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2 David Bruyette, DVM, DACVIM VCA West Los Angeles Animal Hospital 1818 South Sepulveda Blvd Los Angeles, CA (ext 226)

3 Communicating with Owners of Diabetic Pets The number one cause of death in diabetic dogs and cats is 1) Renal failure 2) Pancreatitis 3) Owner elected euthanasia 4) Heart disease

4 Communicating with Owners of Diabetic Pets Importance of Effective Communication 1) # 1 cause of death = owner elected euthanasia 2) Concerns over time commitment and expense 3) Diabetes as a chronic disease 4) Potential for excellent long term quality of life

5 Communicating with Owners of Diabetic Pets What can I expect and how is this disease like diabetes in people? 1) Differences in pathogenesis 2) Differential diagnosis in dogs and cats 3) Long term side effects in humans Nephropathy, retinopathy, neuropathy, vascular disease

6 Communicating with Owners of Diabetic Pets What percentage of dogs develop diabetic induced cataracts with the first 2 years of treatment? 1) 25 % 2) 60 % 3) 70 % 4) 80 %

7 Etiology (Canine) Genetics Infection Insulin resistance Immune-mediated Pancreatitis

8 Canine Age 4-14 years Breeds Miniature poodles Females > Males Dachshunds Schnauzers Beagles

9 Clinical Signs Polyuria/polydipsia Polyphagia Weight loss Dehydration Neuropathies Cataracts Icterus Poor hair coat

10 Goals of Therapy Remission of clinical signs Slow or delay progression of cataracts 75 % within 2 years Maintenance of body weight Avoidance of hypoglycemia

11 Management of Diabetes Diet Insulin Oral hypoglycemic agents Concurrent illness Owner consultation

12 Insulin Therapy Species of origin Beef, beef/pork, pork, human Increasingly difficult to obtain animal origin Focus on use of human origin products Role of antibodies and duration of action Pork > human > beef/pork

13 Ultra Fast Acting Insulins Brand Name Onset Peak Duration Structure Humalog (Insulin lispro; Lilly) 5-15 minutes minutes 3-4 hours Lysine proline substitution Novolog (Insulin aspart; Novo) 5-15 minutes minutes 3-4 hours Aspartate- proline substitution

14 Fast Acting Insulins Brand Name Onset Peak Duration Structure Humulin-R Novlin-R Velosulin minutes 2-5 hours 5-8 Hours Regular insulin Iletin II Pork

15 Intermediate Acting Insulins Brand Name Onset Peak Duration Structure Humulin-L Humulin-N Novolin-L Novolin-N 1-3 hours 2-10 hours 6-24 Addition of protamine and zinc Iletin II-L Iletin II-N Pork

16 Long Acting Insulins Brand Name Onset Peak Duration Structure Humulin-U 1-3 hours Mix of semilente and ultralente PZI (Idexx) 1-3 hours Pork

17 Ultra Long Acting Insulins Brand Name Detemir Onset Peak Duration Structure Lysine at B29 Lantus (insulin glargine; Aventis) 1 hour No peak Constant concentration over 24 hours Addition of arginine and asparagineglycine substitution

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19 Newly Diagnosed Feline Patients Insulin glargine (Lantus): Glargine is a modified, recombinant, long acting insulin analog. Several studies demonstrate a very high rate of remission % in feline diabetics with the use of glargine and a low carbohydrate-high protein diet.

20 Insulin Recall Insulin glulisine Apidra Solostar Same manufacturer as insulin glargine Ultrafast acting insulin

21 Glargine and Cancer Jan 12, At this time, FDA has not concluded that Lantus increases the risk of cancer. Our review is ongoing, including review of information from a current clinical trial, and the Agency will update the public when it has additional information.

22 Newly Diagnosed Feline Patients The recommended starting dose is 0.5 units/kg BID if the fasting blood sugar is greater than 360 mg/dl and 0.25 units/kg BID if the initial fasting blood glucose is less than 360 mg/dl. For additional information see:

23 Newly Diagnosed Feline Patients Recheck blood glucose in 7 days Pre meal/pre insulin 4 hour post Preferably at home

24 If the preinsulin blood glucose concentration is > 360 mg/dl and/or the 4 hour post blood glucose concentration is > 180 mg/dl the dose of insulin is increased by 0.5 to 1 unit BID. If the preinsulin blood glucose concentration is 270 to 360 mg/dl and/or the 4 hour post glucose concentration is mg/dl the dose of insulin is maintained.

25 If the preinsulin blood glucose concentration is mg/dl and/or the 4 hour post glucose concentration is mg/dl use clinical signs and the next preinsulin glucose concentration to determine if the dose is decreased or maintained. If the preinsulin blood glucose concentration is < 180 mg/dl and/or the 4 hour post glucose concentration is < 54 mg/dl the dose of insulin is decreased by 0.5 to 1 unit BID. If the total insulin dose is already unit BID, stop the insulin and check for diabetic remission.

26 Newly Diagnosed Feline Patients Humulin N and Novolin N: Similar to PZI with remission rates of % when used with a low carbohydrate-high protein diet. Starting doses are generally 1-3 units/cat once a day.

27 Newly Diagnosed Feline Patients Vetsulin: Again similar to PZI and Humulin N with remission rates of % when used with a low carbohydrate-high protein diet. Starting doses are generally 1-3 units/cat once a day.

28 Transitioning Feline Patients If you wish to transition them to glargine, I would follow the dosage recommendations as outlined above under newly diagnosed patients. It is important to note that remission rates will be much lower with glargine and a low carbohydrate-high protein diet in long standing diabetic patients (cats with diabetes for more than 6 months) than in newly diagnosed patients.

29 Initial Insulin Treatment NPH vs Lente NPH (Humulin-N) or Vetsulin 0.5 units/kg BID (Canine) - Glargine - Cat - NPH (Humulin-N) or PZI 1-3 units (Cat) Home vs Hospitalization Client Education

30 Changes in Insulin Availability Newly Diagnosed Canine Patients Vetsulin (porcine origin lente) Humulin N or Novolin N (human origin) ProZinc (human recombinant) Glargine (long acting insulin analogue)

31 Changes in Insulin Availability Newly Diagnosed Canine Patients Humulin N or Novolin N (human origin) J Vet Intern Med. Jan-Feb;23(1):50-5, An investigation of the action of Neutral Protamine Hagedorn human analogue insulin in dogs with naturally occurring diabetes mellitus.

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33 Vetsulin 40 IU/ml Porcine origin Lente insulin Intermediate-acting 30% amorphous & 70% crystalline insulin J Vet Intern Med Nov-Dec; , 2008 Anti-insulin antibodies in diabetic dogs before and after treatment with different insulin preparations.

34 Vetsulin

35 Initial Insulin Treatment NPH vs Lente NPH (Humulin-N) or Vetsulin 0.5 units/kg BID (Canine) Home vs Hospitalization Client Education

36 Client Education Clinical signs Injection techniques Handling, storage and mixing of insulin, syringes Signs of hypoglycemia Urine monitoring Trends Not used to adjust dose

37 Dietary Management (Canine) Maintain ideal weight High CHO (50%), low fat (<20%), high fiber (15-25%) Complex carbohydrates Increase insulin sensitivity, increase insulin receptors, post-receptor effects

38 Dietary Management (Canine) Diet Hill s - W/d, Science Diet Light Gaine s - Cycle 3 - Light Purina - Fit and Trim, Low Calorie Formula Iam s - Glucose Control IVD - Hi Factor

39 Dietary Management High Fiber Reduces insulin resistance Decreases post-prandial hyperglycemia Delays gastric emptying

40 Dietary Management J Small Anim Pract Nov;50(11): Lack of advantage of high-fibre, moderate-carbohydrate diets in dogs with stabilized diabetes.

41 Dietary Management Domest Anim Endocrinol Nov;37(4): Improvement in insulin resistance and reduction in plasma inflammatory adipokines after weight loss in obese dogs.

42 Dietary Management Feeding schedule Meals vs free choice Avoid semi-moist foods Ideal vs reality Once daily insulin - 3 meals Twice daily insulin - 4 meals

43 Home Monitoring Clinical signs Urine sugars and ketones Appetite Blood glucose monitoring

44 Long Term Monitoring Clinical Signs Body weight Cataracts CBC, Chemistries, UA with culture Serial BG s Pros and Cons

45 Communicating with Owners of Diabetic Pets Can I monitor my pet s blood glucose s at home? Numerous studies have shown that pet owners can reliably obtain blood samples from cats and dogs More accurate due to lack of stress response Improved glycemic control

46 Communicating with Owners of Diabetic Pets Indications: Initial management Whenever the animal is ill or shows progression in clinical signs Change in insulin dose Aggressive insulin protocols (cats)

47 Communicating with Owners of Diabetic Pets 1) Pre-prandial and pre insulin 2) Every 2 hours (dogs; cats on NPH, ProZinc or Vetsulin) or 4 hours (cats on glargine) post prandial/insulin 3) Samples should be obtained for 12 hours or until the nadir (lowest glucose concentration) is observed

48 Communicating with Owners of Diabetic Pets Dogs on NPH or lente (Vetsulin) Insulin s: If the preinsulin blood glucose concentration is > 360 mg/dl and/or the nadir blood glucose concentration is > 180 mg/dl the dose of insulin is increased by 25% If the preinsulin blood glucose concentration is 270 to 360 mg/dl and/or the nadir blood glucose concentration is mg/dl the dose of insulin is maintained

49 Communicating with Owners of Diabetic Pets Dogs on NPH or lente (Vetsulin) Insulin s: If the preinsulin blood glucose concentration is mg/dl and/or the nadir blood glucose concentration is mg/dl use the nadir, clinical signs and the next preinsulin glucose concentration to determine if the dose is decreased (50%) or maintained If the preinsulin blood glucose concentration is < 180 mg/dl and/or the nadir blood glucose concentration is < 54 mg/dl the dose of insulin is decreased by 50%

50 Glycated Blood Proteins Fructosamine Glycation of serum proteins (albumin) Reflection of glycemic control over the past 2-3 weeks

51 Glycosylated Hemoglobin HbA1c Reflection of glycemic control over the past 4 to 6 weeks Decreased with anemia

52 Feline Insular Amyloid Concentration increases with age Number of affected islets Extent of deposition

53 Feline Insular Amyloid Diabetes Mellitus

54 Feline Insular Amyloid Islet Amyloid (IA) Product of Islet Amyloid Polypeptide (IAPP) Co-produced in beta cell Co-secreted with insulin

55 Feline Insular Amyloid Role of IA and IAPP in Diabetes Physical injury to beta cells Biological activity of IAPP Islet cell membrane effects glucose and insulin transport Glucose toxicty

56 Oral Hypoglycemics Sulfonylureas Glipizide (Glucotrol) Glimepiride (Amaryl) Glyburide (Glynase) Meglitinides Repaglinade (Prandin) Nateglinade (Starlix) Biguanidines Metformin (Glucophage) Alpha-glucosidase inhibitors Acarbose (Precose) Miglitol (Glyset) Thiazolidinediones Pioglitazone (Actos) Rosiglitazone (Avandia)

57 Glipizide (Glucotrol) Stimulates insulin release Decreases glucose production Post-receptor effects Increase in insulin receptors

58 Glipizide (Glucotrol) Dose 2.5 to 5.0 mg BID Glimiperide (Amaryl) Dose 2 mg SID Only effective in NIDDM Stable cats, no ketones, normal to obese

59 Glipizide (Glucotrol) Efficacy Rates 15-20% Effects on beta cells Side-effects Liver enzyme elevations Hypoglycemia

60 Diabetes mellitus Acarbose (Precose) Oral alpha-1 glucosidase inhibitor Reduces absorption of monosaccharides In conjunction with diet and/or insulin Flatulence and diarrhea 12.5 to 25 mg BID to TID (cats) 12.5 to 50 mg BID to TID (dogs)

61 Metformin (Glucophage) Biguanidine derivative No effect on beta cell function Decreases hepatic gluconeogenesis Enhances peripheral sensitivity to insulin

62 Metformin (Glucophage) Used with diet and sulfonylureas Does not result in hypoglycemia Decreases LDL and cholesterol Results in weight loss 125 to 250 mg BID? (cats)

63 Thiazolidinediones Actos and Avandia Facilitates insulindependent glucose disposal in peripheral tissues NIDDM with insulin resistance No hypoglycemia

64 Meglitinides Prandin and Starlix Stimulate release of insulin from beta cells, similar to sulfonylureas Less incidence of hypoglycemia Lowers post prandial hyperglycemia

65 dipeptidyl peptidase

66 Byetta (exenatide) Incretin mimetic Binds to GLP-1 Stimulates insulin secretion Normalizes hypersecretion of glucagon Decreases gastric emptying Improves satiety

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69 Chromium and Vanadium Transition metals Insulinomimetic properties NIDDM and IDDM Acts at post-receptor sites Chromium 100 ug BID Vanadium 200 ug/day in food