Top Clinical Endocrinology Research Abstracts Presented at the 2014 ACVIM Meeting: Diabetes

Last week, I spent a week in Nashville, Tennessee attending the the 2014 American College of Veterinary Internal Medicine Forum. As part of that meeting, a number of research abstracts were presented (oral and poster presentations) that dealt with various aspects of canine and feline endocrinology. I plan to take the next four blog posts to discuss some of the newest and best research findings featured at the ACVIM meeting.

Of all of the excellent endocrine research abstracts presented, I've selected a "top 12 list" of the ones that have the most potential to change what I do in my clinical practice. To do this, I've enlisted the help of Dr. Rhett Nichols, a well-known expert in endocrinology and internal medicine whose day-job is senior member of the veterinarian consulting service for Antech Diagnostics, the world's largest laboratory dedicated to animal health. However, since Rhett also serves as a consultant for the Animal Endocrine Clinic (my practice), it was not that difficult to get him involved in this project!

In this post, we will review 3 of these top 12 abstracts, followed by the remaining 9 abtracts in the upcoming 3 posts. We hope you agree with our selections, but if you don't, remember that you can always post a comment and add your opinion.

Borin-Crivellenti S, Bonagura, JD, Gilor G. Comparison of Precision and Accuracy of U100 and U40 Insulin Syringes. J Vet Intern Med 2014;28:1029.

Day-to-day variability of insulin action is an important factor in attaining glycemic control in diabetics. In part, this variability is caused by imprecise dosing of insulin. 

We hypothesized that a U40 insulin syringe (U40) would be more precise than a U100 insulin syringe (U100). We dispensed 1, 2.5, and 4 international unit (IU) of insulin using 24 syringes for each dose from a BD Ultra-Fine 0.3-cc U100 (1⁄2 Unit Markings) and a VetOne 0.3-cc U40. Each dose was weighed on an analytical scale, and accuracy (mean [± SD] of actual dose–target dose*100/target dose) and precision (the coefficient of variation [SD/Mean] of the actual dose) were calculated. The proportions of CID (clinically important deviation: ≥ ± 20% off target) outcomes were compared between syringe types. 

U40 was more accurate for 1, 2.5 and 4IU (13.2 ± 8.7%; 6.0 ± 2.76%; 3.2 ± 1.6%, respectively) than U100 (28.2 ± 15.4%; 10.7 ± 8.0%; 4.6 ± 2.9%, respectively) (p < 0.05). Precision was lowest for 1IU but improved with increasing dose (U40: 1IU = 15.8%, 2.5IU = 6.4%, 4IU = 3.5%; U100: 1IU = 15.1%, 2.5IU = 8.1%, 4IU = 3.3%). U40 was more precise than U100 for dosing of 2.5IU (p < 0.05) despite the 1/2-unit markings on U100. CID outcomes were more frequent in U100 vs. U40 in 1IU (16/24 vs. 8/24 respectively, p = 0.02) and 2.5IU (3/24 vs. 0/24 respectively, p = 0.07) but did not occur in 4IU. 

For administration of small insulin doses, U40 are more accurate and precise than U100 and are less likely to result in clinically important over- or under-dosing. These results favor the use of U40 for administration of small doses of insulin.

Comments— Although the administration of low doses of U100 insulin (e.g., glargine, detemir, NPH) is common practice in veterinary medicine, this study reveals remarkably high dose error when doses of 4 units or less of U100 insulin are administered.  Since similar findings were reported in human pediatric patients given low doses of insulin (1-3) one to two decades ago, the results of this study should not be all that surprising. The use of U100 syringes can be dangerously inaccurate with administering very low insulin doses, and the use of syringes with 1/2 unit markings has not been shown to improve accuracy or precision (3).

Most human diabetologists recommend diluting the insulin when low doses of U100 insulin must be given (1-3). However, one must remember that there are many problems associated with dilution of these U100 insulins (4,5). First of all, glargine should never be diluted under any circumstances. Other U100 insulins, such as NPH or detemir, can be diluted, but this may alter the absorption kinetics of the insulin. For NPH (Humulin N), one can obtain the special diluent from the insulin manufacturer (Eli Lilly) or the pharmacy. For detemir (Levemir, Novo Nordisk), the insulin manufacturer has a special diluting medium, but the company generally will not provide the diluent to veterinarians. Detemir can be diluted with sterile water or saline, but this dilutes the insulin's antimicrobial additive and increases the risk of bacterial contamination. Therefore, because of the risk of bacterial contamination and changes with efficacy, diluting detemir is not generally recommended (5).

In both human patients and dogs, the use of insulin pen devices have consistently shown to be more accurate than dosing with insulin syringes (2,3,6). In one recent veterinary report (6), an insulin pen device was found to be more accurate than the insulin syringes when low doses (<8 units) of insulin were administered. In that study, insulin syringes tended to over-deliver by approximately 20-25% for very low doses (1 unit). However, for higher doses (16 units), the insulin pen and insulin syringe were comparable in accuracy.

The Bottom Line—Administration of low doses of insulin can be very inaccurate and imprecise, especially when using a U100 insulin and syringe. Use of U40 insulin improves accuracy but still is far from perfect. Either dilution of U-100 insulin (if possible) or use of an insulin pen device will help to improve accuracy when low-dose insulin administration is required.

References:

1. Casella SJ, Mongilio MK, Plotnick LP, et al. Accuracy and precision of low-dose insulin administration. Pediatrics 1993;91:1155-1157. 
2. Gnanalingham MG, Newland P, Smith CP. Accuracy and reproducibility of low dose insulin administration using pen-injectors and syringes. Arch Dis Child 1998;79:59-62. 
3. Keith K, Nicholson D, Rogers D. Accuracy and precision of low-dose insulin administration using syringes, pen injectors, and a pump. Clin Pediatr (Phila) 2004;43:69-74. 
4. Pet Diabetes: Diluting insulin. http://petdiabetes.wikia.com/wiki/Diluting_insulin
5. Roomp K, Rand JS. Management of diabetic cats with long-acting insulin. Vet Clin North Am Small Anim Pract 2013;43:251-266. 
6. Burgaud S, Riant S, Piau N. Comparative laboratory evaluation of dose delivery using a veterinary insulin pen (abstract 121). Proceedings of the WSAVA//FECAVA/BSAVA Congress; 12-15 April 2012;567.

Hall MJ, Adin CA, Borin-Crivellenti S, Rudinsky AJ, Gilor C. Pharmacology of the GLP-1 Analog Liraglutide in Healthy Cats. J Vet Intern Med 2014;28:1025-1026.

GLP-1 is an intestinal hormone that induces glucose-dependent stimulation of insulin secretion while suppressing glucagon secretion and increasing beta cell mass, satiety and gastric-emptying time. Liraglutide is a fatty-acid derivative of GLP-1 with a protracted pharmacokinetic profile that is used in people for treatment of type II diabetes mellitus and obesity. The aim of this study was to determine the pharmacodynamics of liraglutide in healthy cats.

A hyperglycemic clamp was performed on day-1 (Clamp-I) and 13 (Clamp-II) in seven healthy cats. Liraglutide was administered subcutaneously (0.6 mg/cat) once daily on days 7 through 13. During the clamp blood glucose concentrations were measured every 5 minutes and 20% dextrose infusion was adjusted to achieve hyperglycemia (225 mg/dl) at 30 min and to maintain that level of glycemia for 60 min. Plasma insulin and glucagon concentrations were measured at -15, 0, 30, 45, 60, 75, and 90 min.

Weight loss was recorded in all cats at day 13 (9%; P = 0.006). Appetite was subjectively decreased in all cats and one cat was withdrawn on day 10 because of 48 hrs of anorexia. Compared to Clamp-I, there was a trend during Clamp-II towards increased 60 min total glucose infused (median [range] 29% [1-178%], P = 0.087) and insulin concentrations (47% [-11-234%], P = 0.084). Glucagon concentrations (P = 0.67) and baseline glucose concentrations (P = 0.66) did not differ significantly between clamps.

Liraglutide may aid in weight loss in overweight cats but further evaluation is needed to determine its efficacy on improving glycemic control in diabetic cats.

Rudinsky AJ, Adin CA, Borin-Crivellenti S, Hall MJ, Gilor C. The Pharmacology of Exenatide Extended-Release in Healthy Cats. J Vet Intern Med 2014;28:1026.

GLP-1 is an intestinal hormone that induces glucose-dependent stimulation of insulin secretion while suppressing glucagon secretion and increasing beta cell mass, satiety and gastric- emptying time. Exenatide extended-release (ER) is a microencapsulated formulation of the GLP- 1-receptor agonist exenatide. It has a protracted pharmacokinetic profile that allows a once- weekly injection to replace insulin therapy safely and effectively in type-II diabetic people.

Here we studied the pharmacology of exenatide-ER in six healthy cats. A single, subcutaneous injection of exenatide-ER (0.13 mg/kg) was administered on day 0. A hyperglycemic clamp was performed on days -7 (Clamp-I) and 21 (Clamp-II). During the clamp, blood glucose concentrations (BG) were measured every 5 minutes and 20% dextrose infusion was adjusted to achieve hyperglycemia (225 mg/dl) at 30 min and to maintain that level of glycemia for the subsequent 60 min. Plasma insulin and glucagon concentrations were measured at -15, 0, 30, 45, 60, 75, and 90 min. Glucose tolerance was defined as the amount of glucose required to maintain hyperglycemia during the 60 minutes of the clamp.

Comparing Clamp-1 to Clamp-2 using paired t-tests, fasting BG decreased (mean [± SD] = -11 ± 8 mg/dl, p = 0.02), glucose tolerance improved (median [range] +33% [4–138%], p = 0.04) and median glucagon concentrations decreased (-4.7% [0–12.1%], p = 0.04). Insulin concentrations did not differ significantly. No side effects were observed throughout the study.

Exenatide-ER was safe and effective in improving glucose tolerance 3 weeks after a single injection. Further evaluation is needed to determine its efficacy and duration of action in diabetic cats.

Comments on the above 2 GLP-1 studies— Exenatide and liraglutide belong to a class of agents referred to as incretin mimetics. These agents are novel therapeutic options for type 2 diabetes in humans (1). Incretins are hormones released from the gastrointestinal tract during a meal, which potentiate insulin secretion from the beta cells of the pancreas (2). The major and most potent incretin is glucagon-like peptide 1 or GLP-1 (3). The biological actions of GLP-1 is highly glucose dependent, and therefore hypoglycemia does not occur. Additional benefits include stimulation of insulin biosynthesis, beta cell proliferation, resistance to apoptosis, enhanced beta cell survival, and inhibition of glucagon secretion (4,5,6). Extrapancreatic effects include delayed gastric emptying, decreased gastrointestinal motility, and central nervous system effects of satiety and weight loss (4,7).

Because native GLP-1 is rapidly degraded by a ubiquitous enzyme, GLP-1 agonists that are resistant to enzyme degradation were developed (8).  Two agonists are now available commercially:

1. Exenatide was the first GLP-1 agonist used for the treatment of type 2 diabetes in humans and was approved by the FDA in 2005. It is a synthetic peptide discovered in the saliva of the gila monster with a 53% homology with human GLP-1 (9). 
2. Liraglutide was the first genetically engineered GLP-1 agonist and has a 97% homology with native GLP-1 (1,10). It was approved by the FDA in 2010. Adverse effects of these GLP-1 agonists in people include vomiting, nausea, inappetence, and acute pancreatitis (1,9,10).

In these two studies by investigators from The Ohio State University, the pharmacokinetics of the extended-release formulation of exenatide (exenatide-ER) given once SC over a 3 week period and liraglutide given SC daily for 7 days was evaluated in healthy cats using a common research tool called a hyperglycemic clamp (11). With this procedure, glucose is infused into the patient and “clamped”, or held at a certain concentration (225 mg/dl) over time. How much glucose that needs to be infused to keep the blood sugar at that constant high level is a measure of how fast glucose is metabolized. In essence, the hyperglycemic clamp is a way to quantify the beta cell response to glucose. The results of the study showed that all liraglutide-treated cats lost weight and subjectively had a decreased appetite. In addition, there was a trend toward increased glucose utilization and insulin secretion. The exenatide-ER treated cats showed increased glucose tolerance, with no side effects being observed.

The Bottom Line— Preliminary results in normal cats would suggest that liraglutide may aid in weight loss in overweight cats and exenatide-ER may improve glucose tolerance in preclinical and overt diabetic cats without causing adverse side effects.

Clearly, further evaluation of both these agents is needed to determine their efficacy in diabetic cats. The hope is that these agents could one day be used as monotherapy to improve glucose tolerance without causing hypoglycemia and, in addition, increase beta-cell mass with minimal adverse effects such as nausea, vomiting, and inappetence. One potential drawback to their wide use in the treatment of preclinical and overt diabetic cats is their considerable cost.

References:

1. Gallwitz B. GLP-1 analogues for type 2 diabetes mellitus: current and emerging agents. Drugs 2011;72:1675-88
2. Moore B. Edie ES, Abram JH. On the treatment of diabetes mellitus by acid extract of duodenal mucous membrane. Biochem J 1906;1;28-38
3. Kim W, Egan JM. The role of incretins in glucose homeostasis and diabetes treatment. Pharmacol Rev 2008;60:470-512
4. Drucker DJ. The biology of incretin hormones. Cell Metab 2006;3:153-65
5. Li Y, Hansotia T, Yusta B, et al. Glucagon-like peptide-1 receptor signaling modulates beta cell apoptosis. J Biol Chem 2003;278:471-478. 
6. Farilla L, Bulotta A, Hirshberg B, et al. Glucagon-like peptide 1 inhibits cell apoptosis and improves glucose responsiveness of freshly isolated human islets. Endocrinology 2003;144:5149-5158. 
7. Drucker DJ, Nauck MA. The incretin system: glucagon-like peptide-1 receptor agonists and dipeptidyl peptidase-4 inhibitors in type 2 diabetes. Lancet 2006;368:1696-1705. 
8. Mudaliar S, Henry RR. The incretin hormones: from scientific discovery to practical therapeutics. Diabetologia 2012;55:1865-1868. 
9. Eng J, Kleinman WA, Singh L, et al. Isolation and characterization of exendin-4, an exendin-3 analogue, from Heloderma suspectum venom. Further evidence for an exendin receptor on dispersed acini from guinea pig pancreas. J Biol Chem 1992;267:7402-7405. 
10. Phillips LK, Prins JB. Update on incretin hormones. Ann N Y Acad Sci 2011;1243:E55-74. 
11. DeFronzo RA, Tobin JD, Andres R. Glucose clamp technique: a method for quantifying insulin secretion and resistance. Am J Physiol 1979;237:E214-223. 

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