Audrey K. Cook, BVM&S, MRCVS, DACVIM (Small Animal Internal Medicine), DECVIM. Richard W. Nelson, DVM, DACVIM

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1 Audrey K. Cook, BVM&S, MRCVS, DACVIM (Small Animal Internal Medicine), DECVIM & Richard W. Nelson, DVM, DACVIM Feline Insulin Transitioning Dr. Audrey K. Cook Is there a reference for published data on insulin dosing in cats? The suggested doses are derived from clinical reports listing the average doses required to achieve diabetic regulation in cats. Current understanding of feline diabetes: Part 2, treatment. Martin G, Rand J. Journal of Feline Medicine and Surgery 2000:2;3-17 Field Safety and Efficacy of Protamine Zinc Insulin recombinant human insulin for treatment of diabetes mellitus in cats. Nelson RW, Henley K, Cole et al. JVIM 2009:23; Is there any insulin that is safe to dilute? Regular insulin can be safely diluted for immediate use. Glargine should never be diluted. Although diluents for some other insulins may be available, problems often occur. Consult the manufacturer about diluents if you really want to do this. Is the use of Humulin N ever appropriate for feline diabetics? This is generally a very poor choice for cats due to short (8 hr) duration of effect. If a cat has problems with glargine or PZI, this may be an option, but it should NOT be a first choice for a feline diabetic. Page 1 of 11

2 Can you or should you substitute NPH for glargine in an emergency situation due to non-availability instead of not giving insulin at all? Glargine is a routinely used human product, and should be available at ANY human pharmacy. So, it is hard to think of a situation in which availability would be an issue. If this did occur, I d reach for PZI instead, rather than NPH. The curve that you posted for Lantus is that of an under-dosed cat. It shows the typical flat curve that Lantus is capable of in cats; however the reason Lantus use causes so many felines to go into remission is due to having that flat curve but in a euglycemic range. If a client is home testing the BG s, why not aim for that? I deliberately showed an under-dosed cat so as not to imply that every cat on glargine is automatically euglycemic! I wanted to demonstrate the flat effect to contrast with Lente (Vetsulin). But yes, I agree with you about aiming for euglycemia in a diabetic and am a big proponent of at-home testing. What are the chances of a diabetic cat in remission becoming diabetic again? If insulin resistance recurs (obesity, inflammatory disease, use of steroids) then the diabetes is likely to recur. How long can a bottle of glargine be used? If you ask a group of pharmacists, they will say to discard an insulin after 30 days. However, glargine kept in the fridge and handled carefully seems to maintain efficacy for up to 6 months. Clients can by glass syringes containing 3 ml of glargine and use these like a bottle; this means that there is less waste. Vetsulin? I have an unexpired bottle of the old PZI, can I use it to switch a cat from The old PZI was a beef product, so it is different to the new formulation which is human. However, it is likely to have similar results. However, if your old PZI was anything other than the Idexx formulation, I would discard it. Compounding pharmacy insulins have been shown to be variable and should be avoided. Page 2 of 11

3 Can any insulin cause a Somogyi effect? Yes, although it is very unlikely with an insulin such as glargine as the blood sugar is much less labile. It is the rate for decrease in glucose as much as the absolute nadir which determine the likelihood of the Somogyi effect. What are your thoughts on using insulin pens? I have no experience with these. In theory it may be an easy way to deliver a small dose, but I just don t have any familiarity with the technology. Will a Somogyi over-swing cause an elevation in fructosamine levels? Yes; sustained hyperglycemia will increase protein glycosylation and result in increased fructosamine concentrations. Is there an advantage to trying Prozinc insulin over glargine in cats? Not that I can think of, as far as the insulin itself is concerned. I personally reach for glargine in most feline diabetics. However, the U40 formulation for ProZinc does make administration somewhat easier. With such a delayed nadir with glargine and twice daily administration of the insulin, can you use a spot check as effectively as a curve? A spot check may be useful, but most dose adjustments rely on both the pre-insulin BG and the estimated nadir BG. So, I would like both those pieces of information if possible. When switching from old PZI to Prozinc in a cat, do you have to start from scratch with dosing and curves? If I was using a compounded PZI, I would start from scratch as I am just not sure of the real insulin dose the cat was on. If a cat was well regulated on a very low dose of an old PZI product, I d probably use the same dose of ProZinc. Page 3 of 11

4 How are you recommending clients perform glucose curves at home and do you recommend a specific monitor? There is a lot of information available on at-home glucose monitoring on the internet. I strongly recommend if for my feline patients, and suggest that a vet approved monitor is purchased. If the cat is on glargine, I have the client check the BG before the insulin is given, then 4 and 8 hours later. This is enough information to reliably determine effect and make dose adjustments if necessary. curves? Do continuous glucose monitoring systems work well for in home glucose We have a continuous glucose monitor in our hospital, and I try to use if for DKA cats. However, it takes 2 hours to calibrate and you still need to do a few sticks in the first few hours in order to get it to calibrate. Also, ours does not read if the BG is > 400 mg/dl. So, I don t think at home use is practicable at this time. We ve had some problems too with failure of the transducers etc. We have an owner who checks her cat s BG daily. The cat has been on PZI for several years she manages the amount of insulin to administer based on daily readings is this ok or should she be consistent with dosing and monitor less often? If the cat is well regulated and looks great, I wouldn t change anything. She may be unnecessarily micromanaging the cat s disease however, as determining a good dose for consistent use is enough to keep most cats happy, with minimal clinical signs. Unlike in human medicine, our patients do not necessarily benefit for perfect regulation and euglycemia is not necessary for successful management of our diabetics. How often would you recommend a routine glucose curve on a well regulated cat on glargine? I would like to evaluate the cat s status every 2-3 months. This may mean a glucose curve or just a fructosamine, depending on the patient and clinical status. Page 4 of 11

5 How can you tell when a diabetic cat is in remission? Should you wean a cat in remission from insulin or just stop it? Remission should be considered if the glucose is <100 mg/dl. If the cat is on a long-acting insulin such as glargine, I would wean the insulin dose down, rather than an abrupt stop. When the cat is down to 0.5 units BID, I d try SID and then reassess. What type diet do you recommend for an obese diabetic cat? I d suggest any of the diabetic diets (i.e., high protein, low carbs), but fed in an amount designed to facilitate gradual weight loss (1-2% per week). How do you approach a suspected resistance? This is a huge topic and really beyond the scope of this web conference! To be brief, I d rule out insulin issues (out of date, shaken bottle) and client issues (poor technique, wrong syringes) first. Then, I d look for patient issues. In cats, I d first rule out UTI with a urine culture (no matter what the urine looks like) and hyperthyroidism (Total T4 and then free T4 if necessary) and pancreatitis (fpli). Look carefully at the teeth for substantial disease as this may affect insulin responsiveness. Next, I d check carefully for any medication (steroids including topicals, progestins) that may cause insulin resistance. At this point, I d then suggest referral. Is hypoglycemia caused by glargine more difficult to correct? Glargine overdose can cause persistent hypoglycemia. I once had a cat given an accidental overdose who needed IV dextrose for 3 days until the glargine wore off. How important is fasting and preinsulin BG for interpreting a curve? We find most pets will not eat once in the clinic? It is helpful for cats on glargine, but not essential. If anorexia in the clinic is an issue, I d get the client to monitor at home or measure fructosamine. If a cat is stressed enough to refuse food, you are going to have a hard time interpreting the glucose measurements in the clinic; they may be low from anorexia or high from stress. Page 5 of 11

6 What is your experience with glipizide in cats? Very disappointing. I d only try this option to buy some extra time to convince a client to give insulin injections or if I strongly thought the cat would go into remission rapidly (for example, a cat becomes diabetic after a depot steroid injection and I think it may well reverse when the injection wears off). How often should a pet in remission be rechecked? Warn the owner to watch for changes in thirst and urination. Otherwise, I d check the cat every 4-6 months, with a fasted BG (in an unstressed cat) or a fructosamine. What about dental disease and glycemic control? Severe inflammatory disease anywhere in the body can affect insulin sensitivity, and there are reports in the literature about dental disease causing insulin resistance. However, in my experience, it takes SEVERE dental disease to do this. Canine Insulin Transitioning Dr. Richard W. Nelson What do you recommend for inconsistent eaters? First, rule out possible underlying medical reasons for inconsistency, most notably concurrent chronic pancreatitis and oral cavity disease, and treat if identified. Second, consider boredom with the diet, which is common with chronic feeding of diets containing high fiber. Changing diets periodically helps with this problem. In the dog that is finicky and unreliable regarding consumption of food for no apparent reason, I will give the insulin and leave the food out and allow the dog to eat whenever it chooses. For many dogs, appetite will be stimulated when the blood glucose begins to drop. If the dog does not eat the next meal and seems otherwise normal, I give half the dose of insulin and maintain access to food. If the dog does not eat the third meal, I do not give insulin and have the client call me. Do you know if NPH will be going off of the market also? I do not know but it is a distinct possibility sometime in the future. Page 6 of 11

7 If a dog is regulated on SID Vetsulin and is switching to BID NPH does that influence the starting dose of NPH? If a dog is doing well on once a day Vetsulin, I would start NPH once a day and make a decision of whether to go twice a day based on how the dog responds. What are your recommendations for diabetics coming in for surgery/anesthesia? Normal amounts of food and insulin the night before, half the insulin dose the morning of the surgery, monitor blood glucoses during the peri-operative period and give small amounts of regular insulin or begin an IV dextrose infusion if high (> 300 mg/dl) or low (< 100 mg/dl) blood glucose concentrations are identified. Is it possible to regulate a dog on once daily Humulin-N? Yes about 10 to 15% of diabetic dogs will be well controlled on once-a-day insulin. What is your opinion on the use of Lantus in dogs and what dose do you use? Insulin glargine is not my first insulin of choice in dogs I have had inconsistent results using it. I tend to go to glargine when Vetsulin or NPH given twice a day is ineffective in controlling the diabetic state because of short duration of insulin effect. Whenever I change insulin, my typical starting dose is around 0.25 U/kg twice a day, which includes glargine and detemir. insulins? Have you seen diluted U40 insulins potentially having a faster onset than U100 No Page 7 of 11

8 I have a Maltese on NPH the owner believes that there are less clinical signs related to diabetes when she does NOT REFRIGERATE the insulin and uses a new bottle every 30 days. Have you heard of any benefits to not refrigerating NPH? No. The only things that inactivate insulin are heat/direct sunlight, freezing and shaking the bottle. Room temperature does not inactivate insulin per se, but does open up possibilities for loss of action or sterility. I recommend keeping insulin in the refrigerator to ensure a consistent environment. For a dog who is just not responding well to NPH other endocrinopathies and infection have been ruled out which would be your next choice for insulin? It depends on what you believe is the underlying problem. If you suspect poor absorption or insulin resistance or insulin antibodies, I would go to a more potent insulin like human recombinant regular insulin given three times a day to see if it will work. If you suspect problems with rapid absorption causing the Somogyi response or very short duration of effect, I would go to a less potent insulin with a more sustained slower absorption pattern such as glargine or detemir. What type of diet do you recommend for diabetic dogs? That depends on body weight and concurrent disease (eg, pancreatitis, renal failure). Assuming no significant concurrent disease, I recommend a diet designed for weight loss and that contains an increased amount of a mixture of fiber (soluble and insoluble) for an obese dog, a diet designed for maintenance that also contains an increased amount (6 to 8% dry matter) of a mixture of fiber in a dog at ideal body weight (BCS 4-5 out of 9), and a maintenance diet or low fat diet (if pancreatitis is suspected) with minimal to no fiber in a thin dog. When Vetsulin came on the market we changed from NPH and found the doses to typically be the same. Have you found this to be true? Yes as a general rule of thumb. However, I always cut the dose down a bit whenever I change the type of insulin to ensure that problems with hypoglycemia (symptomatic or Somogyi response) do not develop. Page 8 of 11

9 Once a bottle of insulin is opened regardless of type how long do you feel is safe to use the product without compromising the integrity? If the insulin is stored and mixed properly, it will usually be good to the last drop. Recommendations to change every month are coming from the human side and are related to concerns with sterility of the solution more than loss of insulin action. When do you use humolog? Never right now. If regular insulin goes off the market, then the ultra-fast acting prandial insulins like lys/pro and insulin aspart will take the place of regular insulin and primarily be used for treating diabetic ketoacidosis. I have a diabetic canine patient that also has a liver mass. He is not well controlled on Vetsulin. Would you consider changing the insulin in this patient? It would be one way to determine if the poor control is related to a problem with Vetsulin or a problem with insulin resistance induced by the liver mass. I have a juvenile canine diabetic patient that was switched to Vetsulin because of poor response to NPH which insulin would you next in this patient? By juvenile, I assume you mean a dog less than one year of age. Diabetes in dogs less than 1 year of age is very difficult to treat, primarily because the puppy is growing and under the influence of growth hormone. Control tends to be erratic and unpredictable regardless of the insulin used. I always warn the client that the first year is rocky but once we get past that time period control becomes more predictable. I also warn them that the dog will have cataracts develop during that year. Page 9 of 11

10 What kind of insulin is Detemir? Is it more expensive? Is it a better alternative that ProZinc or Lantus? Detemir is an insulin analog that is a basal insulin designed for control of hepatic glucose secretion during periods of fasting. In theory, it has a slow sustained absorption pattern following administration under the skin and lasts for a prolonged period of time. It is intended for administration at bedtime in human diabetics, similar to that of insulin glargine. Anecdotal reports to date suggest that it may be better than glargine for controlling the diabetic state in dogs, although concurrent administration of a low dose of regular insulin may be needed to initially decrease the blood glucose concentration. What are your recommended starting doses for ProZinc and Lantus in dogs? 0.25 U/kg once or twice a day I have a patient with severe atopy who is receiving hyposensitization injections. As we were increasing the dose of the hyposensitization the insulin need decreased. At one point this patient had a hypoglygemic seizure. Should I expect anything like this when switching insulins? I assume that the hyposensitization treatment improved the inflammation associated with atopy which, in turn, improved insulin sensitivity in the dog and led to the hypoglycemic reaction. You can expect a similar problem with any insulin if the insulin dose is increased in response to insulin resistance induced by inflammation and the inflammation suddenly improves or resolves. Similarly, if you switch insulins and base the dose of the new insulin on status of glycemic control at a time when insulin resistance is present, hypoglycemia could occur in the future if the insulin resistance resolves. dose? What is your rule regarding the bigger the dog, the you drop the insulin The bigger the dog, the greater the change in insulin dose, regardless of whether it is up or down. I typically change the insulin dose by 1 to 5 units depending somewhat on dog size. Page 10 of 11

11 Are you having any success with home monitoring of BG in dogs? Yes it is an option for clients who are interested in getting more involved in the control of their diabetic dog. The biggest problem is a tendency for clients to start measuring glucoses frequently every day and then changing the insulin dose based on their perception of results without contacting their veterinarian. This invariably leads to an insulin overdose and induction of the Somogyi response. Do you ever use insulin ½ units and if so how do you measure it? Only in very tiny dogs (< 5 kg). I don t dilute insulin. I just tell the client to draw the bottom of the plunger to approximately half way between the hash marks. I also use 0.3 ml U100 syringes for U100 insulin. Can a hypothyroid state in a dog be onset by diabetes? Is it possible that once the diabetes is regulated the thyroid supplements will no longer be needed? Diabetes does not cause hypothyroidism. The two diseases can occur concurrently in the same dog. Both diseases are believed to be immune-mediated in dogs and both are affiliated with immunoendocrinopathy syndromes in people. Hypothyroidism causes insulin resistance and can be enough of an insult to move a subclinical diabetic dog into a clinical state. Uncontrolled diabetes can also suppress serum T4 and free T4 results in euthyroid dogs (i.e., sick euthyroid syndrome) and give the false impression that the dog is hypothyroid. I always recheck serum thyroid hormone concentrations after the diabetes is under control before accepting a diagnosis of hypothyroidism in a newly-diagnosed or poorly-controlled diabetic dog. Page 11 of 11