Friday, April 4, 2014

Insulin Injection Pen (VetPen): More Questions (and Answers) about this New Diabetic Product



Since the FDA approved the use of a new insulin injection pen (VetPen) made by Merck Animal Health last week (1,2), I've received a number of questions from both veterinarians and owners of diabetic pets. Listed below are some of the most common questions with my responses.

Do we buy a single VetPen and use it forever? Or does the VetPen have to be replaced after a month or two?

The VetPen has been tested for at least 3,000 actuations (i.e., how many times the insulin release button is pressed and released). Therefore, a single VetPen is likely to last a lifetime for the majority of dogs and cats treated with diabetes.

How are the pens and cartridges sold? 
The reusable VetPen is supplied in a Starter Kit which contains everything you need to get started (see below). This included everything except the Vetsulin cartridges, which are supplied separately in cartons of ten, 2.7-mL cartridges.

The VetPen itself is available in 2 sizes. For greater accuracy at low doses, the first option (blue cap) has a maximum total dose of 8 units, allowing for dosing increments of 0.5 unit per injection. If higher insulin doses are being administered, the second VetPen option (tan cap) has a maximum total dose of 16 IU per injection, with dosing increments of 1 unit.

What is in each VetPen Starter Kit?
Each Starter Kit contains either an 8-unit or 16-unit VetPen with an instruction leaflet.

The kit also contains a box of 28-g, ultra-thin needles that feature a silicone coating to help minimize injection discomfort, as well as a needle remover that helps to remove used needles, while minimizing the risk of accidental needle stick injury. There is also a travel pouch to hold all of the components.

The kit also contains two adaptors to assist those with dexterity issues. The dose selector adaptor may be used to provide a better grip when selecting a dose. The release button extension may be used to provide a better grip when giving injections.

Are the VetPens an accurate way for insulin dosing?
The VetPen is ideal for cats and small dogs on low doses of insulin, in which dosing accuracy can be a concern (3,4). A recent study comparing the precision and accuracy of the VetPen to U40 syringes demonstrated that even when doses were drawn up by trained laboratory technicians, syringes were found to deliver at least 20% to 25% more insulin than needed for a 1-unit dose (5).

In contrast, VetPen enables doses to be delivered with accuracy and precision down to 0.5 units. In large dogs, dosing accuracy is generally not a problem.

Do the pens and cartridge need to be refrigerated? Other handling precautions?
The VetPen cartridges should be refrigerated (not frozen) and protected from light before opening.

VetPen does not need to be refrigerated after a cartridge has been started (4), although it probably is best to do so. The loaded VetPen can be stored on its side in the refrigerator.

VetPen should always be stored or carried with the needle removed and the cap on. To clean the device, wipe with a damp cloth. Do not immerse in water.

Are the VetPens expensive? How would the costs of the VetPen compare to those associated with the standard insulin vial/syringe method?

The cost of treatment will depend upon the size of the diabetic pet. For smaller dogs and cats, the price of the VetPen with the Vetsulin cartridges and needles will be similar to the cost of the standard 10-mL Vetsulin vial and U-40 insulin syringes.   For larger dogs, the standard way of administering Vetsulin (via an insulin syringe) would generally be a more economical way to provide insulin treatment.

Bottom Line:

These insulin pen devices are an alternative to the traditional insulin vial-and-syringe method and offer many advantages. In human diabetic patients, insulin pens have also been found to be less painful than the vial-and-syringe method and are often associated with greater patient preference and social acceptability (6-11).  Similar preliminary findings have been documented in dogs and cats (12,13). As a result, this method of insulin delivery may ultimately help to improve glycemic control and should be considered as an alternative insulin delivery method.

Insulin pens are designed to deliver a fixed insulin dose while insulin syringes rely on the ability of the user to accurately draw up the required insulin dose. One recent study reported that for low doses (below 8 units), the VetPens were more precise and accurate than the insulin syringes (5). In particular, insulin syringes tend to over-deliver, compared to the insulin pen, for very low doses (1 unit). For higher doses (16 units), both devices were comparable (5).

Similar findings have been reported in human pediatric patients, in which very low doses of insulin must be administered. One older study looked at the reliability of using U100 syringes for accurately administering low doses of insulin in the hospital by pediatric nurses. In that study, attempts to administer doses of 0.5 U or 1.0 U of U-100 insulin resulted in overdosage of 95% and 66%, respectively (14). Based on this study, it's no wonder that small diabetic dogs or cats are often a challenge to regulate when small insulin doses are needed.

References: 
  1. FDA website. FDA Approves First Insulin Product for Use with Automatic Injection Pen in Cats and Dogs.
  2. Press release. Merck Animal Health Receives FDA Approval of VetPen  
  3. Merck Caninsulin website. Caninsulin® VetPen® helps make pet diabetes management easier 
  4. Pet Diabetes website. What you need to know about the Caninsulin VetPen
  5. Burgaud S, Riant S, Piau N. Comparative laboratory evaluation of dose delivery using a veterinary insulin pen. Proceedings World Congress ASAVA/FECAVA/BSAVA 2012;567.
  6. Molife C, Lee LJ, Shi L, et al. Assessment of patient-reported outcomes of insulin pen devices versus conventional vial and syringe. Diabetes Technol Ther 2009;11:529-538. 
  7. Pearson TL. Practical aspects of insulin pen devices. J Diabetes Sci Technol 2010;4:522-531. 
  8. Wright BM, Bellone JM, McCoy EK. A review of insulin pen devices and use in the elderly diabetic population. Clin Med Insights Endocrinol Diabetes 2010;3:53-63. 
  9. Cuddihy RM, Borgman SK. Considerations for diabetes: treatment with insulin pen devices. Am J Ther 2013;20:694-702. 
  10. Davis EM, Foral PA, Dull RB, et al. Review of insulin therapy and pen use in hospitalized patients. Hosp Pharm 2013;48:396-405. 
  11. McCoy EK, Wright BM. A review of insulin pen devices. Postgrad Med 2010;122:81-88. 
  12. Burgaud S, Guillot R, Harnois-Milon G. Clinical evaluation of a veterinary insulin pen in diabetic cats. Proceedings World Congress ASAVA/FECAVA/BSAVA 2012;499.
  13. Burgaud S, Guillot R, Harnois-Milon G. Clinical evaluation of a veterinary insulin pen in diabetic dogs. Proceedings World Congress ASAVA/FECAVA/BSAVA 2012;568.
  14. Casella SJ, Mongilio MK, Plotnick LP, et al. Accuracy and precision of low-dose insulin administration. Pediatrics 1993;91:1155-1157. 

Wednesday, March 19, 2014

FDA Approves First Insulin Automatic Injection Pen for Diabetic Dogs and Cats

VetPen, for use with Vetsulin (in USA) and Caninsulin (outside USA)
The U.S. Food and Drug Administration (FDA) has approved the first insulin injection pen (VetPen, Merck Animal Health) for diabetic cats and dogs, the agency announced today, March 19, 2014 (1).

2 Sizes of VetPens
The VetPen may now be used to administer Vetsulin insulin cartridges, also made by Merck Animal Health. The refillable VetPen automatically measures the prescribed insulin dose and provides the owners of diabetic dogs and cats with an additional option for insulin delivery.

There are two sizes of refillable VetPens. One (tan cap) dispenses insulin doses from 1-16 units per dose in full unit increments. The other (blue cap) dispenses 0.5-8 unit doses in full or half unit increments. Both pens use 2.7 ml insulin cartridges which hold a total of 108 units (IU) of U-40 Vetsulin (or Caninsulin).

Vetsulin is an FDA-approved insulin for use in dogs and cats (2). This insulin is identical to Caninsulin, the brand name of the insulin sold in Europe (3).

Merck said the VetPen is easier to dose and administer and is more accurate than traditional delivery systems, such as syringes and vials (4). “For years, insulin pens have made managing diabetes more convenient for human diabetics,” the company said. “Merck Animal Health has now brought the same technology to veterinary medicine.”

An informational website (2) provides tools for both veterinarians and pet owners to make managing pet diabetes easier. More online information about the VetPen can also be found on the Caninsulin website (5); the Pet Diabetes website has an informational brochure that can be downloaded (6).

Administering insulin to a cat with the VetPen
For questions on how to obtain Vetsulin or the VetPen, please contact Merck Animal Health Customer Service at 800-521-5767.

References: 

  1. FDA website. FDA Approves First Insulin Product for Use with Automatic Injection Pen in Cats and Dogs.
  2. Merck Vetsulin website. www.vetsulin.com
  3. Merck Caninsulin website. www.caninsulin.com
  4. Press release. Merck Animal Health Receives FDA Approval of VetPen  
  5. Merck Caninsulin website. Caninsulin® VetPen® helps make pet diabetes management easier 
  6. Pet Diabetes website. What you need to know about the Caninsulin VetPen

Wednesday, March 12, 2014

What's the Best Insulin for Treating Dogs with Diabetes Mellitus?

I am writing you regarding my 11-year old male Weimaraner, Duke. He has always been in good health but over this past week he has had 2 ”accidents” where he has urinated in the bed. He has also been drinking a lot more water than usual and urinating more too.

I  took him to the vet because I had a feeling he might be diabetic. My veterinarian confirmed that it was indeed diabetes mellitus and started him on 10 units of NPH, once after breakfast and once after dinner.  He has improved since starting the insulin, but remains quite thirsty and continues to urinate excessively.

Now I know that this will not give very good control alone because NPH is only a long-acting insulin. I am a Type 1 diabetic, diagnosed when I was 12 years old, so I have quite a bit of experience dealing with this disease. I want my poor puppy to be as controlled as possible so he does not feel like I do when my sugars are out of control— lethargic, nausea, headaches, unquenchable thirst, urinating all the time, and just plain crappy! Not to mention the stress this puts on the on the rest of the body.

If dogs are anything like people, I believe that Duke needs an insulin mixture that will bring his blood glucose down to normal and keep it leveled out. I have been giving him the rapid-acting insulin analog Humalog (insulin lispro) along with the NPH and that seems to be working really well, with marked improvement in his thirst and urination.  The only problem is that he needs 4-6 injections of Humalog each day. I was hoping you have had experience with something that would give him the same control as Humalog but with less injections daily.

In the past, I have used short-acting Regular insulin (before Humalog was invented) but I do not remember how the dosing went. I do have much better control with the Humalog but I am also on an insulin pump, so NPH insulin is no longer necessary.

Any help you can give to allow my dog Duke better control long term without so many injections would be greatly appreciated.

My Response:

In dogs, veterinarians commonly start with an intermediate-acting insulin (NPH or Vetsulin) twice a day (1,2). In some dogs, I find it necessary to add a short-acting insulin to the longer-acting insulin preparation, but many dogs can achieve adequate glucose control without giving more than 2 injections per day.

Insulin of choice for canine diabetics
In my opinion, the insulin of choice for most dogs is Vetsulin (porcine insulin zinc suspension; Merck Animal Health) (3). The main advantage of Vetsulin (known as Caninsulin outside the USA (4), is that it is actually composed of both short- and long-acting insulin components (see Figure below, showing the duel peaks of activity) (5,6). So giving Vetsulin is like administrating NPH together with a second, short-acting insulin preparation, like you are doing now.  However, Vetsulin works better than NPH for most dogs because it has a longer duration of action than NPH.

Timing of meals and insulin injection
The short-acting amorphous fraction of the Vetsulin, which composes 35% of the insulin activity, acts like regular insulin or Humulog, mainly to control the rise in blood glucose after each meal (6).  To help prevent severe rises in glucose after meals, however, it is also important to give the insulin before meals, instead of after the food is ingested, as you are doing now. This protocol will allow the short-acting insulin to be absorbed into the blood stream and ready to act to lower the blood sugar as soon as the food is absorbed from the gastrointestinal tract (7).

The only time I don't do this insulin-feeding protocol is in dogs that don't always eat their meal well; but even in those dogs, I never wait long after the meal is finished to give the insulin. Instead, I always give the insulin injection as soon as possible, once the dog has eaten a sufficient amount of food.

Vetsulin (porcine insulin zinc suspension), with it's 2 peaks of insulin activity

References:

  1. Nelson RW. Canine diabetes mellitus In: Ettinger SJ, Feldman EC, eds. Textbook of Veterinary Internal Medicine: Diseases of the Dog and Cat. Seventh Edition ed. St. Louis: Saunders Elsevier, 2010;1449-1474.
  2. Davison LJ. Canine diabetes mellitus In: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. Fourth ed. Quedgeley, Gloucester: British Small Animal Veterinary Association, 2012;116-132.
  3. Vetsulin website. www.vetsulin.com 
  4. Caninsulin website. www.caninsulin.com
  5. Monroe WE, Laxton D, Fallin EA, et al. Efficacy and safety of a purified porcine insulin zinc suspension for managing diabetes mellitus in dogs. J Vet Intern Med 2005;19:675-682.
  6. Fleeman LM, Rand JS, Morton JM. Pharmacokinetics and pharmacodynamics of porcine insulin zinc suspension in eight diabetic dogs. Vet Rec 2009;164:232-237.
  7. Cobry E, McFann K, Messer L, et al. Timing of meal insulin boluses to achieve optimal postprandial glycemic control in patients with type 1 diabetes. Diabetes Technol Ther 2010;12:173-177. 

Friday, February 21, 2014

U-40 Insulin Syringes Recalled

Med-Vet International Issues Recall of 1/2-cc U-40 Insulin Syringes Due to Mismarked Syringe Barrels (1).  


On February 14, 2014 , Med-Vet International initiated a voluntary nationwide recall of 140 boxes of 1/2-cc U-40 insulin syringes (1). The syringes are incorrectly labeled as 40 units per 1/2-cc syringe, whereas they should be marked with only 20 units per 1/2 cc. Obviously, this could potentially result in a lower-than-prescribed dose of insulin being administered, and lead to relapse of signs of diabetes, as well as development of ketoacidosis.

Consumers who have these insulin syringes should quarantine all products subject to recall. In addition, if you, as the veterinarian, may have sold these syringes, please inform the clients at once about this product recall so they can change to another insulin syringe.

The following 1/2-cc U-40 insulin syringes have been recalled:
  • 140 boxes of 1/2-cc insulin syringe U-40 with 29g x 1/2” needle. Lot Number: 20120610
  • The product can be identified by Item number: MV1/2CCINS-40 or 1/2CCINS-40 by Oasis.
Med-Vet International is arranging for return of all recalled 1/2-cc U-40 insulin syringes. Consumers with questions may contact the company via telephone at (800) 544-7521 or via e-mail at customerservice@shopmedvet.com.

References:
  1. FDA website (www.fda.gov). Med-Vet International Issues Nationwide Recall of Veterinary 1/2cc U-40 Insulin Syringes Due to Mismarked Syringe Barrels

Tuesday, February 18, 2014

How to Manage Hyperthyroid Cats that Become Resistant to Methimazole


I have a 19-year old female DSH cat who was diagnosed with hyperthyroidism 5 years ago. I chose not to do the radioactive treatment because that treatment required her being away for several days. I didn't want to do surgery to remove the thyroid gland because she was very weak at the time of the initial diagnosis. 

Therefore, I have been treating her with methimazole over all these years. Initially, her daily dosage was 5 mg (divided twice daily). Over the years, it has become necessary to increase this first up to 10 mg/day, then to 15 mg (daily doses divided into 2-3 doses per day). This 15-mg dosage was effective at controlling her hyperthyroidism for a short time, but now her serum thyroid value is high again. Because of the persistent hyperthyroidism, many of her clinical signs have returned. She has lost weight, despite the fact that her appetite has increased.  I have just increased the methimazole dose up to 10 mg twice a day (20 mg/day) but this still does not appear to be helping.  Now I am worried about the effects of the medicine on her kidneys.

Do cats just become accustomed to the methimazole and always need an increasing amount?  How high can we go with the dosage of the methimazole?  

Thank you. 

My Response: 

This scenario that you are describing isn't that uncommon in cats treated with methimazole on a long-term basis. All hyperthyroid cats, as you may know, have one or more thyroid adenomas (benign thyroid tumors), which will continue to grow larger with time (1-7).

Thyroid scans of hyperthyroid cats, illustrating that all of these cats will have a thyroid tumor that will continue to grow larger over time. In some cats, these tumors will become very large or huge, which can lead to "resistance" to methimazole.

How methimazole works to control hyperthyroidism
Methimazole and other antithyroid drugs work by being taken up by the thyroid tumor where the drugs inhibit thyroid hormone production and secretion (1-4,7). Therefore, most hyperthyroid cats will require higher dosages of methimazole to inhibit thyroid hormone secretion as their goiters become larger and the thyroid tumor volume increases.

The methimazole does not change the tumor pathology and cannot stop the tumor from growing (5,6).  In some of these cats, the thyroid adenoma also may transform into a thyroid carcinoma as the disease progresses (6,8). Again, methimazole does nothing to the tumor pathology and cannot stop this from happening.

Why methimazole may become ineffective with time
In answer to one of your questions, hyperthyroid cats do not just become accustomed to the methimazole and need an increasing amount. There is a good explanation for the dose increases and why the drug will fail to work in some cats, especially in those treated chronically.

After use of medical treatment for a number of months to years, many hyperthyroid cats will have fairly large palpable goiters (thyroid enlargement). Because of the large goiter size, these cats can be difficult to regulate and make euthyroid, even when very high daily doses of oral or transdermal methimazole are administered (7). The reason for this is simple— with time, we just can't give a dose of methimazole that is high enough to block thyroid secretion from all of the thyroid tumor cells. In other words, the cat just has too much thyroid tumor tissue and thyroid oversecretion can no longer be adequately suppressed by the methimazole.

How high can we go with the methimazole dose in this cat?
So, what do you do?  The dose of methimazole needed to control hyperthyroid cats is based on what it takes to lower the serum T4 concentration into the reference range, so there is not an upper limit to what methimazole dosage can be used. I've gone as high as 30 mg per day in some cats, although the incidence of side effects tends to be higher as you raise the dose (7). So in your cat, I would continue to raise the dose up to 25 mg and then 30 mg/day, as needed. If this fails to completely control the hyperthyroidism, addition of other drugs such as beta-adrenergic blockers (e.g., atenolol) and/or L-carnitine could also be considered (9, 10).

If your cat was younger, I would strongly recommend definitive therapy (i.e., surgery or radioiodine) in order to remove or destroy the thyroid tumor(s). However, at 19-years of age, that may no longer be feasible, depending on your cat's overall clinical condition.

My Bottom Line:
The underlying cause of hyperthyroidism in all affected cats is a hyperfunctional thyroid tumor. Unless surgically removed or irradiated with radioiodine, these thyroid tumors will tend to grow larger with time, as the disease progressed. If methimazole is used as initial treatment, the drug may eventually become ineffective, even when higher dosages of the drug are used.

Overall, I believe that we should be curing the thyroid tumor in the hyperthyroid cat with definitive treatments, not just controlling the hyperthyroid state for the rest of the cat's life with methimazole. In most hyperthyroid cats, especially those that are young to middle-aged, the use of surgical thyroidectomy or radioiodine are, therefore, the treatments of choice. I do not generally recommend using methimazole on a long-term basis, unless we don't believe that the cat will live for another couple of years. Both surgery and radioiodine can be more difficult in cats with large goiters and severe hyperthyroidism, so early definitive therapy is always best.

References:
  1. Peterson ME. Hyperthyroid diseases In: Ettinger SJ, Feldman EC, eds. Textbook of Veterinary Internal Medicine: Diseases of the Dog and Cat. Fourth ed. Philadelphia: WB Saunders Co, 1995;1466-1487.
  2. Baral R, Peterson ME. Thyroid gland disorders In: Little SE, ed. The Cat: Clinical Medicine and Management. Philadelphia: Elsevier Saunders, 2012;571-592.
  3. Mooney CT, Peterson ME. Feline hyperthyroidism In: Mooney CT, Peterson ME, eds. Manual of Canine and Feline Endocrinology Fourth ed. Quedgeley, Gloucester: British Small Animal Veterinary Association, 2012;199-203.
  4. Peterson ME. Hyperthyroidism in cats In: Rand JS, Behrend E, Gunn-Moore D, et al., eds. Clinical Endocrinology of Companion Animals. Ames, Iowa Wiley-Blackwell, 2013;295-310.
  5. Gerber H, Peter H, Ferguson DC, et al. Etiopathology of feline toxic nodular goiter. Vet Clin North Am Small Anim Pract 1994;24:541-565.  
  6. Peterson M. Hyperthyroidism in cats: What's causing this epidemic of thyroid disease and can we prevent it? J Feline Med Surg 2012;14:804-818. 
  7. Peterson ME. Treatment of severe, unresponsive, or recurrent hyperthyroidism in cats. Proceedings of the 2011 ACVIM Forum; 2011 June 15–19; Denver, CO. American College of Veterinary Internal Medicine, pp 104–106.
  8. Peterson ME, Broome MR. Hyperthyroid cats on long-term medical treatment show a progressive increase in the prevalence of large thyroid tumors, intrathoracic thyroid masses, and suspected thyroid carcinoma. J Vet Intern Med 2012;26:1523.
  9. Peterson ME. Alternative medical treatments for hyperthyroid cats. Conference Proceedings North American Veterinary Conference (NAVC) Conference 2012: Small Animal & Exotics Proceedings 2012;852-858.
  10. Peterson ME. Alternative Medical Treatments for Hyperthyroid Cats. Animal Endocrine Clinic blog, September 13, 2012.

Sunday, February 9, 2014

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.  

Friday, January 31, 2014

What's the Expected Time for Signs of Feline Hyperthyroidism to Resolve after Treatment?


My 16-year old cat was recently treated with radioiodine (I-131) for his severe hyperthyroidism. How long after radioiodine treatment will the thyroid values normalize and the symptoms of the hyperactive thyroid begin to resolve so he feels better? 

My cat lost about half of his body weight, much of it in muscle mass. Will his wasted muscles ever return to normal? If so, when can I expect to see improvement?

My Response: 

You have asked two good questions, which, on the surface seem simple enough to answer. The answers to "how long for clinical signs to resolve" however, depend on a number of factors. I'll do my best to explain why it's not possible for me to give you the definitive answers you want.

How long does it take for serum thyroid hormone levels to normalize after I-131?
Depending on the dosing protocol used, about 90% of cats will have serum thyroid hormone concentrations (e.g., T4 and T3) within reference range limits by 30 days after I-131 treatment. Most of the remaining cats will show a nice drop in T4 and T3 levels when rechecked in a month, but it will take longer to for their thyroid hormone concentrations to completely normalize.

In general, the full extent of the radioiodine treatment will be evident by 3 months after treatment, although a few cats continue to show even more (minor) improvement when rechecked at 4 to 6 months.

As the thyroid values normalize, the clinical signs we see also gradually resolve. Some signs, such as nervousness or rapid heart rate, generally resolve fairly quickly, whereas other signs, such as marked weight loss and muscle wasting, obviously take much longer.

How fast do we want the serum thyroid values to fall after radioiodine treatment?
My goal in treating hyperthyroid cats with radioiodine is to gradually normalize the high serum thyroid hormone concentrations— not lower the values too quickly. I'd rather that the thyroid values fall slowly over the first month after treatment, allowing the rest of the body to gradually get used to being euthyroid once again. This is especially true in cats with concurrent kidney disease, when a drastic fall in thyroid values can aggravate the serum kidney values and can even lead to severe renal failure.

To achieve this gradual fall in the high serum thyroid hormone levels, I administer the smallest dose necessary to cure the hyperthyroidism. By giving individualized, lower doses of radioiodine, we can also reduce the incidence of post-treatment hypothyroidism (underactive thyroid condition) in these cats.

How often does the radioiodine fail to cure the hyperthyroidism?
About 5% of cats that I treat will remain slightly hyperthyroid at the 3-month follow-up period. Many treatment facilities will claim a higher rate of cure (98-100%) than I do, which is made possible by administering higher doses of radioiodine to their cats. In addition to decreasing the incidence of persistent hyperthyroidism, the use of higher radioiodine doses will also hasten the rate of decline in the serum thyroid hormone concentrations.

So why not use this high-dose I-131 protocol instead of my lower-dose approach? Simple — the downside of administering higher radioiodine doses is that this method will lead to a higher rate of iatrogenic hypothyroidism as both the thyroid tumor, as well as most normal thyroid tissue, are irradiated and destroyed (1,2). As I've previously discussed (see my post, Estimating the Radioiodine Dose to Administer to Cats with Hyperthyroidism), more that 30% of cats will become hypothyroid using the standard high-dose treatment protocol, but this incidence could in fact be much higher, possibly up to 75%.

Diagnosing iatrogenic hypothyroidism
To monitor for iatrogenic hypothyroidism, we routinely run a serum thyroid panel (i.e., total T4, T3, free T4, and TSH) at 1 and 3 months after treatment (2,3). Most facilities recommend monitoring just the total T4 concentration, but this is not adequate for monitoring since many hypothyroid cats will maintain a low-normal total T4 value, despite being hypothyroid.  Based on our studies, it's becoming increasing clear that feline hypothyroidism can only be diagnosed by finding low to low-normal T4 and T3 values in conjunction with high TSH values.

Restoring lost body weight and muscle mass
Once euthyroidism is reestablished, most cats will gain weight within a few weeks (certainly by 2-3 months). If marked muscle wasting has occurred, it may not be possible to completely regain the lost muscle. Remember that it will help to feed a diet that's higher in protein (40-50% of calories), higher in fat (40-50% of calories), and relatively low in carbs (less than 15% of calories) (4). For more information, check out my post on The Best Diet to Feed Hyperthyroid Cats.

References:
  1. Peterson ME, Broome MR. Radioiodine for feline hyperthyroidism In: Bonagura JD, Twedt DC, eds. Kirk's Current Veterinary Therapy, Volume XV. Philadelphia: Saunders Elsevier, 2014.
  2. Peterson ME. Feline focus: Diagnostic testing for feline thyroid disease: hypothyroidismCompend Contin Educ Vet 2013;35:E4. 
  3. Peterson ME. Diagnosis and management of iatrogenic hypothyroidism In: Little SE, ed. August's Consultations in Feline Internal Medicine: Elsevier, 2014;in press.
  4. Peterson ME. Nutritional management of endocrine disease in cats. Proceedings of the Royal Canin Feline Medicine Symposium 2013;23-28.

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