to the point where it all evens out—and we get the patient regulated faster.

We also discuss the side effects. I send clients home with a few doses of dexamethasone oral tablets at 0.1 mg/kg. I tell them that if over the next few days the dog has an episode of vomiting or diarrhea, especially more than once, but is doing okay otherwise, they can call us to make sure they don’t need to come into the hospital. If not, they can give the dexamethasone until our next appointment.

Dr. Wasik: For clients trying to operate on tighter budgets, many dogs will be adequately controlled on the labeled once-a- day recommendation. But there are certain cases, too, where I absolutely want to initiate therapy twice a day: Diabetics and patients with calcinosis cutis tend to do better on twice-a-day dosing. If a client is tending toward euthanasia because he is overwhelmed with the clinical signs and something has to happen right away, twice a day is probably a better idea.

Dr. Byers: There are so many options. Yes, the label dosing frequency is every 24 hours, based on the original FDA study in which 86% of patients completed the study successfully with very happy owners. That’s great, but as with any good therapy, we’ve continued to study it and we have evidence-based data¹ showing a viable option is using a lower-dose, albeit off-label, twice-daily regimen. Anecdotal evidence, similar to published evidence, suggests that dogs actually respond more quickly, to the delight of their owners.

Dr. Lathan: I used to start all patients on once-a-day because my experience was they improved and most clients were happy. Then we started a study that involved giving trilostane twice daily. Patients were relieved of their clinical signs so much faster and dosage changes became less necessary. So now I start them on twice-a-day.

Given that trilostane doesn’t last for 24 hours in the blood, it makes sense that giving it twice a day would work better. But until I saw the clinical change, I didn’t see any point in giving it twice a day because of the cost. I do a 50/50 split between day and night. I’ve heard of people giving a different dose in the morning versus the evening to fit better with the capsule sizes, but patient monitoring should really be after their highest dose.

We ask the owner to call if the dog stops eating or has vomiting or diarrhea. Sometimes within the first couple of days dogs will show a slight decrease in  appetite and maybe vomit once or twice. I tell them to make sure that they contact me if so; then we can decide our next steps. I make sure they understand to contact us if anything emergent is happening.

Dr. Wasik: This is where the critical aspect of a strong technician team comes in. They can be checking in during those first initial days, or a couple of times during the first week, to make sure things are going well. If things are going south, you can intervene sooner rather than later.

Dr. Lathan: I dispense trilostane for 3 weeks and tell clients to come back for a recheck in 2 weeks, and definitely before they run out of medication.

Dr. Byers: I also recheck at 10 to 14 days, at which time they fill out a brief questionnaire, confirming the drug was given that day, that it was given with food, and the time it was given so we can plan a 4- to 6-hour post-pill testing if we are doing the traditional treatment per the FDA label. We also review their journal and obtain a complete patient history and a thorough physical examination. We re-evaluate electrolytes and the biochemical profile. We do have patients come in fasted, with the exclusion of the food they receive with their VETORYL Capsules dose. We evaluate only a post-ACTH stimulation cortisol level as a cost-saving measure.

Dr. Zimmerman: The VETORYL Capsules package insert says the ACTH stimulation test should be done 6 hours after administration. A study by Audrey Cook² examined basal cortisol after the medication, and then a recent UK publication looked at basal cortisol before the medication was given. What are some pros and cons of those methods?

Dr. Lathan: Measuring the pre-pill cortisol makes sense in that if the value is above our concern range (eg, >2 µg/dL) and the patient is doing great otherwise, then I think it’s logical that we can continue with the current dose. If the pre-pill cortisol is <2 and the dog is doing great, I think an ACTH stimulation test is needed. The benefit of the pre-pill cortisol is it takes less time and it’s less expensive. The caveat: You cannot identify iatrogenic Addison’s based on its results.

In addition, there are some dogs that may have consistently lower pre-pill cortisols but their post-stim cortisol results are fine. Pre-pill cortisol is probably most useful in patients whose HAC has been successfully controlled and that are undergoing 6-month monitoring. We then know the patient is doing well clinically on the current dose; we just need to determine whether continuing is safe.  

I tell referring veterinarians to, for the first few ACTH stimulation tests, have patients come in first thing in the morning (before their dose) and collect blood for a pre-pill cortisol. Then give VETORYL Capsules with food, start an ACTH stimulation test 3 hours after giving VETORYL Capsules, and submit all 3 samples together because 3 samples of cortisol are not much more expensive than 2. They can then look at the trends and see if they would have done anything different based on the pre-pill value. That helps people get more comfortable with actually using the test. 

Dr. Byers: Obviously when we’re talking about an FDA-approved drug used in an off-label fashion, we tell owners that and ideally have them sign an informed consent. When you’re using pre-pill cortisol levels or alternative monitoring strategies, not the ACTH stimulation test, which is the label recommendation, how does that conversation go with your clients? 

Dr. Lathan: I tell owners and residents that the normal monitoring test can be used, but it takes a bit of time and costs $200 or more. We have begun monitoring a steroid, a cortisol concentration, before your dog gets the medication to see if that tells us that it’s safe to continue the medication. There haven’t been many studies on this yet, but especially if you are having a hard time affording all the testing and the medication together, then this is a way that we can try to decrease the expense and still regulate your dog. There are some pitfalls to this approach, and sometimes we need to do an ACTH stimulation test anyway, but I think this works in the majority of patients.

Dr. Zimmerman: Any other thoughts on monitoring tests?

Dr. Lathan: The most frequent question I get from veterinarians is, “Do we really have to monitor?” Yes, we have to monitor in some way. I understand that people have financial constraints, but we first must do no harm. If we continue a dog on medication that might be resulting in Addison’s and we haven’t monitored it, we are morally and legally liable. 

Dr. Wasik: But here’s the great news. We’ve got multiple modalities by which we can safely monitor most patients: ACTH stimulation, pre-pill cortisol levels, basal cortisol levels. Work with the client to figure out what’s possible. If they’re not able to do any objective monitoring or close monitoring of resolution of clinical signs, they should not be giving the drug. 

Dr. Lathan: There are different ways that a patient can develop Addison’s when on trilostane. The first is because trilostane inhibits cortisol production excessively. In these situations, it’s usually temporary: You stop the medication, wait for the clinical signs of HAC to return, ideally measure cortisol prior to restarting the medication at a lower dose, and continue monitoring as usual long-term.

Dr. Zimmerman: When you get your post-ACTH stimulation result after the first dose of trilostane, what is your expectation and next step?

Dr. Lathan: I want to make sure the dog is not Addisonian. The key is making sure that it’s safe to continue. If at the 2-week mark it were below even 2.5 µg/dL, I would probably be nervous because trilostane should have even more effect at 4 weeks at the same dose, so I would worry that at 4 weeks we would bottom out. That isn’t always the case, but it is a worry. 

Also, look at clinical signs and specifically ask the owner about water intake and urination. I don’t necessarily change the dose even if it is higher than my ideal stimulation number (2-6 µg/dL). But if it’s 10 at 2 weeks, there is a good chance it will continue coming down. If it’s 20 at 2 weeks, I might increase the dose. 

Dr. Wasik: It depends what’s going on clinically. If the dog is dramatically improved, then I’m not so worried about a 20. My preferred cortisol concentration range for dogs with controlled signs is 2 to 6 µg/dL pre- and post-ACTH stimulation.

Dr. Lathan: It also depends on the owner. If he or she is very attentive, you are less worried about a 3.

Dr. Wasik: My sweet spot is approximately >2, <6 at the 2-week mark. 

As to clinical signs, patients should be more active. They look like they feel better. The owners perceive that there is a definite improvement, whether in PU, panting, or overall.

Dr. Lathan: Certain patients that are doing better clinically still have PU/PD and are not well controlled. If so, we would increase the dose. But if we just heard it’s doing great we would not. Each clinical sign is really important.

Dr. Zimmerman: So the report from the client is that the patient is doing well with no adverse effects. If you’re happy with the cortisol results, what’s your next step?

Dr. Byers: Repeat the process another month. If all continues to go well, review the patient’s journal, get a patient history, perform the examination, re-evaluate chemistry and electrolytes, and run a post-ACTH stimulation cortisol level. 

Dr. Lathan: I often have them come back 2 weeks later, but I’m fine with 2 to 4 weeks after the initial recheck. 

Dr. Byers: The more important point in terms of when you have them return is anytime you do decide to make a change to the VETORYL Capsules dose, see them in 2 weeks. One reason for this is that I want the family to report that there has been an improvement in the clinical signs. But I also want to see the ACTH number to help me gauge if it’s safe to make a dosage adjustment. Clinical signs help me decide whether treatment is effective; the number helps me know whether making needed adjustments is safe. 

Dr. Zimmerman: When you do decide to make a dosage adjustment, even if it’s a rare event, what is your typical increase and what do you expect from it?

Dr. Lathan: It depends on 3 things: 1) how bad are the clinical signs, 2) how much are they driving the owner crazy, 

1. how high is the pre-pill or post-ACTH stimulation cortisol. If the ACTH value is 8 to 9, maybe a 15% to 20% increase. If the ACTH value is 20, then I might do a little bit more. Pill size is a guiding factor in the adjustment. If I can change to get just one pill twice a day, that would be optimal. 

Dr. Wasik: My dose reductions are typically just dropping down a capsule size. I’ve not found this to be too dramatic clinically. I’m a bit more cautious when ramping up the dose. I’ll usually increase the daily dose or one or both of the doses if giving it twice daily by 5 to 10 mg per administration. I’m comfortable taking a dog on 60 mg once a day down to 30 mg if I’m worried I may be pushing too hard with respect to how the cortisol values are trending. How the dog is doing clinically and the cortisol values (emphasis on clinical signs) help me decide. A lot of it is more an “art” than a “science.” From a cost-savings standpoint, I’ve become comfortable just decreasing down to the next pill size, as many dogs I see are still controlled with a 50% dose reduction. Obviously, everyone is less worried about causing a crisis when decreasing the dose versus increasing the dose.

Dr. Byers: It’s important that the decision is based on the individual patient and not on cost. I bring this up because I know many colleagues would reach for a compounded formulation here to save money. While I can appreciate that, it’s just not acceptable.

Dr. Zimmerman: Tell me a little bit more about your thoughts and understanding of compounded trilostane.

Dr. Byers: I am not anti-compounding. I don’t think a veterinarian today can be anti-compounding, but one should follow compounding best practices. One of those is simply a straight up fact: that as a veterinarian no one should compound to save money—period. 

If one feels that absolutely an 18.5-mg capsule or a liquid formulation is needed because perhaps an owner is at risk for being bitten and they have immunosuppressive disease themselves, then the compounded formulation should be from the FDA-approved drug, not from the active pharmaceutical ingredient. 

If you are using a compounding pharmacy, clients must understand the compound is not a generic drug and that the pharmacy should be approved by the Pharmacy Compounding Accreditation Board. I would never work with a non-accredited pharmacy.

Dr. Lathan: Compounded trilostane from bulk chemical is less consistent, and even though it might be less expensive initially, if you have variations in regulation and you have to keep changing the dose, then that is not less expensive in the long run.

Dr. Zimmerman: Are there any other points you can share about monitoring VETORYL Capsules therapy?

Dr. Lathan: We look to clinical signs to decide whether we need to increase the dose. Then we need to use a cortisol monitoring technique to determine whether it’s safe at the current dose and an increase is safe. 

Dr. Wasik: Trends are important, too. Have cortisol values been consistently 1 to 3 for 6 months, or is this the first 1 to 3 result you are seeing? And what’s the overall picture? How’s the dog doing? What is the history? It’s putting all the pieces of the puzzle together versus just trying to make a decision based on one single data point.

Dr. Zimmerman: What are some of the conversations that you have with the client as the dog is being treated? Do they report a noticeable difference in the dog? Do they see the value of the diagnostic procedures and treatment?

Dr. Lathan: The biggest thing that I have reported is the degree of PU/PD. But several have definitely noted that their older dog, who they thought just didn’t play with toys anymore because of age, is playing again, or who would stay right beside the owner during walks previously will now wander off more energetically and show interest in the surroundings. One of my friends actually said that in hindsight she was pretty certain that her dog had been depressed, which is interesting because it is such a common finding in people that have HAC. 

Dr. Byers: The difference clients see in pets is very important. I’ve had many pet owners tell me that they had started to resent their dog from always having to fill the water bowl, clean up urinary accidents, return to my office repeatedly for various problems, be woken during the night by the dog’s panting. 

All that stops once therapy is initiated. The bond between owner and dog is restored. They don’t care about having to give the pet medication; they actually look forward to doing it because the annoyances have stopped. It is an overall positive experience for owners. 

Dr. Lathan: When owners come in the first time, you can tell they are at wit’s end. They love their dog, but they are not the most enthusiastic. But when the clinical signs have improved, you can just tell they are happier people overall. No more sleep deprivation! 

Dr. Byers: In some dogs, it takes 4 to 6 weeks to start seeing improvement. Those clients are a bit grumpier about having to go through the whole process. With lethargy, just about anything can cause it, so it does not always respond to treatment. But improvement in activity, responsiveness, and interaction with the family coupled with reduced panting makes for a happy client.

Dr. Zimmerman: How quickly do owners report a change in polyuria and panting?

Dr. Wasik: Usually pretty quickly, within a week or 2. The panting seems to respond most quickly in my experience, followed by lethargy. PU may take a bit longer. 

Dr. Lathan: I would say exactly the opposite. I feel the PU/PD and attitude improve within the first 2 to 4 weeks, whereas the panting takes a month or 2 to really get under control.

Dr. Zimmerman: Could that be related to their weight? Is the panting worse in severely obese dogs, and does it improve as they start losing weight?

Dr. Lathan: There is more panting in the more obese dogs. The answer to whether it gets better as they lose weight is kind of difficult because they are losing weight as they have more treatment, so I don’t know whether it’s the weight loss or the treatment itself.

Dr. Zimmerman: What do you tell clients about how long it’s going to take for their dogs to start to feel better with treatment?

Dr. Byers: Effective treatment requires the owner to be an active participant. I need owners to keep a journal because what they record and bring to me at each recheck is just as important as a number on paper. In general, I want the panting, lethargy, and PU/PD to no longer be an issue within 8 to 12 weeks. I do tell them that some dogs will see unusual improvement within 2 weeks, and that is supported by the initial FDA trial of VETORYL Capsules, but I try not to set unrealistic expectations. For dermatologic manifestations, I set an expectation of 4 to 6 months.

Dr. Lathan: I tell clients to expect at least 6 months for dermatologic resolution to begin. In general, I tell them not to expect any significant changes in any sign for at least a month. Then they are pleasantly surprised if something happens in a week or 2. 

I agree about keeping a journal. Monitoring clinical signs is more important than numbers, as long as the numbers are in a safe range. For that reason, I think it’s really helpful to have clients fill out a questionnaire regarding the severity of the clinical signs at every visit. Then you can show them the difference over time. 

Dr. Byers: Clients like to keep the journal. They feel that they are an active participant in their pet’s care. 

Dr. Lathan: They do enjoy doing the journal! Those who are most engaged in their pet’s treatment and progression like it best.

Dr. Zimmerman: What are some of the most common concerns that pet owners voice about therapy for HAC?

Dr. Wasik: That they are going to kill their dog with therapy. Because of Dr. Google or Facebook groups, they have some information and seem to be scared to treat before they even walk in the door. 

Dr. Lathan: I find it helps to explain that we are using lower doses of trilostane these days than is reflected in many consumer sources.

Dr. Zimmerman: We talked about recurrent infections. How do you handle such secondary conditions, and what expectations do you set for the client?

Dr. Wasik: Although usually less likely in the age group that develops hyperadrenocorticism, if T4 levels remain low despite improvement in clinical signs, particularly if hair is not growing back to the owner’s satisfaction, screening further for hypothyroidism may be appropriate. I generally instruct veterinarians to suspend any thyroid testing until we get the HAC under better control. I try to be minimalistic with regard to systemic antimicrobials during that time, which helps in preventing development of methicillin resistance. Then if 3, 4, 5 months down the line we are still having some dermatologic problems or the hair is not growing and the T4 is still low, I consider a more extensive profile, especially if any hypercholesterolemia isn’t improving either. 

Dr. Lathan: In patients with dermatologic signs, especially if they have infections or atopy on top of that, I sometimes think that the excess cortisol has been decreasing the inflammation, so when you start treatment, they may have exacerbation. We need to warn owners about this phenomenon and then come up with a treatment plan for those affected. I usually consult with our dermatologist.

Dr. Zimmerman: Do you ever find in dogs with recurrent infections that once the hyperadrenocorticism is stabilized the infection responds as expected to topical or systemic therapy?

Dr. Byers: Yes. I see more UTIs than bacterial pyoderma. With effective management of hypercortisolemia, the recurrence of UTIs is dramatically reduced. You will have patients that develop a hardy biofilm in the urinary bladder, and those are more challenging. But, at least in my experience, that has not been common. 

Dr. Wasik: I don’t know if the infection is eradicated. But instead of an incident every couple of months, maybe the dog has a couple per year.

Dr. Zimmerman: Are there any other pitfalls that can occur beyond just monitoring for this disease? When you are treating the patient for other things that come up in its life, like common drug interactions or otherwise?

Dr. Byers: If you are dealing with a concurrent endocrine combination like Cushing’s and diabetes, you have to prepare the client for the inevitability that the patient’s insulin requirements are going to drop—and if you don’t prepare them and empower them with tactics to address it, or if you just keep the insulin dose the same as you are addressing the hypercortisolemia, prepare the team for an iatrogenic hypoglycemic event. I ask them to monitor urine glucose on a daily basis around the same time of day and I give them guidelines by which to adjust their insulin dose.

Dr. Zimmerman: What do you see more commonly: the diabetic who then gets Cushing’s, or the Cushing’s who then becomes diabetic?

Dr. Lathan: I feel like we definitely see both of them. They were probably cushingoid before we diagnosed the diabetes as well. I don’t think it’s that Cushing’s came afterwards—I think the Cushing’s had been there all the time. 

One drug side effect to note is with ketoconazole: You do not want to give ketoconazole concurrently with trilostane, as this can precipitate hypocortisolism.

Dr. Zimmerman: Many of these patients are also overweight and they tend to have a lot of abdominal fat. Do you ever recommend a weight loss diet or a diet change?

Dr. Lathan: I try to prescribe a metabolic and mobility diet for every single one.

Dr. Byers: I take a more human–animal bond approach. If an overweight or obese human’s physician tells her to get more exercise, the likelihood of her doing so is low. If you tell her that her dog needs to lose weight and needs to achieve at least 30 minutes of exercise per day so the dog loses weight, she is going to do it. I counsel to increase their activity level and feed 5% to 10% less per day (and help them with a calculation), but I don’t change the diet. 

Dr. Lathan: Some of these dogs also have joint disease. We start treating them for Cushing’s, and their joint disease can worsen because the anti-inflammatory effects of cortisol are decreased, so I use a metabolic and mobility diet with other joint supplements, which, to me, is an ideal combination. 

Dr. Byers: I’m always hesitant to change diets because I’m concerned the patient is going to develop food aversion. However, a potential negative effect of my approach includes a regular comment of, “She’s just staring at me. She wants the food.” We encourage clients to use that time to further enhance the human–animal bond: Go do an activity with the pet and get food off the mind. Now they’re getting more exercise, expending more calories, and, theoretically, improving the bond.

Dr. Zimmerman: Are there any major developments other than necrosis that you see when you’re treating dogs with Cushing’s?

Dr. Byers: We make sure that we use the term lifelong therapy. The perception of many owners is, “Now that my pet is back to normal, I don’t need to continue the medication,” and they just stop it. They then typically come back in pretty quickly.

Dr. Lathan: I have learned, with all endocrinopathies, not to micromanage or rely so much on the numbers and to put the focus back on treating patients, addressing clinical signs, and monitoring to avoid causing harm. If the clinical signs are well-controlled, even if the number is a little higher than the norm, don’t adjust the dose.

HAC = Hyperadrenocorticism, PD = Polydipsia, PU = Polyuria, UTI = Urinary tract infection