Considerations in Wound Closure

Maintenance Insulin Therapy in Dogs

Intermediate-acting insulin preparations continue to be the most commonly used and recommended preparations for the management of canine diabetics. The two currently available intermediate-acting insulin preparations are NPH (Humulin® N, Novolin® N) and Vetsulin®.

Dosing Recommendations

• NPH and Vetsulin®
• 0.25–0.5 U/kg subcutaneously every 12 hours
• Acceptable glycemic control achieved with 0.5–1 U/kg every 12 hours in most dogs
• Begin suspecting and evaluating for causes of insulin resistance when dose is ≥1.5 U/kg
• Consider changing insulin formulation if dose ≥2 U/kg and no cause of resistance or lack of acceptable glycemic control identified
• Insulin should be administered at the time of feeding to avoid hypoglycemia and minimize postprandial hyperglycemia

Dietary Recommendations

It is most important that the type and amount of food remain consistent and that all or most of the calories (including treats) be consumed at or near the time of insulin administration. Ideally, food consumption would coincide with maximal insulin activity, but this could be challenging to predict, create unnecessary stress for the pet owner, and increase the risk of hypoglycemia because of variability in the onset of action. It is possible to achieve acceptable glycemic control in most dogs that consume a balanced maintenance diet at the time of insulin administration. It is also worth noting that it has not been possible to identify a clear benefit to feeding high-fiber, moderate-carbohydrate, and moderate-fat diets. High-fiber, calorie restricted diet formulations should not be fed to dogs that are underweight and/or have decreased lean body mass.

Goals of Therapy

• Resolution of clinical signs
• Normal activity level and good quality of life
• Stable body weight
• Avoidance of hypoglycemic episodes
• Ideal glycemic control (BG <250 mg/dL for majority of the day) is nice but not always necessary to achieve the above goals

Reasons for Poor Regulation

• Insulin therapy
• Underdosing (common cause)
• Insulin time-action profile not appropriate
• Handling issues and/or inactivation
• Administration issues
• Treatment regimen
• Inconsistent feeding and/or insulin administration time
• Access to food and/or treats throughout the day
• Increased activity/exercise
• Insulin resistance
• Urinary tract infection
• Pancreatitis
• Cardiac disease
• Renal disease
• Diestrus
• Hyperlipidemia
• Hyperadrenocorticism
• Hypothyroidism

Monitoring and Insulin Dosage Adjustment

Changes in the insulin dose should be based on clinical assessment combined with some assessment of glycemic control (blood glucose curves or continuous glucose monitoring). The parameters that are considered when determining how much the insulin dosage should be increased include the degree of hyperglycemia, the size of the dog, and the current insulin dose (U/kg). Although dependent on the degree of hyperglycemia, the dose is typically increased by 1–2 units per dose in small dogs and 2–3 units per dose in larger dogs.

Continuous Glucose Monitoring (Dogs and Cats)

The FreeStyle Libre continuous glucose monitoring system provides a readily available, cost-effective way to continuously assess glycemic control over a 14-day period. This system does not require calibration so the owner does not have to obtain blood samples from the pet to check the blood glucose concentration. Continuous glucose monitoring is the recommended assessment method for any challenging diabetic and could replace the blood glucose curve in most diabetics.

Home Blood Glucose Curve Protocol (Dogs and Cats)

• Use a hand-held glucometer that has been designed and validated for use in dogs and cats
• Blood glucose before food and insulin administration
• Feed and administer insulin
• Blood glucose 1 hour after food and insulin, then every 2 hours (every 4 hours in cats receiving long-acting preparations) until the next dose of insulin

Despite substantial day-to-day variation in BG curves, a complete 12-hour BG curve can provide useful information when evaluating a poorly regulated diabetic, especially if continuous glucose monitoring is not an option. Blood glucose curves may provide more accurate information when performed in the home environment. It is recommended that BG curve data from multiple days during a 2- to 3-week period be evaluated prior to recommending significant changes such as a change in the insulin formulation. This will allow the clinician to evaluate trends rather than basing the decision on a single BG curve that may not be an accurate representation of the overall glycemic control. Routine blood glucose monitoring also plays an important role in detecting subclinical hypoglycemia.

Dietary Management of Unregulated Diabetic Dogs

Consider a moderately to markedly carbohydrate-restricted diet (15–30% metabolizable energy from carbohydrate) in dogs with unacceptable glycemic control that appears to be associated with postprandial hyperglycemia. Dietary fat restriction is recommended for diabetic dogs that have persistent hypertriglyceridemia and/or recurrent pancreatitis.

Using Long-Acting Insulin Formulations in Dogs

Based on the currently available clinical data, there does not appear to be an obvious benefit to using long-acting insulin analogs in most dogs. The low potency of Lantus® (insulin glargine 100 U/ml) and Toujeo® (insulin glargine 300 U/ml) make them useful in small dogs that are unregulated but have recurrent hypoglycemia with small doses of NPH or Vetsulin®. These formulations have a slower onset of action and a more gradual glucose lowering effect. Levemir® (insulin detemir 100 U/ ml) is an option for dogs in which acceptable glycemic control cannot be achieved with NPH or Vetsulin®. The author has observed improved glycemic control when switching to Levemir® even if a short duration of action is not the cause of poor regulation.

Levemir® is a potent insulin formulation and a dosage reduction is necessary when switching from NPH or Vetsulin®. The recommended starting dose for insulin detemir is 0.1-0.2 U/kg, which limits the use of this insulin in small dogs. The long-acting insulin analogs are substantially more expensive than NPH and Vetsulin®. For this reason, the use of long-acting analogs is often reserved for cases in which acceptable glycemic control cannot be achieved with standard therapy.

Using Rapid-Acting Insulin Analogs at Mealtime

It is standard practice to use two insulin formulations in the management of human diabetics. One preparation is a short or rapid-acting insulin that is administered at mealtime (bolus), while the other has an intermediate or long duration of action (basal insulin) and maintains the BG during periods of fasting. This is not commonly recommended in diabetic dogs because it increases the risk of hypoglycemia and because it is often possible to achieve acceptable glycemic control with a single insulin preparation administered twice daily.

The use of a rapid-acting insulin analog administered concurrently with NPH was investigated in a small group of dogs. Insulin lispro (Humalog®) was administered with NPH at mealtime in six dogs that were considered to have well-regulated diabetes while receiving NPH, but continued to have a profound postprandial spike in blood glucose. Subcutaneous insulin lispro at a dose of 0.1 U/kg was well tolerated and blunted the postprandial spike (decreased the blood glucose 60 and 90 minutes after eating). Although this approach may prove beneficial in dogs that have unacceptable glycemic control related to postprandial hyperglycemia, this combination protocol is likely not necessary for the majority of canine diabetics and could increase the risk of hypoglycemia.

When initiating this protocol, it is recommended that the maintenance insulin dose be reduced by at least as many units as the number of units of rapid-acting insulin being added (i.e., total units of insulin being administered is the same or less). This will hopefully decrease the potential for hypoglycemic complications. It is not appropriate to substitute regular insulin for a rapid-acting analog in this protocol. Regular insulin has a slower onset of action, longer duration of effect, and will increase the risk of hypoglycemia.

Case example: 20 kg dog receiving 30 units of NPH every 12 hours but continues to have profound postprandial hyperglycemia associated with unacceptable glycemic control.

Recommendation: Add insulin lispro at the starting dose of 0.1 U/kg =2 units

New insulin dosing protocol: 25–28 units NPH (dosage reduction) + 2 units insulin lispro every 12 hours.

Recommend performing a blood glucose curve (or using a continuous glucose monitor) following the first administration of the rapid-acting analog to confirm that hypoglycemia is not an immediate concern.

Maintenance Insulin Therapy in Cats

It is possible to achieve ideal glycemic control in most cats with twice daily administration of long-acting insulin formulations. The time-action profile of these insulins is more appropriate in cats than intermediate-acting insulin formulations and higher remission rates are reported in cats receiving long-acting insulin preparations. Currently available formulations that are routinely used in cats include insulin glargine (Lantus®), PZI (ProZinc®), and insulin detemir (Levemir®). The recommended starting dose for these long acting formulations is 1–2 U/cat every 12 hours. The majority of cats will have acceptable glycemic control at a dose of 1–6 U/cat every 12 hours. Twice daily insulin administration is recommended and is likely to result in better glycemic control than once daily administration. If it is not possible to administer insulin twice daily, once daily administration of Levemir® or Toujeo® (starting dose: 1–2 U/cat) may provide acceptable control of clinical signs and decrease the occurrence of complications associated with untreated diabetes mellitus. Toujeo® has been studied in healthy cats, but there is limited information about clinical use available.

Dietary Recommendations

• Low carbohydrate diet (Purina DM, Hill’s Prescription Diet m/d)
• Associated with better clinical control, reduce insulin requirements, and increased remission rates
• Meal feeding is ideal, but eating does not need to be coordinated with insulin administration (grazing is allowed).
• Recommend weight loss in obese cats
• 1–2% loss of body weight per week
• Have had success with Hill’s Prescription Diet Metabolic when cats gain weight or fail to lose weight with classic high-protein/low-carbohydrate diets.

Goals of Therapy

• Resolution of clinical signs
• Normal activity level and good quality of life
• Stable body weight
• Possible to achieve ideal glycemic control in most cats with long-acting insulin
• Diabetic remission

Reasons for Poor Regulation

• Insulin therapy
• Underdosing
• Time-action profile is not appropriate (use of intermediate-acting insulin)
• Handling issues and/or inactivation
• Administration issues
• Insulin resistance
• Hypersomatotropism/acromegaly recommend screening (measure IGF-1 concentration) all diabetic cats 6–8 weeks after initiating insulin therapy.
• Urinary tract infection
• Pancreatitis
• Renal disease
• Hyperthyroidism
• Hyperadrenocorticism

Monitoring and Insulin Dosage Adjustment

Increases in the insulin dosage should be based on the presence of clinical signs combined with an objective assessment of glycemic control (see above continuous glucose monitoring [FreeStyle Libre], home blood glucose curves, fructosamine concentration, HbA1c, +/urine glucose monitoring). Routine blood glucose monitoring allows for assessment of glycemic control as well as detection of subclinical hypoglycemia. This is especially important in cats because of the possibility of diabetic remission (return to a noninsulin-dependent state). The insulin dose in cats is typically increased by 1–2 U per dose.

References

1.  Brunton S, Heile M, Schneider D, Meneghini L, Reid T, King A. Update on insulin management in type 2 diabetes. The Journal of Family Practice. 2012;61:S4–S12.

2.  Fleeman L, Rand JS (2013). Canine Diabetes Mellitus. In J. Rand (Ed.), Clinical Endocrinology of Companion Animals. Ames, Iowa: John Wiley & Sons, Inc.

3.  Gilor C, Graves TK. Synthetic insulin analogs and their use in dogs and cats. Vet Clin N Am Small Anim Pract. 2010;40:297307

4.  Marshall RD, Rand JS, Morton JM. Treatment of newly diagnosed diabetic cats with glargine insulin improves diabetic control and results in higher probability of remission than protamine zinc and lente insulins. J Feline Med Surg. 2009;11L683–689.

5.  Rand JS (2013). Feline Diabetes Mellitus. In J. Rand (Ed.), Clinical Endocrinology of Companion Animals. Ames, Iowa: John Wiley & Sons, Inc.

6.  Roomp K, Rand JS. Management of diabetic cats with long-acting insulin. Vet Clin N Am Small Anim Pract. 2013;43:251–266.

7.  Sako T, Mori A, Lee P, et al. Time action profiles of insulin detemir in normal and diabetic dogs. Res Vet Sci. 2011;90:396–403.

8.  Bertalan AV, Drobatz KJ, Hess RS. NPH and lispro insulin for treatment of dogs with diabetes mellitus [abstract]. J Vet Intern Med 2014;28:1026.