Diagnosing and Managing the Diabetic Patient. Learning objectives. Diabetes mellitus

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1 Diagnosing and Managing the Diabetic Patient Peter P. Kintzer, DVM, DACVIM Learning objectives o After completing this webinar, you should be able to: Discuss the diagnostic approach to the canine and feline diabetic patient. Choose an appropriate insulin type for an individual canine or feline diabetic patient. Discuss protocols for monitoring and adjusting therapy in the diabetic patient. Establish goals for treating diabetic ketoacidosis IDEXX Laboratories, Inc. All rights reserved. Diabetes mellitus o Common endocrine disorder Prevalence dogs 1: , cats 1: * o Absolute or relative deficiency of insulin or insulin action o Uncomplicated diabetes mellitus o Diabetic ketoacidosis (DKA) * Source: Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. 4th ed. Gloucester, UK: British Small Animal Veterinary Association; IDEXX Laboratories, Inc. All rights reserved. 1

2 Diabetes mellitus: Signalment 1,2,3 o Dogs Mean age: 8 years (range 4 14 years) Female predisposition Increased risk: keeshond, Puli, miniature pinscher, Samoyed, Cairn terrier Possible increased risk: poodle, dachshund, miniature schnauzer, beagle o Cats Mean age: 10 years (range 1 19 years) 75% are 8 13 years Male predisposition No breed predilection Sources: Tilley LP, Smith FWK. The 5-Minute Veterinary Consult: Canine and Feline. 2nd ed. Philadelphia, PA: Williams and Wilkins; Ettinger SJ, Feldman EC, eds. Textbook of Veterinary Internal Medicine. 7th ed. St Louis, MO: Elsevier Saunders; Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. 4th ed. Gloucester, UK: British Small Animal Veterinary Association; IDEXX Laboratories, Inc. All rights reserved. Diabetes mellitus: Diagnosis o Compatible clinical signs Polyuria/polydipsia (PU/PD), polyphagia, weight loss Cataracts, diabetic neuropathy o Hyperglycemia/glucosuria o Stress hyperglycemia Cats versus dogs o Increased fructosamine concentrations o DKA ketonemia/acidosis/ketonuria IDEXX Laboratories, Inc. All rights reserved. Polling question 1 True or false? Compared to dogs, cats have a low incidence of stress hyperglycemia, so a fructosamine concentration is rarely used to confirm a diagnosis of diabetes mellitus IDEXX Laboratories, Inc. All rights reserved. 2

3 Diabetes mellitus: Treatment o Insulin o Diet o Oral hypoglycemic agents o Treat underlying causes of insulin resistance IDEXX Laboratories, Inc. All rights reserved. DKA treatment goals o Correct dehydration. o Correct ketonemia/acidosis. o Correct electrolyte derangements. o Correct hyperglycemia. o Correct underlying problem(s) IDEXX Laboratories, Inc. All rights reserved. DKA treatment: Fluid therapy o Intravenous fluids 0.9% NaCl initially Correct dehydration (24 36 hours) Supplement based on serial electrolytes, Phos o Regular insulin Constant rate infusion (CRI) Low-dose intramuscular (IM) protocol High-dose subcutaneous (SQ) protocol IDEXX Laboratories, Inc. All rights reserved. 3

4 DKA treatment o Provide 24-hour intensive care. o Monitor blood gases, electrolytes, hydration, blood pressure frequently. o Monitor complete blood count (CBC), chemistry, blood gases depending on status. o Switch to longer-acting insulin once stable and nonketotic IDEXX Laboratories, Inc. All rights reserved. Commonly used insulins in dogs and cats, 2016 o Short-acting Regular (Humulin R, Novolin R) o Intermediate-acting Lente (Vetsulin /Caninsulin ) NPH (Humulin N, Novolin N) o Long-acting PZI (ProZinc ) Insulin glargine (Lantus ) Insulin detemir (Levemir ) IDEXX Laboratories, Inc. All rights reserved. Insulin potency and duration Sources: Ettinger SJ, Feldman EC, eds. Textbook of Veterinary Internal Medicine. 7th ed. St Louis, MO: Elsevier Saunders; Mooney CT, Peterson ME, eds. BSAVA Manual of Canine and Feline Endocrinology. 4th ed. Gloucester, UK: British Small Animal Veterinary Association; IDEXX Laboratories, Inc. All rights reserved. 4

5 What s the best insulin for dogs? How about for cats? o Amino acid sequence of insulin (species of origin) o Insulin concentration (U-100 versus U-40) o Insulin potency versus duration of action o Insulin shelf life o Insulin cost IDEXX Laboratories, Inc. All rights reserved. Species of origin of insulin o Human and canine insulins are quite similar. Differ by only one amino acid o Canine and porcine insulin are identical. o Feline and bovine insulin differ by only a single amino acid. o Feline insulin is quite different from pork or human insulin. o Dogs can develop antibodies directed against bovine insulin IDEXX Laboratories, Inc. All rights reserved. Insulin amino acid sequence Amino acid chain and position Species A #8 A #10 A #18 B #30 Porcine, canine Thr Ile Asn Ala Human Thr Ile Asn Thr Feline Ala Val His Ala Bovine Ala Val Asn Ala IDEXX Laboratories, Inc. All rights reserved. 5

6 Insulin amino acid sequence Amino acid chain and position Species A #8 A #10 A #18 B #30 Porcine, canine Thr Ile Asn Ala Human Thr Ile Asn Thr Feline Ala Val His Ala Bovine Ala Val Asn Ala IDEXX Laboratories, Inc. All rights reserved. Insulin amino acid sequence Amino acid chain and position Species A #8 A #10 A #18 B #30 Porcine, canine Thr Ile Asn Ala Human Thr Ile Asn Thr Feline Ala Val His Ala Bovine Ala Val Asn Ala IDEXX Laboratories, Inc. All rights reserved. Insulin amino acid sequence Amino acid chain and position Species A #8 A #10 A #18 B #30 Porcine, canine Thr Ile Asn Ala Human Thr Ile Asn Thr Feline Ala Val His Ala Bovine Ala Val Asn Ala IDEXX Laboratories, Inc. All rights reserved. 6

7 Insulin amino acid sequence Amino acid chain and position Species A #8 A #10 A #18 B #30 Porcine, canine Thr Ile Asn Ala Human Thr Ile Asn Thr Feline Ala Val His Ala Bovine Ala Val Asn Ala IDEXX Laboratories, Inc. All rights reserved. Insulin concentrations o U-100 standard for all human insulin o U-40 becoming standard for veterinary insulin ProZinc Vetsulin /Caninsulin o Easier to give small doses with U-40 insulin o No matter what insulin is used, insulin concentration must match insulin syringe! IDEXX Laboratories, Inc. All rights reserved. Insulin syringes o U-100 All human insulins and insulin analogs are U-100. U-100 insulin syringes manufactured with 0.25 ml, 0.3 ml, 0.5 ml, and 1 ml capacities. Low-dose U-100 syringes should be used in most dogs and all cats. Insulin pens for some human preparations o U-40 ProZinc and Vetsulin/Caninsulin are U-40. U-40 insulin syringes are generally manufactured with 0.5 ml capacity. Insulin syringe must match the insulin concentration! IDEXX Laboratories, Inc. All rights reserved. 7

8 Polling question 2 Which of the following statements is true? A. Insulin detemir and NPH insulin are considered long-acting insulins. B. ProZinc and Vetsulin are U-40 insulins. C. Lose-dose U-100 insulin syringes are not recommended for administered insulin glargine to cats. D. Regular insulin is less potent than ProZinc or NPH. E. None of the above IDEXX Laboratories, Inc. All rights reserved. Insulin treatment of cats with uncomplicated diabetes mellitus o Initiate treatment with a long-acting insulin. o The insulin dose is typically adjusted by units per injection, based on the clinical response and laboratory evaluations, including fructosamine concentrations. o Monitor for remission. o Feed a low-carbohydrate diet unless contraindicated IDEXX Laboratories, Inc. All rights reserved. ProZinc o Protamine zinc insulin (PZI) o Long-acting insulin preparation o Recombinant human insulin o U-40 insulin; requires U-40 syringes o FDA-approved for cats o Start at 0.25 U/kg (1 U/cat/dose) o Twice-daily dosing always recommended if remission is the goal IDEXX Laboratories, Inc. All rights reserved. 8

9 Compounded insulin o Specialists recommend against use of insulin products from compounding pharmacies: Diabetic dogs and cats tend to have more problems with glycemic control o No published data documenting quality and consistency of compounded insulin products o Initiated a study* to evaluate compounded PZI o Most common insulin product provided by compounding pharmacies * Source: Scott-Moncrieff JC, Moore GE, Coe J, Lynn RC, Gwin W, Petzold R. Characteristics of commercially manufactured and compounded protamine zinc insulin. JAVMA. 2012;240(5): IDEXX Laboratories, Inc. All rights reserved. Materials and methods of compounded PZI study o PZI ordered from 13 different commercial sources: 1 manufacturer, 12 compounding pharmacies 3 vials from each source U ml bottles o Vial disposition: One vial from each source repackaged into masked container by pharmacy technicians One masked vial and one original vial shipped to IDEXX Laboratories for analysis o Study repeated every 2 months for 4 repetitions Source: Scott-Moncrieff JC, Moore GE, Coe J, Lynn RC, Gwin W, Petzold R. Characteristics of commercially manufactured and compounded protamine zinc insulin. JAVMA. 2012;240(5): IDEXX Laboratories, Inc. All rights reserved. Compounded PZI study findings: Insulin potency o USP specification 90% 110% labeled concentration U/mL (U-40) o Range insulin concentration in study (U-40) 24.5 U/mL to 41.8 U/mL o Insulin concentration below the USP specification 6 products 2 to 8 occasions o Large amounts of free insulin in supernatant in three insulin products Source: Scott-Moncrieff JC, Moore GE, Coe J, Lynn RC, Gwin W, Petzold R. Characteristics of commercially manufactured and compounded protamine zinc insulin. JAVMA. 2012;240(5): IDEXX Laboratories, Inc. All rights reserved. 9

10 Compounded PZI study: Summary o Most sources of compounded PZI insulin do not meet USP specifications: Low potency Interlot variability in potency Incorrect ph Free insulin in supernatant Variability in zinc content Endotoxin o Potential for adverse clinical consequences o Results support recommendations to avoid compounded insulin Source: Scott-Moncrieff JC, Moore GE, Coe J, Lynn RC, Gwin W, Petzold R. Characteristics of commercially manufactured and compounded protamine zinc insulin. JAVMA. 2012;240(5): IDEXX Laboratories, Inc. All rights reserved. Insulin glargine (Lantus) o Long-acting U-100 insulin analog o Asparagine replaced by glycine in -chain and 2 arginine molecules added to C-terminus of -chain o In the vial, it is in solution at a ph of 4, but it forms crystals that are absorbed slowly when injected SQ, where ph is close to IDEXX Laboratories, Inc. All rights reserved. Insulin glargine: Newly diagnosed cats o Insulin glargine Long-acting Nadir prolonged but variable 0.25 U/kg (1 U/cat/dose) Give twice daily if remission is goal Diet is again important IDEXX Laboratories, Inc. All rights reserved. 10

11 Study: Glargine, PZI, and lente in new diabetic cats* o Trial of 24 cats o Remission in 8/8 treated with glargine o Remission in 3/8 treated with PZI o Remission in 2/8 treated with lente o All cats fed a low-carbohydrate diet o 50% Burmese cats * Sources: Marshall RD, Rand JS, Morton JM. Treatment of newly diagnosed diabetic cats with glargine insulin improves glycaemic control and results in higher probability of remission than protamine zinc and lente insulins. J Feline Med Surg. 2009;11(8): Marshall RD, Rand JS. Treatment with glargine results in higher remission rates than lente or protamine zinc in newly diagnosed diabetic cats [ACVIM Abstract 95]. J Vet Intern Med. 2009;19(3): IDEXX Laboratories, Inc. All rights reserved. Study: Glargine and lente in new diabetic cats* o Trial of 90 cats o Diet not constant o Remission in 50% cats 53% cats treated glargine 47% cats treated lente o Age, cholesterol, body weight, and glucose concentration influenced likelihood of remission and duration * Source: Zini E, Hafner M, Osto M, Franchini M, Ackermann M, Lutz TA, Reusch CE. Predictors of clinical remission in cats with diabetes mellitus. J Vet Intern Med. 2010;24(6): IDEXX Laboratories, Inc. All rights reserved. Insulin detemir (Levemir) o Insulin detemir (Levemir ) is a long-acting insulin analog that was FDA-approved in Acylated fatty acid chain added. Slows SQ absorption and enables reversible binding to plasma proteins resulting in slow release from plasma proteins IDEXX Laboratories, Inc. All rights reserved. 11

12 Insulin detemir: Newly diagnosed cats o Long-acting insulin analog o Preliminary reports in cats Lower initial dose than PZI and glargine (0.5 U/cat/dose) Similar remission rates Similar time to remission Median maximum dose used about 30% lower than glargine o Give twice daily if remission is goal o Diet is again important IDEXX Laboratories, Inc. All rights reserved. Insulin treatment: Cats with diabetes mellitus o Lente Longer duration and more effective than NPH Also results in diabetic remission in some cats More potent so good choice in cats with concurrent illness Dose U/kg or 1 3 units per cat; give twice daily o NPH Consistent rapid absorption Effectively lower blood glucose Too short a duration of action (<12 hours) for optimal blood glucose control in some cats, even with twice-daily dosing IDEXX Laboratories, Inc. All rights reserved. How common is diabetic remission? Number cats in remission Percent cats in remission Reference Notes 12/18 67% Roomp, JFMS 2012 Intense protocol 7/17 41% Tschuor, JVIM /90 50% Zini, JVIM /24 54% Marshall, JFMS /55 64% Roomp, JFMS 2009 Intense protocol 2/12 17% Hall, JFMS /46 17% Michiels, JFMS /12 58% Sieber-Ruckstuhl, 2008 Cats with DKA 13/32 40% Alt, Vet Sci /63 55% Bennett, JFMS /13 31% Weaver, JVIM IDEXX Laboratories, Inc. All rights reserved. 12

13 Insulin use in cats with diabetic remission? Reference Number of cats in remission Percent cats in remission Type of insulin Roomp, /18 67% Detemir Tschuor, /17 41% Glargine/Lente Zini, /90 50% Glargine/Lente Marshall, /24 54% Glargine, PZI, Lente Roomp, /55 64% Glargine Hall, /12 17% Glargine Michiels, /46 17% Lente Sieber-Ruckstuhl, /12 58% Glargine/Lente Alt, /32 40% Lente Rand, /25 28% Lente Bennett, /63 55% PZI, Lente, Ultralente, NPH Weaver, /13 31% Glargine/Lente IDEXX Laboratories, Inc. All rights reserved. Feline nutrition o Cats are obligate carnivores. o Natural diet of cats in the wild is meat-based (rodents, birds) that contains few carbohydrates. o Cats have not developed the metabolic pathways for processing high-carbohydrate diets that omnivores have IDEXX Laboratories, Inc. All rights reserved. Dietary recommendations for cats with diabetes mellitus o Low-carbohydrate diet (ideally 7% 10%) o Normal to higher protein o Higher fat o Prescription and commercial IDEXX Laboratories, Inc. All rights reserved. 13

14 Polling question 3 Of the following insulins, which is the best choice for a newly diagnosed uncomplicated feline diabetic? A. Humulin R B. Humulin N C. ProZinc D. Novolin N IDEXX Laboratories, Inc. All rights reserved. Insulin treatment of dogs with uncomplicated diabetes mellitus o Use species-specific insulin if possible: Pork insulin best for dogs (Vetsulin ) Human insulin second choice (Humulin N, Novolin N) o Intermediate-acting insulin, administered twice daily, works best and is effective in most cases. o U-40 is easier to administer in small dogs IDEXX Laboratories, Inc. All rights reserved. Insulin treatment of dogs with uncomplicated diabetes mellitus o Initiate treatment with an intermediate-acting insulin Dose of U/kg every 12 hours subcutaneously o Based on the clinical response and laboratory evaluations, the insulin dose is adjusted by 1 5 units per injection, depending on the size of the dog. o Diet must be addressed: Low fat, high fiber Weight loss, if obese IDEXX Laboratories, Inc. All rights reserved. 14

15 Insulin detemir in dogs o Four times more potent in dogs than other insulins Initial dose 0.1 U/kg o May limit use in small dogs o If transitioning, start at 25% of dose of the previous insulin IDEXX Laboratories, Inc. All rights reserved. ProZinc in dogs o Recent study from UCD 6 new diabetics; 11 poorly controlled with NPH o Clinically effective in most dogs o Poor control based on blood glucose curves or fructosamine o Variable time to nadir Overlap of effect in some patients o Consider if NPH and detemir ineffective * Source: Maggiore AD, Nelson RW, Dennis J, Johnson E, Kass PH. Efficacy of protamine zinc recombinant human insulin for controlling hyperglycemia in dogs with diabetes mellitus. J Vet Intern Med. 2012;26(1): IDEXX Laboratories, Inc. All rights reserved. Insulin glargine in dogs o Two published studies in dogs* 10 dogs, 12 dogs Clinically effective most dogs Poor control based on blood glucose curves one study Good control based on blood glucose curves other study Neither study evaluated fructosamine o Consider glargine as another option after ProZinc for longer-acting insulin in dogs in which lente or NPH ineffective because of short duration action * Sources: Fracassi F, Boretti FS, Sieber-Ruckstuhl NS, Reusch CE. Use of insulin glargine in dogs with diabetes mellitus. Vet Record. 2012;170:52. Hess RS, Drobatz KJ. Glargine insulin for treatment of naturally occurring diabetes mellitus in dogs. JAVMA. 2013;243(8): IDEXX Laboratories, Inc. All rights reserved. 15

16 Long-term monitoring of diabetes mellitus in dogs and cats o Clinical response History, clinical signs, physical examination are critical for evaluating response to therapy o Blood glucose curves o Urine glucose determinations o Fructosamine levels o Evaluate patient every 2 3 weeks during the initial regulation and then every 3 6 months during long-term management IDEXX Laboratories, Inc. All rights reserved. Long-term monitoring of diabetes mellitus: blood glucose curves o In hospital vs. at home o Ideally every 2 hours for 8 12 hours if on twice-daily insulin o Generally, owner feeds and administers insulin at home o Pros and cons of blood glucose curves Blood Glucose mg/dl Time IDEXX Laboratories, Inc. All rights reserved. Long-term monitoring of diabetes mellitus: fructosamine o Stable complexes of serum carbohydrates and proteins that are related to circulating glucose concentration o Assessment of the average blood glucose level over the previous 2 3 weeks o Used concurrently with blood glucose curves and clinical response to monitor the effectiveness of insulin therapy o Pros and cons IDEXX Laboratories, Inc. All rights reserved. 16

17 Fructosamine on the Catalyst Dx or the Catalyst One o Fructosamine slide for use on the Catalyst Dx Chemistry Analyzer or the Catalyst One Chemistry Analyzer: o Dynamic range ( μmol/l) o Accurate results in <9 minutes o Correlates very well with reference laboratory assay R2 = 0.93 in dogs; R2 = 0.97 in cats* o Reference ranges and interpretive comments are aligned with those of IDEXX Reference Laboratories o Improved work flow diagnose and/or adjust therapy during the patient visit * Source: Data on file at IDEXX Laboratories, Inc. Westbrook, Maine USA IDEXX Laboratories, Inc. All rights reserved. Fructosamine on the Catalyst Dx Source: Data on file at IDEXX Laboratories, Inc. Westbrook, Maine USA IDEXX Laboratories, Inc. All rights reserved. The value of interactive communication VetConnect PLUS IDEXX Laboratories, Inc. All rights reserved. 17

18 Polling question 4 Fructosamine: A. Provides an assessment of the average blood glucose concentration over the previous 2 3 months B. Is a useful parameter for monitoring insulin therapy in dogs but is not useful in cats C. Determination is often used for the confirmation of diabetes mellitus in dogs D. Evaluation in isolation is the recommended way to monitor diabetic patients E. None of the above IDEXX Laboratories, Inc. All rights reserved. Treatment of feline diabetes: Potential developments* o Incretin-based therapies Are replacing insulin in human type 2 diabetes Are as or more effective in improving glycemic control o Safer and more convenient Decreased risk of hypoglycemia Weight loss instead of gain o Incretins Glucagon-like peptide 1 (GLP-1) Glucose-dependent insulinotropic polypeptide (GIP) * Source: Gilor, C. Advances in Diabetes Therapy: GLP-1-Based Drugs in Veterinary Medicine. Presented at: ACVIM 2016 Forum; June 10, 2016; Denver, CO IDEXX Laboratories, Inc. All rights reserved. GLP-1 physiology o L cells in gut secrete GLP-1 in response to food in lumen o Augments insulin secretion by increasing the sensitivity of beta cells to glucose o Inhibits glucagon secretion o Acts to do these actions during hyperglycemia in a glucosedependent manner Source: Gilor, C. Advances in Diabetes Therapy: GLP-1-Based Drugs in Veterinary Medicine. Presented at: ACVIM 2016 Forum; June 10, 2016; Denver, CO IDEXX Laboratories, Inc. All rights reserved. 18

19 GLP-1 physiology o Slows gastric emptying o Increases satiety o Promotes weight loss o Promotes expansion of beta cell mass o Protects beta cells from apoptosis Glucotoxicity Lipotoxicity Dexamethasone Source: Gilor, C. Advances in Diabetes Therapy: GLP-1-Based Drugs in Veterinary Medicine. Presented at: ACVIM 2016 Forum; June 10, 2016; Denver, CO IDEXX Laboratories, Inc. All rights reserved. GLP-1 analogs o GLP-1 has a very short half-life o Analogs have a prolonged half-life o Current formulations of analogs are for subcutaneous injection o Other delivery systems are being researched Oral Inhaled Sublingual Source: Gilor, C. Advances in Diabetes Therapy: GLP-1-Based Drugs in Veterinary Medicine. Presented at: ACVIM 2016 Forum; June 10, 2016; Denver, CO IDEXX Laboratories, Inc. All rights reserved. GLP-1 analogs: Exenatide (Byetta ) o Synthetic version of the exendin-4 peptide isolated from Gila monster venom o 3 4 hour half-life in people (once to twice daily injections) o As effective as glargine with fewer side effects o In healthy cats, results in glucose-dependent insulin secretion after subcutaneous injection Induces weight loss Low risk of hypoglycemia Source: Gilor, C. Advances in Diabetes Therapy: GLP-1-Based Drugs in Veterinary Medicine. Presented at: ACVIM 2016 Forum; June 10, 2016; Denver, CO IDEXX Laboratories, Inc. All rights reserved. 19

20 GLP-1 analogs: Exenatide XR (Bydureon ) o Once-weekly to biweekly subcutaneous injection in people o More effective than once-daily glargine with less hypoglycemia and with weight loss, not gain o Studied in healthy cats using hyperglycemic clamp Insulin secretion increased Glucagon secretion decreased Glucose tolerance increased o Preliminary studies in diabetic cats Source: Gilor, C. Advances in Diabetes Therapy: GLP-1-Based Drugs in Veterinary Medicine. Presented at: ACVIM 2016 Forum; June 10, 2016; Denver, CO IDEXX Laboratories, Inc. All rights reserved. GLP-1 analogs: Albiglutide (Tanzeum ) o Recombinant GLP-1 albumin fusion protein o Full spectrum of GLP-1 actions o Has been investigated in people as a weekly, biweekly, and monthly injection o FDA-approved for people in 2014 Source: Gilor, C. Advances in Diabetes Therapy: GLP-1-Based Drugs in Veterinary Medicine. Presented at: ACVIM 2016 Forum; June 10, 2016; Denver, CO IDEXX Laboratories, Inc. All rights reserved. Summary o After completing this webinar, you should be able to: Discuss the diagnostic approach to the canine and feline diabetic patient. Choose an appropriate insulin type for an individual canine or feline diabetic patient. Discuss protocols for monitoring and adjusting therapy in the diabetic patient. Establish goals for treating diabetic ketoacidosis IDEXX Laboratories, Inc. All rights reserved. 20

21 IDEXX Learning Center resources For more information, visit the IDEXX Learning Center The IDEXX Guide to Diabetes Learning More about the Catalyst Dx Analyzer Diagnosing and Managing the Diabetic Patient Taking Advantage of the Fructosamine Diabetes Mellitus Link The Diabetes Challenge IDEXX Laboratories, Inc. All rights reserved. Thank you! 21

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