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Jon  Fletcher

Louisiana State University Veterinary Clinical Sciences
After receiving his DVM from Louisiana State University, Dr. Fletcher completed a rotating internship in small animal medicine and surgery at Auburn University before returning to LSU for his small animal internal medicine residency. Following his residency, he spent a number of years in a private specialty hospital in New Orleans before returning to join the faculty at Louisiana State University in 2011. His clinical and research interests include the prevention and management of small animal endocrine and metabolic diseases as well as diagnostic endocrine testing.

Author Of 6 Presentations

Update on Insulin Therapy: What’s available and when to use it

Lecture Time
08:30 AM - 09:20 AM
Authors
Room
Hall 717
Date
07/16/19, Tuesday
Time
08:30 AM - 09:20 AM

Abstract

Abstract Body

UPDATE ON INSULIN THERAPY:

WHAT’S AVAILABLE AND WHEN TO USE IT

Jon M. Fletcher, DVM, DACVIM

Louisiana State University, Baton Rouge, LA, USA

jmfletcher@lsu.edu

OVERVIEW AND CLASSIFICATION OF INSULIN

Insulin is classified by source, duration of action, and preparation. Today, the majority of available insulin preparations are human recombinant or synthetic insulin. In fact, Vetsulin® is the only remaining animal source (porcine) insulin in use today. When classified by onset and duration of action, insulin preparations are classified as rapid-acting, short-acting, intermediate-acting, or long-acting. The rapid-acting and majority of the long-acting insulin preparations are human insulin analogs, which are created by modifying the amino acid structure of recombinant human insulin. In general, these alterations make absorption and duration of action more consistent and predictable. This has led to an overall decrease in the occurrence of hypoglycemic episodes in human diabetics. This is in comparison to crystalline insulin preparations (e.g. NPH, Vetsulin®, PZI) where the addition of protamine and/or zinc promotes the formation of insulin hexamers leading to a slower onset and longer duration of action. Hexamer dissociation is associated with greater variability in absorption and duration of action, and increases the risk of hypoglycemic events.

CURRENTLY AVAILABLE INSULIN PREPARATIONS

Rapid-acting: Insulin lispro (Humalog®)

Insulin aspart (NovoLog®)

Insulin glulisine (Apidra®)

Short-acting: Regular insulin (Humulin® R, Novolin® R)

Intermediate-acting: NPH (Humulin® N, Novolin® N)

Lente insulin- 30% semilente + 70% ultralente (Vetsulin®)

Long-acting: Insulin glargine- 100 U/ml (Lantus®, Basaglar®)

Insulin glargine- 300 U/ml (Toujeo®)

Insulin detemir- 100 U/ml (Levemir®)

Protamine Zinc Insulin (ProZinc®)

INSULIN THERAPY IN DOGS

Intermediate-acting insulin formulations continue to be the most commonly used and recommended insulin preparations for the management of canine diabetics. The two currently available intermediate-acting insulin formulations are NPH and Vetsulin®. The starting dose is 0.25-0.5 U/kg every 12 hours with acceptable glycemic control being achieved in most dogs with a dose of 0.5-1 U/kg every 12 hours. The long-acting insulin formulations have been evaluated in dogs, and there does not appear to be a clear benefit to using insulin glargine (Lantus®) or PZI (ProZinc®) in the management of dogs. Insulin detemir (Levemir®) results in improved glycemic control in some dogs but the potency (Levemir® starting dose: 0.1-0.2 U/kg) of the formulation limits its use in small dogs. The low potency of Lantus® and Toujeo® make these formulations useful in small dogs that are unregulated but have recurrent hypoglycemia with small doses (1-3 U) of NPH or Vetsulin®. Long-acting insulin analogs are an option for dogs in which acceptable glycemic control cannot be achieved with NPH or Vetsulin®.

The use of a rapid-acting insulin analog administered concurrently with NPH has been investigated in a small group of dogs. This protocol (i.e., administration of a rapid-acting insulin with an intermediate-acting maintenance insulin) is similar to protocols commonly used to manage human diabetics. In the trial, insulin lispro 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 at 60 and 90 minutes). 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 increases 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.

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 insulins 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 more likely to result in good glycemic control. 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.

INSULIN THERAPY FOR DIABETIC KETOACIDOSIS (DKA)

The three protocols for the treatment of DKA that have been described in veterinary medicine include administration of human regular insulin via intravenous constant rate infusion (CRI), hourly intramuscular (IM) insulin, and IM insulin administered every 4 to 6 hours. Many clinicians consider intravenous CRI the standard of care although the ideal route of administration remains a matter of debate. More recently, insulin lispro and insulin aspart administered as an intravenous CRI have been successfully used to treat DKA in dogs. It was concluded that these rapid-acting analogs are a safe and effective alternative to regular insulin although a clinically significant benefit was not identified.

To the author’s knowledge, subcutaneous administration of rapid-acting insulin analogs for the treatment of DKA in dogs and cats has not yet been investigated. This treatment may provide an alternative to CRI and IM regular insulin protocols in cats and dogs, and may have advantages when compared to traditional protocols. Results obtained in the author’s research laboratory in healthy cats combined with the clinical data obtained in people suggests that a subcutaneous insulin aspart protocol could be an effective treatment for cats with DKA. This type of intermittent treatment protocol could be a better option for intermediate care wards or veterinary facilities that do not have an intensive care unit or access to numerous intravenous fluid pumps. The ability to use rapid-acting analogs to treat dogs and cats with DKA may be of greater importance in the future if regular insulin becomes unavailable due to decreasing demand for the management of human diabetics.

REFERENCES

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.

Fleeman L, Rand JS (2013). Canine Diabetes Mellitus. In J. Rand (Ed.), Clinical endocrinology of companion animals. Ames, Iowa: John Wiley & Sons, Inc.

Gilor C, Graves TK. Synthetic insulin analogs and their use in dogs and cats. Vet Clin N Am Small Anim Pract. 2010;40:297-307

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.

Rand JS (2013). Feline Diabetes Mellitus. In J. Rand (Ed.), Clinical endocrinology of companion animals. Ames, Iowa: John Wiley & Sons, Inc.

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

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.

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.

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How to Deal with Problem Diabetics

Lecture Time
09:25 AM - 10:15 AM
Authors
Room
Hall 717
Date
07/16/19, Tuesday
Time
09:25 AM - 10:15 AM

Abstract

Abstract Body

HOW TO DEAL WITH PROBLEM DIABETICS

Jon M. Fletcher, DVM, DACVIM
Louisiana State University, Baton Rouge, LA, USA
jmfletcher@lsu.edu


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 2-3 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;40:297-307
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.
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But it has to be Cushing’s… Challenges in diagnosing canine hyperadrenocorticism

Lecture Time
11:15 AM - 12:05 PM
Authors
Room
Hall 717
Date
07/16/19, Tuesday
Time
11:15 AM - 12:05 PM

Abstract

Abstract Body

BUT IT HAS TO BE CUSHING’S…CHALLENGES IN DIAGNOSING CANINE HYPERADRENOCORTICISM

Jon M. Fletcher, DVM, DACVIM
Louisiana State University, Baton Rouge, LA, USA
jmfletcher@lsu.edu

DIAGNOSING HYPERADRENOCORTICISM (HAC)

Testing is divided into screening (confirming the presence of HAC) and differentiation (pituitary dependent hyperadrenocorticism or functional adrenal tumor). It may be necessary to perform multiple screening tests or repeat testing at a later date in order to confirm the diagnosis in early or more challenging cases.

SCREENING TESTS

Urine cortisol to creatinine ratio (UCCR)

-Most commonly used to rule out HAC when there is a low clinical index of suspicion
-False-positive results are common because stress/non-adrenal illness can cause an increase in the UCCR
-Recommend performing a low-dose dexamethasone suppression test or ACTH stimulation test after obtaining a positive UCCR because of the lack of specificity (high risk of false positive results)

-Protocol:

---Client/owner collects a urine sample at home. Urine should not be collected in the hospital or within 48-72 hours of a clinic/hospital visit because the stress of a clinic/hospital visit has been shown to increase the UCCR and increases the possibility of a false-positive result.
------Typically recommend first urination in the morning
------Using pooled samples (3 consecutive days) may provide a more representative result

-Interpretation:

---Normal ratio (below the laboratory cut-off)– HAC is very unlikely
---Abnormal ratio (above the laboratory cut-off)– recommend performing another screening test (low-dose dexamethasone suppression test or ACTH stimulation test) to confirm HAC prior to initiating therapy

Low-dose Dexamethasone Suppression Test (LDDS)

-Highly sensitive test
-Greater chance of false-positive result with non-adrenal illness than ACTH stimulation test (not a significant concern if screening an appropriate population)
-Can also serve as a differentiating test if positive and meet criteria for pituitary dependent HAC



-Protocol:

---Collect baseline blood sample
---Administer 0.01-0.015 mg/kg of dexamethasone or dexamethasone SP intravenously (preferred) or intramuscularly
---Collect blood samples at 4 and 8 hours after the administration of dexamethasone

-Interpretation:

---Normal dog- complete suppression at 4 and 8 hours
---Consistent with HAC- lack of suppression at 4 and/or 8 hours
------Lack of suppression does NOT confirm the presence of a functional adrenal tumor (FAT).
---Consistent with pituitary dependent hyperadrenocorticism (PDH)
------Suppression at 4 hours with an escape at 8 hours
------Suppression at 4 and/or 8 hours to less than 50% of the baseline cortisol concentration

ACTH Stimulation Test

-Less sensitive test than LDDS test
-Less chance of false-positive result than LDDS test
-Only test that can diagnose iatrogenic HAC

-Protocol:

---Obtain baseline blood sample
---Administer synthetic ACTH (cosyntropin or tetracosactrin) intravenously at a dose of 5 μg/kg (maximum dose 250 μg/dog)
---Obtain blood sample 1 hour after administering ACTH (post-ACTH). Some clinicians also collect a 2-hour post-ACTH sample in order not to miss (get a false-negative result) the small percentage of dogs that have peak cortisol secretion after 2 hours rather than 1 hour.

-Interpretation:

---Normal dog- post ACTH cortisol concentration below the laboratory cut-off
---Consistent with HAC- post ACTH cortisol concentration above the laboratory cut-off

Basal or Resting Cortisol Concentration

-No diagnostic value for HAC

Below is the author’s approach to screening for HAC. The decision to perform additional screening tests following a negative LDDS test is based on the degree of clinical suspicion. In situations of high clinical suspicion, it is important to remember that no screening test is perfect. It may be necessary to perform multiple screening tests or repeat testing at a later date in order to confirm the diagnosis in early or more challenging cases.

cushings1.png

DIFFERENTIATING TESTS

High-dose Dexamethasone Suppression Test

-Protocol (same as LDDS test but with higher dose of dexamethasone):

---Collect baseline blood sample
---Administer 0.1 mg/kg of dexamethasone or dexamethasone SP intravenously (preferred) or intramuscularly
---Collect blood samples at 4 and 8 hours after the administration of dexamethasone
-Results can support the presence of PDH
-Results CANNOT confirm the presence of a FAT

-Interpretation:

---Consistent with PDH
------Complete suppression at 4 and/or 8 hours
------Cortisol concentrations less than 50% of baseline concentration at 4 and/or 8 hours
--Lack of suppression does NOT confirm the presence of a FAT.

Endogenous ACTH Concentration

-Single blood sample
-Immediately centrifuge and separate plasma from cells and freeze until shipping. Ship overnight on ice. This will minimize the amount of degradation, which is a concern with inappropriate sample handling.
-Possible to confirm PDH or an FAT

-Interpretation:

---Consistent with PDH- ACTH concentration is normal or increased
---Consistent with presence of a FAT- ACTH is low or undetectable

Ultrasonography

-Evaluate size and appearance of adrenal glands
-Can confirm presence of an adrenal tumor
-Aid in the detection of concurrent illness

Below is the author’s approach to differentiating PDH from FAT. The author believes it is important to confirm a FAT with ultrasound and endogenous ACTH prior to surgery because asymmetric adrenal gland enlargement and nodular hyperplasia is not uncommon with PDH.

cushings2.png


OCCULT HYPERADRENOCORTICISM

-Historically known as “atypical hyperadrenocorticism”
-Clinical signs, physical examination findings, and clinicopathologic findings support a diagnosis of HAC, but the UCCR, LDDS test, and ACTH stimulation test fail to support the diagnosis.
-It has not been proven that sex hormones are responsible for this syndrome.
-Reasons to suspect Occult HAC
---Clinical signs consistent with HAC
---Cortisol concentrations on ACTH stimulation test and LDDS test are below the reference interval
-Presence of an adrenal tumor supports the diagnosis
---Lack of tumor does not rule out diagnosis
-If clinical signs are mild, retest for classical HAC when signs worsen
-If clinical signs are moderate/severe, perform an abdominal ultrasound
---Normal adrenal glands- reconsider diagnosis
---Bilateral adrenomegaly- consider confirming PDH with cross-sectional imaging
-May be mild or early HAC
-May be food-dependent HAC (considered rare)
-Specificity of sex hormone panel is low- interpret with caution


REFERENCES

Behrend E.N., Melian C. Hyperadrenocorticism in dogs. In J. Rand (Ed.), Clinical endocrinology of companion animals. Ames, Iowa: John Wiley & Sons, Inc; 2013.
Behrend E.N. Canine Hyperadrenocorticism. In EC Feldman, RW Nelson, C Reusch, JC Scott-Moncrieff (Eds). Canine and Feline Endocrinology. Elsevier Health Sciences; 2014.
Behrend E.N., Kooistra H.S., Nelson R., Reusch C.E., Scott-Moncrieff J.C. Diagnosis of spontaneous canine hyperadrenocorticism: 2012 ACVIM consensus statement (small animal). J Vet Intern Med; 2013
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Trilostane Treatment and Monitoring: Is the ACTH stimulation test gone for good?

Lecture Time
12:10 PM - 12:35 PM
Authors
Room
Hall 717
Date
07/16/19, Tuesday
Time
12:10 PM - 12:35 PM

Abstract

Abstract Body

TRILOSTANE TREATMENT AND MONITORING: IS THE ACTH STIMULATION TEST GONE FOR GOOD?

Jon M. Fletcher, DVM, DACVIM

Louisiana State University, Baton Rouge, LA, USA

jmfletcher@lsu.edu

TRILOSTANE

Trilostane (Vetoryl®, Dechra Pharmaceuticals) is licensed for use in dogs for the treatment of pituitary-dependent hyperadrenocorticism as well as for hyperadrenocorticism resulting from a functional adrenocortical tumor. It is an orally active synthetic steroid analog that inhibits 3-beta-hydroxysteroid dehydrogenase (and 11-beta hydroxylase) in the adrenal cortex leading to decreased production of cortisol and to a lesser extent aldosterone. Trilostane is not cytotoxic and does not damage the adrenal cortex so withdrawal of the drug should result in a fairly rapid increase in the cortisol concentration unless adrenal necrosis has occurred. Adrenal necrosis is an uncommon complication that can occur during treatment with trilostane and is thought to be related to an increased ACTH concentration (endogenous and potentially exogenous from repetitive ACTH stimulation testing associated with therapeutic monitoring). Numerous clinical trials have confirmed the efficacy of trilostane for the treatment of hyperadrenocorticism, and the majority of dogs have good clinical response with minimal side effects/complications.

DOSING RECOMMENDATIONS

The manufacturer recommends starting trilostane therapy at a dose of 2.2 – 6.7 mg/kg (1 – 3 mg/lb) once daily with food (Vetoryl® package insert).

The most common starting dose in our hospital is 1 – 2 mg/kg (0.5 – 1 mg/lb) every 12 hours with food. Some authors have recommended administering this dose once daily, but in our experience once daily administration in this dosage range (1 – 2 mg/kg) does not provide adequate cortisol suppression and clinical control in most cases.

Dosing frequency continues to be a topic of debate. While once daily administration may improve compliance and reduce the cost of treatment, it is our experience that twice daily administration of a lower dose results in superior clinical control and reduces the risk of complications associated with excessive cortisol suppression.

The commercially available capsule sizes (5 mg, 10 mg, 30 mg, 60 mg, 120 mg) allow the targeted dose to be administered to most dogs without the need for compounding. If an additional size is needed, the commercially available product (Vetoryl®) can be reformulated into the appropriate capsule size by a compounding pharmacy.

MONITORING AND DOSAGE ADJUSTMENT

Dechra’s European division has recently changed the monitoring recommendations for Vetoryl® because of a shortage of synthetic ACTH in Europe. Research performed at the University of Glasgow and surrounding veterinary practices in the United Kingdom found that the pre-trilostane (before the next dose) resting cortisol concentration correlated better with clinical control than did the post-pill resting (baseline) and/or post-ACTH cortisol concentrations. It is important to recognize that the pre-trilostane resting cortisol is not the same as the post-trilostane resting cortisol (baseline sample of the ACTH stimulation test performed after trilostane administration), which is not a useful monitoring tool. Although multiple research groups have shown that the post-trilostane ACTH stimulation test (historical monitoring approach) is not a very useful monitoring tool, they have been unable to identify an alternative and superior monitoring option. The pre-trilostane (before the next dose) resting cortisol concentration may be a better alternative to the post-trilostane ACTH stimulation test. In Europe, the manufacturer recommends combining clinical assessment with the pre-trilostane resting cortisol concentration (ideal range: 1.5 – 5 mg/dL [40 nmol/L – 140 nmol/L]) to determine if a dosage change is necessary. It is important to note that clinical assessment and the presence of clinical signs should always be considered when determining if an increase in the trilostane dosage is warranted regardless of the monitoring protocol utilized. It should also be noted that using the pre-trilostane resting cortisol concentration for monitoring should be reserved for dogs that are clinically well. Dogs that are exhibiting signs of cortisol deficiency should have a complete evaluation including an ACTH stimulation test performed.

Although the monitoring recommendations have not “officially” changed in the United States, a number of institutions in the US are evaluating the use of the pre-trilostane resting cortisol concentration for monitoring trilostane therapy. Similar to what has been reported by researchers in the UK, we have found the pre-trilostane cortisol concentration and clinical assessment/response to be an effective and safe way to monitor most dogs that are clinically well. If a single cortisol measurement is to be used for monitoring purposes (synthetic ACTH is not available or an ACTH stimulation test cannot be performed because of financial limitations), the pre-trilostane cortisol concentration will likely provide the most clinically useful information.

Current Monitoring Options

Pre-trilostane resting cortisol concentration (attractive because inexpensive and convenient)

Post-trilostane ACTH stimulation test (remains most common monitoring protocol in US)

Pre-trilostane cortisol + post-trilostane ACTH stimulation test (recommended for any dog exhibiting signs of cortisol deficiency)

It is very important that clinical control and/or persistence of clinical signs associated with hypercortisolemia be considered when interpreting the results of any monitoring test/protocol and determining if a trilostane dosage increase is necessary.

Author’s Recommendations Based on the Post-ACTH Cortisol Concentration 2-4 hours after trilostane administration.

Post-ACTH Cortisol Concentration

Recommendation

< 1 mg/dL (< 28 nmol/L)

Stop treatment. Evaluate electrolytes; ACTH stimulation test (off of trilostane) in 2 weeks and/or re-start trilostane at a lower dose if/when clinical signs reoccur.

< 1.8 mg/dL (< 50 nmol/L)

Temporarily stop treatment. Re-start at a lower dose

1.8 – 9.1 mg/dL (50 – 250 nmol/L)

Either: Continue current dose if clinical signs are well controlled

Or: Dosage increase based on clinical assessment and persistence of clinical signs

> 9.1 – 16.3 mg/dL (> 250 – 450 nmol/L)

Either: Continue current dose if clinical signs are well controlled

Or: Dosage increase based on clinical assessment and persistence of clinical signs

> 16.3 mg/dL (> 450 nmol/L)

Dosage increase based on clinical assessment and persistence of clinical signs

Author’s Recommendations Based on the Pre-trilostane Cortisol Concentration (modified from the Pre-VetorylÒ Cortisol monitoring guidelines; Dechra Europe)

Pre-trilostane Cortisol Concentration

Recommendation

< 1 – 1.5 mg/dL (< 28 – 40 nmol/L)

Consider a lower dose

1.5 – 5 mg/dL (40 – 140 nmol/L)

No clinical signs of HAC- continue current dose

Or: Increase dosage or dosing frequency (once to twice daily) if inadequate clinical control/persistent clinical signs

3 – 5 mg/dL (80 – 140 nmol/L)

No clinical signs of HAC- continue current dose

Or: Increase dosage or dosing frequency (once to twice daily) if inadequate clinical control/persistent clinical signs

> 5 mg/dL (> 140 nmol/L)

No clinical signs of HAC- continue current dose

Or: Increase dosage or dosing frequency (once to twice daily) if inadequate clinical control/persistent clinical signs

Monitoring Frequency and Recommended Testing

10 – 14 days after initiating therapy or a dosage change: confirm that the dog is clinically well; no hormone testing necessary if no signs of cortisol deficiency

4 – 6 weeks: cortisol monitoring (see Current Monitoring Options)

2 – 3 months: cortisol monitoring (see Current Monitoring Options)

4 – 6 months: cortisol monitoring (see Current Monitoring Options), electrolytes

Recommend re-evaluation 2 – 3 times per year as long as the dose is stable, clinical signs are well-controlled, and the dog is doing well.

Dosage Adjustment

Dosage adjustments should be based on a combination of clinical assessment (persistence of clinical signs) and serum cortisol concentrations.

The trilostane dose should be increased by 5 – 10 mg/dose depending on the cortisol concentrations, severity of clinical signs, size of the dog, current dose, and frequency of administration.

If the dog is receiving once daily trilostane and the cortisol concentrations are within the recommended/acceptable ranges but clinical signs are not well-controlled (persistent polyuria, polydipsia, polyphagia, and/or other signs), divide the dose and administer twice daily. If the cortisol concentration(s) are above the recommended range(s), divide the dose for twice daily administration and increase by 10-25%.

REFERENCES

References available upon request.

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Monitoring canine and feline diabetics: beyond the glucose curve

Lecture Time
12:35 PM - 01:00 PM
Authors
Room
Hall 717
Date
07/16/19, Tuesday
Time
12:35 PM - 01:00 PM

Abstract

Abstract Body

MONITORING CANINE AND FELINE DIABETICS: BEYOND THE GLUCOSE CURVE

Jon M. Fletcher, DVM, DACVIM
Louisiana State University, Baton Rouge, LA, USA
jmfletcher@lsu.edu



MONITORING AND INSULIN DOSAGE ADJUSTMENT

Increases in the insulin dose should be based on the presence of clinical signs (polyuria and polydipsia, changes in body weight) combined with proof of hyperglycemia and/or unacceptable glycemic control (continuous glucose monitoring, blood glucose [BG] curves, glycated proteins [fructosamine, HbA1c]). Prior to recommending an insulin dosage increase, one should consider the severity of clinical signs, degree of hyperglycemia, size of the animal (typically increase by 1 unit/dose in cats/small dogs and 2-3 units/dose in larger dogs), and the current insulin dose (consider causes of insulin resistance or need to change formulations when dose is >1.5-2 U/kg). In order to avoid overdosing and hypoglycemia, it is recommended to wait at least 7-10 days following an increase in the insulin dose before considering another dosage increase.

Urine Glucose Quantification
Semi-quantitative urine glucose measurement is a crude assessment of glycemic control that confirms hyperglycemia in excess of the renal threshold (180-220 mg/dL in the dog and 200-280 mg/dL in the cat). The detection of glucosuria is of limited utility in dogs because given the current approach to managing canine diabetes, even well-regulated dogs would be expected to exceed the renal threshold for glucose at some point during the day. In most cases, it is possible to obtain similar clinical information by questioning the owner about observed polyuria and polydipsia. If urine glucose is used for monitoring in dogs, the author recommends only using it to assess for over supplementation/persistent hypoglycemia (i.e., recommend decreasing the insulin dose after documenting the absence of glucosuria) and not as a guide for increasing the insulin dose. Urine glucose measurement is no longer recommended as the only assessment of glycemic control in dogs and better monitoring techniques are available.
Urine glucose quantification can be used to assess glycemic control in cats because it is possible to safely maintain their blood glucose below the renal threshold (~250 mg/dL) for most/all of the day with long-acting insulin formulations. As a result, the presence of glucosuria suggests inadequate glycemic control and the need for more insulin. Urine glucose monitoring cannot be used to detect/confirm persistent hypoglycemia in cats that are in a diabetic remission (non-insulin dependent state) receiving insulin so blood or interstitial glucose monitoring must be used to confirm remission.

Blood Glucose Curves
Despite substantial day-to-day variability in BG curve results, 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 data collected in the home environment is likely more representative of the actual glycemic control than monitoring in the clinic or hospital. This is especially true in cats because of stress hyperglycemia. The author does not recommend in clinic/hospital monitoring for cats even if it appears they are tolerant/”not stressed”. It is recommended that BG curve data from multiple days during a 2-3 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 a single BG curve which may not be an accurate representation of the glycemic control. Routine blood glucose monitoring also plays an important role in detecting subclinical hypoglycemia, the occurrence of diabetic remission, and/or the return to an insulin-dependent state in cats.


Home Blood Glucose Curve Protocol

- Use a hand-held glucometer that has been 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

Continuous Glucose Monitoring

The FreeStyle Libre continuous glucose monitoring system provides a readily available, cost-effective way to continuously assess glycemic control over a 14-day period. The system measures the interstitial glucose, stores up to 8 hours of data, and does not require blood sampling for calibration. Continuous glucose monitoring is the recommended assessment method for any challenging diabetic and has replaced blood glucose curves for monitoring in most diabetics in the author’s practice.

Glycated Proteins
The fructosamine concentration provides an estimate of glycemic control/average blood glucose concentration during the preceding 1-3 weeks. Factors or conditions known to affect the fructosamine concentration include hypoproteinemia, hyperlipidemia, azotemia, and hyperthyroidism. The fructosamine concentration is infrequently measured in our practice and may provide additional information about glycemic control in fractious diabetic cats that will not tolerate home blood glucose curves or continuous glucose monitoring or to establish a diagnosis of diabetes mellitus.
Glycated hemoglobin or HbA1c plays an important role in the detection of pre-diabetes and assessment of long-term glycemic control in people. Although previously studied in dogs and cats, species differences affected the performance of human assays and greatly limited the utility of this monitoring technique. A canine and feline specific HbA1c (A1CARETM, http://baycomdiagnostics.com) test has been developed and is now commercially available. Glycated hemoglobin provides information about the average blood glucose during the preceding ~110 days in the dog and ~70 days in the cat (lifespan of the red blood cell). This test is expected to prove useful in screening and early detection of diabetes/pre-diabetes and will likely provide a better assessment of long-term glycemic control than fructosamine.

REFERENCES

References available upon request.

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Screening for Primary Glucocorticoid Deficiency

Lecture Time
11:40 AM - 12:05 PM
Authors
Room
Hall 713
Date
07/18/19, Thursday
Time
11:40 AM - 12:05 PM

Abstract

Abstract Body

SCREENING FOR PRIMARY GLUCOCORTICOID DEFICIENCY

Jon M. Fletcher, DVM, DACVIM
Louisiana State University, Baton Rouge, LA, USA
jmfletcher@lsu.edu


Basal or Resting Cortisol Concentration

- Convenient and inexpensive way to rule out hypoadrenocorticism. Recommend in dogs that have nonspecific signs (inappetence, weight loss, vomiting, diarrhea) that could be due to glucocorticoid deficiency without electrolyte abnormalities.

- > 2 mg/dL (55 nmol/L)- rules out hypoadrenocorticism

- 1-2 mg/dL (28-55 nmol/L)- hypoadrenocorticism is less likely, but an ACTH stimulation test is needed to confirm/rule out the diagnosis

- < 1 mg/dL (28 nmol/L)- an ACTH stimulation test is needed to confirm/rule out the diagnosis

- Many laboratories have decreased the detection limit of the cortisol assay from 1 mg/dL (28 nmol/L) to 0.2 mg/dL (5.5 nmol/L). Although this has improved the ability of the basal cortisol concentration to differentiate dogs with and without hypoadrenocorticism (i.e., a cortisol concentration < 0.2 mg/dL in a dog that has not received corticosteroids is highly suspicious for hypoadrenocorticism), an ACTH stimulation test or cortisol to ACTH ratio is still recommended to confirm/rule out the diagnosis in dogs with a low basal cortisol concentration.


ACTH Stimulation Test

- Still considered the gold standard for diagnosing hypoadrenocorticism

- Recommend in dogs that have clinical signs consistent with hypoadrenocorticism and hyponatremia and/or hyperkalemia.

- Can use a 1 μg/kg dose of synthetic ACTH (cosyntropin or tetracosactrin) for screening. Repeat with a 5 μg/kg dose to confirm the diagnosis if results are borderline/equivocal with the 1 μg/kg dose.



Cortisol to ACTH Ratio (CAR)

- Single blood sample can be used to confirm/rule out primary hypoadrenocorticism

- Eliminates the need for synthetic ACTH and to perform an ACTH stimulation test

- Samples must be collected before the administration of corticosteroids

- Sample handling important for endogenous ACTH measurement (review laboratory recommendations)- immediately centrifuge, separate plasma from cells, and freeze until shipping. Ship overnight on ice. This will minimize the degradation of ACTH, which is a concern with inappropriate sample handling.

- Unlike the basal cortisol and endogenous ACTH concentrations, there is no overlap of the CAR between healthy dogs, dogs with non-adrenal illness, and dogs with hypoadrenocorticism

- Not useful for cases of secondary hypoadrenocorticism (low ACTH). An ACTH stimulation test is recommended to rule out/confirm hypoadrenocorticism in dogs with low basal cortisol and ACTH concentrations.

- Interpretation:

- Calculate the ratio of basal cortisol to ACTH
- CAR = cortisol (mg/dL) ¸ ACTH (pg/mL)

- Median CAR from Lathan et al. J Vet Intern Med 2014
- Healthy = 2.27
- Non-adrenal illness = 2.84
- Hypoadrenocorticism = 0.000714

- CAR range from Lathan et al. J Vet Intern Med 2014
- Glucocorticoid deficient hypoadrenocorticism: 0.0004-0.01
- Mineralocorticoid and glucocorticoid deficient hypoadrenocorticism: 0.0004-0.0310






REFERENCES

1. Lathan P. Hypoadrenocorticism in dogs. In J. Rand (Ed.), Clinical endocrinology of companion animals. Ames, Iowa: John Wiley & Sons, Inc; 2013.
2. Scott-Moncrieff JC. Hypoadrenocorticism. In EC Feldman, RW Nelson, C Reusch, JC Scott-Moncrieff (Eds). Canine and Feline Endocrinology, Edition 4. Elsevier Health Sciences; 2015.
3. Lennon EM, Boyle TE, Hutchins RG, Friedenthal A, Correa MT, Bissett SA, Moses LS, Papich MG, Birkenheuer AJ. Use of basal serum or plasma cortisol concentrations to rule out a diagnosis of hypoadrenocorticism in dogs: 123 cases (2000-2005). JAVMA 2007;231(3):413-416.
4. Gold AJ, Langlois DK, Refsal KR. Evaluation of basal serum or plasma cortisol concentrations for the diagnosis of hypoadrenocorticism in dogs. J Vet Intern Med 2016;30:1798-1805.
5. Lathan P, Scott-Moncrieff JC, Wills RW. Use of the cortisol-to-ACTH ratio for diagnosis of primary hypoadrenocorticism in dogs. J Vet Intern Med 2014;28:1546-1550.
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