Insulin: why, when, which, and how

Insulin: why, when, which, and how

Leah A. Cohn, DVM, PhD, DACVIM (SAIM) Professor, University of Missouri

Insulin administration is still the only treatment option for diabetic dogs and is often the best treatment option for diabetic cats. For several decades, people with type I diabetes mellitus (DM) were treated the same way we still treat dogs and cats. Insulins were administered twice a day, causing a decline in glucose over several hours to reach a nadir with a rebound over several more hours. This is no longer the way human diabetics are managed. Typically, humans now either use an insulin pump or administer a basal or “peakless” long acting insulin with multiple additional daily injections of a rapid acting, short duration insulin; this is the basal-bolus model, similar to normal physiology. The basal insulin has a long duration with a constant sustained activity rather than causing a nadir with rebound the way that traditional intermediate insulins work. On top of this sustained basal insulin, multiple additional daily injections of rapid insulin are administered based on carbohydrate intake, premeal blood glucose, and anticipated physical activity to mimic what the pancreas would do in health. The frequent monitoring and multiple injections daily is impractical for pet animals. Further, pharmacokinetics/dynamics of the insulins preparations differ between humans vs. dogs and cats with no true basal insulin choices for pets. Insulins vary in source, administration route, potency, concentration, and absorption characteristics, which in turn impact onset and duration of action. The large majority of insulins are now some form of recombinant product similar to human origin insulin. The only commercially available animal derived insulin is Vetsulin® from a porcine source. Insulins in suspension (NPH, Vetsulin, PZI) require thorough mixing prior to use while soluble insulin formulations (most insulins for human use) do not; inconsistent mixing can lead to dosing inconsistencies. Features including binding (eg, zinc, protamine), crystal size, and pH impact absorption after injection. Most insulins are hexamers that dissociate to active monomers and dimers. Other factors that impact absorption include volume, injection site, and local blood flow. Some of the newer basal insulins are more highly concentrated types, which also slows absorption (eg, Insulin glargine U-300). All of the insulins made for use in long term management of DM are designed for subcutaneous (SQ) administration. It is crucial that pet owners understand insulin syringe size/dosing relationships. Veterinary insulins are made as 40 units per ml because of the small doses used in dogs and cats, while human insulins are typically 100, or even more units per ml for the very concentrated slow absorption types (eg, Toujeo is glargine 300U/ml). If a pet owner uses an incorrect syringe for insulin concentration, over (U-100 given in a U-40 syringe) or under (U-40 given in a U-100 syringe) dosing will occur. However, this syringe/drug matching can also be used to advantage when a pet needs an extremely small dose (or dose change) of a U-40 insulin (eg, Vetsulin) by administering it in a U-100 syringe. The U-40 insulin dose can be multiplied by 2.5 to come up with the marking to fill to on the U-100 syringe; for example, if you want to administer 0.5 units of Vetsulin, 0.5 x 2.5 = 1.3, so the owner could pull up enough Vetsulin in a U-100 syringe to come be just beyond the one unit mark. U-100 syringes are available in 0.3,

0.5, and 1 ml capacities; it is easier to see the marks per unit using the smaller capacity syringes. Never administer a U-100 insulin in a U-40 syringe due to the risk of overdosing. Most types of insulin should NOT be diluted due to changes in dose and to absorption variability. For many insulins, “pen” administration devices allow the dose to be dialed in. Only VetPens® made for use with Vetsulin have ½ U increments while all pen insulins for humans have 1 unit increments.

Insulin pens

Insulin pens offer major advantages over the use of a needles/syringe and insulin vial. Both inadequate mixing of insulin suspensions (NPH, Vetsulin, PZI) and imprecise dosing lead to dosing errors for the insulins most frequently prescribed by veterinarians to be administered using a needle/syringe and vial of insulin. In fact, when using doses of <5 Units, a >20% error in dosing has been reported to occur >50% of the time. Inaccuracies with use of vial and syringe/needle are especially problematic for pet owners with issues related to vision or manual dexterity, conditions that frequently impact older pet owners. The only true downside to the use of pens is cost. In essentially every study, insulin pens are more accurate and precise than syringe and vial. Essentially every human recombinant solution insulin can be purchased in a pen form. Pens for use with Vetsulin (VetPen®) can be purchased with ½ unit marks allowing easy administration of tiny doses or tiny dose changes. The human recombinant pens are labeled for storage at room temperature with disposal after about 42 days. Because dogs and cats use much smaller dosages than people, there is a huge amount of insulin left over at the end of this time that would be wasted if disposed of per label instructions. It appears that insulin solution pens can be safe and effective for much longer than 42 days. Many vets will have clients use the pen until empty with two caveats; first, the pen should be kept in the refrigerator to discourage bacterial growth if contaminated, and second, the insulin cartridge should be checked occasionally for discoloration or opacity and disposed of if there is a change in insulin appearance. Another difference in veterinary use of insulin pens has to do with priming the pen. The instructions for human use call for the pen to be primed with 1 to 3 units wasted before each injection. This amount of waste is negligible for human use but would cut the number of dosages available dramatically for dogs and cats. It seems that a first use priming is adequate without ongoing dose wasting for every injection. Skipping the prime does risk “air bubbles” making for inaccurate dosing but if the pen is held with the needle down and pen upright, the air bubbles should rise and not interfere with injection. If bubbles are seen on cartridge inspection, the pen can be held in a way that an additional waste shot eliminates the air bubble. A final consideration for the use of pens is needle size. Needles for human use may be extremely fine and short, but pets have thicker skin and fur. A reasonable size for pen needles for use in animals is a one half inch 29 gauge needle.

Insulin types commonly used in dogs and cats:

(U-40) Vetsulin® (Merck Animal Health) is FDA approved for dogs and cats and is the usual “first choice” insulin for diabetic dogs. Vetsulin is a porcine zinc suspension and a lente type insulin. It is considered intermediate acting, with a duration of 8-14 hours in cats and 10-24 hours in dogs. It is typically used twice daily. Nadir is reported to be 2-8 hours in cats and 1-10

hours in dogs. It can be given by routine SQ injection by syringe or by use of an insulin pen (VetPen®) with increments of 0.5 U to 1 U (depending on pen size) for ease of delivery. A unique aspect of Vetsulin is that the bottle should be shaken vigorously, while for most insulins shaking is to be avoided. Starting dose: dogs = 0.2 U/kg q 12h, cats = 1U/CAT q 8-12 hr (U-40) PZI (Prozinc®, Boehringer Ingelheim Animal Health) has been FDA approved for cats for many years and was approved for dogs in 2019. It is considered an intermediate to long acting insulin suspension, with a duration of 8-24 hours and a nadir of 5-7 hours in cats. In dogs, the nadir is reported to be 8-12 hours. PZI is one of two good “first choice” insulins for diabetic cats. Starting dose: dogs = 0.4 U/kg q 12-24h, cats = 1 U/CAT q 12 hr (U-100 or U-300) Glargine is a long acting insulin made for humans and not FDA approved for pets. Nevertheless, it is often considered a “first choice” insulin for cats in the U-100 formulation and is used occasionally in dogs; in these species it is closer to intermediate action than to a basal or peakless insulin. The duration of U-100 (eg, Lantus®, Semglee®, others) in cats and dogs, respectively, are 12-24 hours and 12-20 hours. In humans, this is a “peakless” or basal insulin type that can be coupled with short or ultrashort acting insulins on a prn basis. However, it is used as a typical intermediate to long acting insulin in veterinary medicine as a stand-alone insulin. In cats the nadir is 12-14 hours, while it is 6-10 hours in dogs. This insulin type comes in a pen with a dial but the demarcations are only in 1 unit increments. The pharmacokinetics of the glargine U-300 glargine (Toujeo®) differ from the U-100, with an even longer duration and more predictable absorption. Due to the more concentrated insulin, administration of the necessary small volume is a challenge in cats so it is used less often than U-100 glargine. It may be useful as a once daily insulin in either dogs or cats, however. U100 (Lantus) Starting dose: dogs = 0.2 U/kg q 12, cats = 1 U/CAT q 12 hr U300 (Toujeo) Starting dose: dogs = 0.4 U/kg q 12-24h, cats = 2 U/CAT q 24 hr (U-100) NPH is an intermediate acting insulin for humans that is not FDA approved for pets. Common brand names include Humulin® N (Lilly) and Novolin® N (NovoNordisk) but it also comes as an inexpensive OTC insulin (ReliON from Walmart). It has been used in dogs with DM for decades and continues to be a reasonable choice in the species. The duration and nadir are 4-10 hours and 0.5-8.5 hours, respectively. NPH has a short enough duration in cats that it is not recommended for use. The major advantage is that this insulin type is sold over-the-counter (OTC) at a very reasonable price. Owners should be carefully instructed what to ask for if they choose to buy OTC insulin as both regular (short acting) insulin and 70/30 insulin are also sold OTC. Starting dose: dogs = 0.2 U/kg q 8-12, cats not recommended due to need for q 8 hr dosing (U-100) Regular insulin is a rapid acting, short duration insulin. It is not FDA approved for animals but is routinely used for the management of diabetic ketoacidosis in dogs and cats. Duration and nadir depend on route of administration (interestingly, any insulin works quickly and with shorter duration if given IV). Most often, it is administered as a constant rate infusion with near immediate action and extremely short duration, but it can be given by the intramuscular or subcutaneous route once animals are rehydrated. Using the IM/SQ route, the peak is about 0.5 to 3 hours, with a duration of 1 to 4 hours.

(U-100) Lispro, Aspart, glulisine insulins are also rapid acting, short duration insulins used in humans on a prn basis (bolus insulins) in addition to a basal insulin. They are not FDA approved for animals but can be used for the management of diabetic ketoacidosis in dogs and cats. Because of the extremely short duration of action, they are only suitable for in-hospital management of animals. (U-100) 70/30 is a mixture of NPH (70%) and regular (30%) insulin. It is not FDA approved for pets and is used only rarely in dogs that have a suitable duration of response to NPH but have a post-prandial glucose increase shortly after feeding and insulin administration. It can be purchased OTC. (U-100) Detemir (Levemir®) is a basal insulin for humans and not FDA approved for pets but it is occasionally used in pets. It binds albumin in a way that prolongs insulin absorption to give a long and steady duration with reduced variability. Due to the fact that it is manufactured with more inulin molecules per unit, it is a very potent insulin in dogs, and they especially require a lower starting dose than for other insulin types. It should be used with caution in small dogs due to possible hypoglycemic episodes. In cats it is slightly more potent than glargine, but is fairly similar and is not particularly potent. Starting dose dogs 0.1 U/kg q 12 h, cats 1 U/CAT q 12 h. (U-100 or U-200) Degludec (Tresiba®) is a basal insulin solution for humans and not FDA approved for pets. In people, it reaches a steady state after several days of use and is truly peakless. Unfortunately, it acts as more of an intermediate insulin in pets and cannot be used once daily in cats but might work once daily in dogs. Though not often used in pets, there are publications demonstrating that this insulin can work well in dogs at least (Miller et al, 2021, Oda et al 2018). Starting dose dog 0.2 U/kg q 24 h, 1 U/CAT q 12 h For owners where once daily dosing is the only practical option, consider the use of either glargine U300 (Toujeo®) or degludec (Tresiba®) for dogs or glargine U300 (Toujeo®) for cats.

Dose adjustment

It is crucial that pet owners understand that dose adjustment is normal and expected! The single most important determinant of a need for change in dose is how the pet is doing. However, glucose curves can also be helpful, especially when frequent readings are done over several days such as with the flash interstitial glucose monitoring systems. Dose adjustment is beyond the scope of this talk, but attention should be paid to glucose nadir and rate of decline (rapid drop or repeat hypoglycemia should trigger return to starting dose insulin to avoid Somogyi overswing), timing of insulin effect and duration of action, and proportion of time spent in a target glucose range of ~90 to 300 mg/dL. For cats and small dogs an increase of 1 unit at a time is reasonable, while for larger dogs a 10-20% increase is reasonable. It is fine to give a slightly higher dose in the morning than the afternoon when small dose adjustment are necessary.

Suggested reading:

Behrend E, et al. 2018 AAHA Diabetes Management Guidelines for Dogs and Cats. J Am Anim Hosp Assoc 2018; 54:1–21. DOI 10.5326/JAAHA-MS-6822. Updates 2022.

Fracassi, Federico, et al. Comparison of lente insulin and NPH insulin therapy for the treatment of newly diagnosed diabetic dogs: a randomised study. Vet Rec 183.8 (2018): 262-262. Gilor C, et al. One hundred years of insulin: is it time for smart? J Sm Anim Pract 63:654-660, 2022. Hulsebosch SE, et al. Ultra-long-acting recombinant insulin for the treatment of diabetes mellitus in dogs. J Vet Intern Med 36:1211-1219, 2022. DOI: 10.1111/jvim.16449 Miller, M., et al. (2021) Day-to-day variability of porcine lente, insulin glargine 300 U/mL and insulin degludec in diabetic dogs. J Vet Intern Med 35, 2131-2139. https://doi.org/10.1111/jvim.16178 Oda H, et al. Time-action profiles of insulin degludec in healthy dogs and its effects on glycemic control in diabetic dogs. J Vet Med Sci 80, 1720-1723. https://doi.org/10.1292/jvms.170714. 2018.

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