Managing Addison's Dogs with Concurrent, Uncontrolled Diabetes

I have a 10-year old male Terrier dog named Scooter who now weighs in at 11 pounds (5 kg). He was originally diagnosed diabetes mellitus that we could not get regulated with Vetsulin, even at doses as high as 8 units twice daily. 

Scooter was subsequently diagnosed with with pituitary-dependent Cushing's disease and was treated with mitotane (Lysodren). Once we got the Cushing's disease under control, his daily insulin requirements fell to 3 units twice a day, and the diabetes was well regulated based on glucose curves done at my vet's hospital. However, after a few months of treatment with mitotane, it was apparent that Scooter had been severely overdosed with the medicine, which resulted in complete adrenal insufficiency and threw him into a severe Addison's crisis. It was a near death experience for him, but he has pulled threw and is now doing much better off of the mitotane and on treatment for his iatrogenic Addison's disease. 

Now we have spent the last 3 months trying to stabilize his iatrogenic Addison's disease and concurrent diabetes. Currently, he is on 2.5 mg of fludrocortisone (Florinef) twice day along with 1.25 mg of prednisone twice daily. The Florinef dose has had to be gradually increased to keep his serum electrolytes (sodium and potassium) within their proper ratio and ranges. Based on his last blood test, we may have to increase it yet again, since his serum potassium remains slightly high. 

To make matters even worse, his diabetes is now completely out of control, as evidenced by his intense thirst and excessive urinations with heavy amount of glucose in the urine. Serial blood glucose monitored done at my veterinarian's clinic confirms that the blood glucose readings remain very high throughout the day. We have gradually increased the insulin dose back up to 7 units twice daily, but it just doesn't seem to be working at all at this point. 

What do you recommend that I do? We need to get the Addison's disease controlled but as we have raised the doses of the Florinef and prednisone, Scooter's diabetes is getting worse! My vet has suggested that I transition Scooter from the Florinef tablets to Percorten injections in order to stabilize his serum electrolytes. He also told me that the Florinef contains some steroid activity which may be contributing to his high insulin doses.  Is the steroid in Florinef any less hard on him than the prednisone?   

Any advice would be greatly appreciated. 

My Response: 

With Scooter, we need to address both his poorly-regulated Addison's disease and his uncontrolled diabetes, as well as the increased thirst (polydipsia) and urination (polyuria). There is a lot going on with Scooter, so let's take one problem at a time.

Mineralocorticoid replacement: Florinef vs. Percorten-V? 
For mineralocorticoid replacement for dogs with Addison's disease, either oral fludrocortisone acetate (Florinef) or injectable desoxycorticosterone pivalate (DOCP; Percorten-V) can be used successfully (1-3).

In your dog, however, I would definitely make the switch to Percorten-V. Some dog's just don't respond very well to treatment with Florinef, and it's not uncommon for dogs to require increasing doses of daily Florinef over time to control the serum electrolyte concentrations (1-3). With high doses of Florinef, this can lead to signs of increased thirst and urination, and may also lead to problems with management of diabetes, as you are seeing in Scooter.

Since you are having problems controlling the serum electrolytes, I'd recommend starting with the label dose of 2.2 mg/kg, injected every 25-30 days (4). If this drug works to stabilize the serum sodium and potassium levels (and I expect that it will), then we can try to gradually lower the Percorten dosage after a few weeks to months (e.g., I generally try reducing the dose by 10% or so each month). Many dogs will maintain normal serum electrolyte levels on doses between 1-1.5 mg/kg per month, and a few will even need less (1,5).

Glucocorticoid supplementation in Addison's disease
Now let's next turn to your dog's glucocorticoid needs. Dogs with Addison's disease, either spontaneous or iatrogenic (that is, drug-induced, as it was in Scooter), will require replacement glucocorticoids (e.g., prednisone or prednisolone) in addition to the mineralocorticoid supplementation (1-3). Some dogs will do fine without any glucocorticoid supplementation, but the vast majority of dogs will feel better with a small daily dose of glucocorticoid administered daily. Since we know that these dogs cannot secrete normal amounts of cortisol, it certainly makes a great deal of sense to use low-dose glucocorticoid replacement.

Unfortunately, many dogs with Addison's disease are treated with too much glucocorticoid. Remember that our goal with glucocorticoid supplementation is to provide the same amount of steroid that the dogs would normally produce if their adrenals had not failed.

For dogs, the daily glucocorticoid maintenance dose for prednisone is only 0.1-0.2 mg/kg/day (3), so that calculates out to only 0.5-1.0 mg per day for Scooter, quite a bit lower that what you are currently giving (2.5 mg per day). That would certainly be enough to cause an increased thirst by itself, but would also contribute to glucocorticoid-induced insulin resistance, making the diabetes uncontrollable despite the higher insulin doses.

Therefore, we should try to lower the prednisone dosage first down to 1.0 mg once daily (or divided). If he is doing well clinically (i.e., normal appetite and no vomiting), then the dose can be lowered even further, down to 0.5 mg per day. Prednisone or prednisolone are available in 1-mg tablets, as well as an oral solution, making it possible to administer these smaller dosages (6,7).

Florinef also contains significant glucocorticoid activity
In addition to the fact that Addison's dogs are commonly overdosed with prednisone, it's very important to realize that fludrocortisone acetate also possesses moderate glucocorticoid activity, as well as having marked mineralocorticoid potency (2,3). By comparison, fludrocortisone has 10-times the glucocorticoid activity and 125-times the mineralocorticoid activity of cortisol, the glucocorticoid hormone secreted by the adrenal gland. In this regard, fludrocortisone is very different than Percorten-V, which possess no glucocorticoid activity (2,3).

For the dog with Addison's disease, a glucocorticoid is a glucocorticoid —it makes no difference to Scooter if this glucocorticoid activity comes from prednisone or from the Florinef.  This potent glucocorticoid activity of fludrocortisone explains why some dogs will develop polydipsia and polyuria, common side effects associated with higher-dose glucocorticoid treatment in dogs (8). This is another reason why we need to get Scooter off of the Florinef and switch to the Percorten-V.

Glucocorticoid-induced insulin resistance
In all likelihood, the reason for Scooter's poorly controlled diabetes is related to insulin resistance associated with glucocorticoid excess (9,10). By stopping the Florinef and providing mineralocorticoid replacement with Percorten-V instead, we will remove one source of excess glucocorticoid. Lowering his daily prednisone dose will also help.

As we remove the cause of the insulin resistance, the dose of insulin will again fall. You should monitor Scooter closely during this period to ensure that insulin overdosage and hypoglycemia do not occur, and lower the insulin dose as needed.

Don't forget to rule out urinary tract infections
Finally, don't forget that diabetic dogs, no matter what the cause, will commonly develop urinary tract infections. Think about it: a bladder full of sugar-laden urine is a perfect breeding ground for bacteria to thrive! Such urinary tract infections will also commonly contribute to insulin resistance (9,10) but can also lead to kidney failure, if the infection ascends from the bladder up to the kidneys.

For this reason, I always recommend checking a complete urinalysis and urine culture in all dogs (and cats) with insulin resistance. However, even if the diabetes is well-controlled, I still recommend doing a urinalysis with culture twice yearly in all of my diabetic patients.

References: 

1. Kintzer PP, Peterson ME. Treatment and long-term follow-up of 205 dogs with hypoadrenocorticism. J Vet Intern Med 1997;11:43-49. 
2. Church DB. Canine hypoadrenocorticism In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Fourth ed. Quedgeley, Gloucester: British Small Animal Veterinary Association, 2012;156-166.
3. Kintzer PP, Peterson ME. Canine hypoadrenocorticism In: Bonagura JD, Twedt DC, eds. Kirk's Current Veterinary Therapy, Volume XV. Philadelphia: Saunders Elsevier, 2014; pp 233-237.  
4. Lynn RC, Feldman EC, Nelson RW. Efficacy of microcrystalline desoxycorticosterone pivalate for treatment of hypoadrenocorticism in dogs. DOCP Clinical Study Group. J Am Vet Med Assoc 1993;202:392-396. 
5. Bates JA, Shott S, Schall WD. Lower initial dose desoxycorticosterone pivalate for treatment of canine primary hypoadrenocorticism. Aust Vet J 2013;91:77-82. 
6. Peterson ME: Treating small-breed Addison's dogs with low doses of prednisone or prednisolone. Animal Endocrine Clinic blog, December 14, 2013. 
7. Plumb, DC. Plumb's Veterinary Drug Handbook. Seventh Edition, Wiley-Blackwell. 2011.
8. Melián C, M. Pérez-Alenza, D, Peterson ME. Hyperadrenocorticism in dogs, In: Ettinger SJ (ed): Textbook of Veterinary Internal Medicine: Diseases of the Dog and Cat (Seventh Edition). Philadelphia, Saunders Elsevier, 2010;1816-1840.
9. Hess RS. Insulin resistance in dogs. Vet Clin North Am Small Anim Pract 2010;40:309-316. 
10. Peterson ME. Diagnosis and management of insulin resistance in dogs and cats with diabetes mellitus. Vet Clin North Am Small Anim Pract 1995;25:691-713.  

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