J Vet Intern Med 2006;20:234–238

Use of Glargine and Lente in Cats with Mellitus

Kelli E. Weaver, Elizabeth A. Rozanski, Orla M. Mahony, Daniel L. Chan, and Lisa M. Freeman

The goals of this study were to compare the efficacy of once-daily administered Glargine to twice-daily administered Lente insulin in cats with diabetes mellitus and to describe the use of a high-protein, low-carbohydrate diet designed for the management of diabetes mellitus in cats. All cats with naturally occurring diabetes mellitus were eligible for inclusion. Baseline testing included a physical examination, serum biochemistry, urinalysis and urine culture, serum thyroxine concentration, and serum fructosamine concentration. All cats were fed the high-protein, low-carbohydrate diet exclusively. Cats were randomized to receive either 0.5 U/kg Lente insulin q12h or 0.5 U/kg Glargine insulin q24h. Re-evaluations were performed on all cats at weeks 1, 2, 4, 8, and 12, and included an assessment of clinical signs, physical examination, 16-hour blood curve, and serum fructosamine concentrations. Thirteen cats completed the study (Lente, n 5 7, Glargine, n 5 6). There was significant improvement in serum fructosamine and glucose concentrations in all cats but there was no significant difference between the 2 insulin groups. Four of the 13 cats were in complete remission by the end of the study period (Lente, n 5 3; Glargine, n 5 1). The results of the study support the use of once-daily or twice-daily Lente insulin in combination with a high-protein, low-carbohydrate diet for treatment of feline diabetes mellitus. Key words: Carbohydrate; Diet; Fructosamine; Lantus; Protein.

iabetes mellitus is a common endocrinopathy in injections to regulate blood glucose concentrations. This D cats with a reported frequency ranging from 1 in represents a significant commitment on the part of the 50 to 1 in 400 animals.1,2 Diagnosis is based on clients, and thus may result in lower compliance rates or identification of clinical signs including polyuria, poly- a higher risk of complications. dipsia, and weight loss despite good appetite, and by Recently, an innovative new human insulin analog, laboratory findings including persistent fasting hyper- Glargine (LantusH), has been developed for use in glycemia and glucosuria. Treatment options for diabetes people as once-daily basal insulin. Glargine was mellitus in cats include insulin therapy, dietary manage- approved for use in people by the U.S. Food and Drug ment, and oral hypoglycemic agents. Of these, insulin Administration in April 2000.7 It was developed by therapy is the most effective means of achieving glycemic recombinant DNA technology using Escherichia coli control. A number of different types of insulin, including plasmid DNA.7 Glargine insulin is produced by animal origin and human recombinant products, are substituting the amino acid asparagine with glycine at available for use in cats. Feline endogenous insulin is position A21 of the human insulin molecule and by the considered to be most homologous to bovine insulin.3 addition of 2 positively charged arginine molecules at Most cats with diabetes mellitus require insulin therapy the C terminus of the B chain.7,8 These modifications administered twice daily to prevent symptomatic hyper- result in decreased solubility of Glargine at a neutral pH glycemia and the development of ketosis.3 Protamine such as that found in subcutaneous tissue. This leads to zinc insulin (PZI) has been used in cats as a once-daily microprecipitate formation in the subcutaneous tissue, insulin, but one study noted that twice-daily adminis- which permits a slower absorption rate and therefore tration of PZI was necessary to maintain adequate a slower onset of action and relatively constant peakless glycemic control.4 Other insulin types, including beef- basal insulin supply.7 The effect observed is a steady pork and human recombinant neutral protamine Hage- action profile relatively free from peaks and troughs. dorn (NPH), Ultralente, and Lente insulin have been This effect has been demonstrated in people by use of used successfully to manage diabetes mellitus in cats but the euglycemic clamp technique.7 Glargine also has been also require twice-daily administration due to inade- proposed for use in cats. The theoretical benefits of this quate duration of action.3,5 One report demonstrated no insulin in the treatment of cats with diabetes mellitus difference in glycemic control in cats among Ultralente, include 24-hour maintenance of near normal glycemia Lente, and NPH insulin types.6 Thus, the insulin resulting in improved glycemic control with possible preparations currently available are considered less than resolution of diabetes, the ability for once-daily insulin ideal because most cats require twice daily insulin administration, prevention of hypoglycemic episodes, and potentially, the prevention of long-term complica- tions or euthanasia due to treatment failures. The use of From the Department of Clinical Sciences, Cummings School of Glargine insulin has not been widely described in Veterinary Medicine, Tufts University, North Grafton, MA. Oral animals. A clinical trial of Glargine in diabetic cats abstract presented at the 2005 ACVIM Forum, Baltimore, MD. showed that it was effective when used at a dosage of Reprint requests: Elizabeth A. Rozanski, DVM, DACVIM, 0.5 U/kg ideal body weight q12h in combination with DACVECC, Department of Clinical Sciences, Cummings School of a high-protein low-carbohydrate diet. Pharmacokinetic Veterinary Medicine, Tufts University, 200 Westboro Road, North studies in normal cats demonstrated that the duration of Grafton, MA 01536; e-mail: [email protected]. Submitted April 15, 2005; Revised June 21, 2005, July 21, 2005, action is longer with Glargine compared with that of August 26, 2005; Accepted August 26, 2005. PZI or Lente, and that a dosage of 0.25 U/kg q12h Copyright E 2006 by the American College of Veterinary Internal produced a longer glucose lowering effect in comparison Medicine to 0.5 U/kg q24h.a In a small pilot study, high remission 0891-6640/06/2002-0003/$3.00/0 rates were observed, which were believed to be due to Once-Daily Glargine in Cats 235 improved glycemic control leading to decreased glucose Table 1. Type of diet before enrollment. toxicity.b Appropriate dietary therapy in addition to insulin Diet Lente Group Lantus Group therapy is believed essential for optimal control of High-protein, low-carbohydrate 2 3 diabetes mellitus in cats. Recent studies suggest that High fiber 2 3 a commercial high-protein, low-carbohydrate diet is beneficial in the management of some cats with diabe- tes.9,b Cats are obligate carnivores and therefore are well number of cats with effective control between the 2 insulin groups suited to use protein rather than carbohydrates as a source were compared using chi-square analysis. Changes from baseline to the end of the study between insulin groups were compared using of glucose. High-protein, low-carbohydrate diets have Mann-Whitney U analyses. Glucose and fructosamine concentra- been shown to reduce insulin requirements and lead to tion changes over time between the 2 insulin groups were compared 9 early diabetic remission in some cats with diabetes. using analysis of variance with repeated measures. A value of P , The purpose of this study was to prospectively .05 was considered significant. Commercial statistical software was evaluate the effects on glycemic control of once-daily used for all analyses.d administered insulin Glargine in comparison to twice- daily administered Lente insulin in cats with naturally Results occurring diabetes mellitus in combination with a com- mercial high protein, low carbohydrate diet. Seventeen privately owned cats were enrolled in the study. Breeds included Domestic shorthair and longhair Materials and Methods (n 5 16) and Abyssinian (n 5 1). Nine cats were castrated males and 8 were spayed females. Ages ranged from 7 to All cats with naturally occurring diabetes mellitus that were 16 years (median, 10 years), BW ranged from 3.2 to patients at the Foster Hospital for Small Animals at Cummings 10 kg (median, 5.9 kg), and BCS ranged from 3 to 9 School of Veterinary Medicine at Tufts University were eligible for (median, 8). All cats were diagnosed with naturally inclusion of the study. The study was approved by the Tufts occurring diabetes mellitus based on detection of Institutional Animal Care and Use Committee, and all owners consistent clinical signs including polyuria, polydipsia, signed an informed consent form before enrolling cats in the study. weight loss and increased appetite, (blood At the initial visit (day 0) history, physical examination including body weight (BW) and body condition scores (BCS; 1– glucose .250 mg/dL), and glucosuria. Eight cats were 9) was performed, and CBC, serum biochemical profiles, serum newly diagnosed and untreated, and 9 cats were being thyroxine concentrations, serum fructosamine concentrations, and treated with insulin with poor glycemic control. Types of urinalyses and urine cultures were obtained. Cats were randomized insulin being used before enrollment in the study included to receive either Glargine or human recombinant Lente insulin recombinant human NPH (n 5 5), Lente (n 5 2), using a computer-generated randomization program. The insulin Glargine (n 5 1), and PZI (n 5 1). Types of diets starting dosages were 0.5 U/kg (actual BW) Lente SQ q12h or previously fed either alone or in combination included 0.5 U/kg (actual BW) Glargine SQ q24h. The clients and the a high-protein, low-carbohydrate diet (n 5 5), a high- attending clinician were not blinded as to the type of insulin fiber diet (n 5 5), and a typical adult maintenance dry diet received by the cats. All cats were fed Purina DMH, a commercial (n 5 4) (Table 1). Diabetes was considered poorly high-protein, low-carbohydrate diet, exclusively throughout the study period. Cats were fed either dry or canned food, or controlled on the basis of persistent clinical signs and a combination based on their preference. Re-evaluations were hyperglycemia (glucose nadir .250 mg/dL during a 10- performed on all cats at weeks 1, 2, 4, 8, and 12, and included an hour blood glucose curve). Poor control was suspected to assessment of clinical signs, physical examination findings in- be due to inadequate insulin dosing and adjustments cluding BCS and BW, a 16-hour blood glucose curve, and serum rather than , but definitive assessment fructosamine concentrations. For the purposes of this study, for , pancreatitis, and other disorders con- effective glycemic control was based on the owner’s perception of tributing to insulin resistance was not performed. resolution of clinical signs, average (over 16 hours) blood glucose One cat was excluded because of aggressive behavior concentration ,300 mg/dL, blood glucose nadir ,200 mg/dL, and and 3 died during the study (diabetic , n 5 , a serum fructosamine concentration 450 mmol/L. Adjustments in 1; anesthetic accident, n 5 1; metastatic pulmonary dosages of insulin were made as needed with the goal of 5 maintaining most blood glucose measurements between 100 and adenocarcinoma, n 1). Therefore, 13 cats completed 300 mg/dL and a glucose nadir between 80 and 120 mg/dL. Blood the 12-week study (Lente, n 5 7; Glargine, n 5 6). All glucose concentrations were measured by use of a hand-held subsequent results will be for these 13 cats only. portable blood glucose monitor (PBGM).c The same PBGM was Concurrent disorders for these 13 cats diagnosed based used on all cats for each blood glucose curve measurement. The on results of history, physical examination, CBC, serum PBGM used reflectance photometry to measure production of biochemistry profile, serum thyroxine concentrations, a colored chromogen by a glucose oxidase-peroxidase reaction. urinalysis and urine culture included periodontal disease Detectable glucose concentrations ranged from 20 to 500 mg/dL (n 5 9), heart murmur (n 5 3), and urinary tract Blood glucose concentrations ,20 mg/dL or .500 mg/dL regis- infection (n 5 1). The cat with a urinary tract infection tered Lo or Hi on the PBGM, respectively. was treated by administration of appropriate antimicro- bials based on the results of a urine culture. Echocar- Statistical Analysis diograms were not performed on the cats with heart Data are presented as mean 6 SD (for normally distributed murmurs. Serum thyroxine concentrations were in the data) or median and range (for skewed data). Differences in the reference range for all cats. 236 Weaver et al

Table 2. Baseline characteristics of 13 cats that completed the study (median [range]).

Variable Lente Group Lantus Group P Value Age (years) 10 (7–16) 10 (9–14) .96 Sex 5 castrated males; 4 castrated males; .20 2 spayed females 6 spayed females Fructosamine (mmol/L) 538 (425–677) 556 (375–621) .90 Weight (pounds) 14.0 (7.0–21.0) 12.3 (8.0–22.2) .81 Body condition score 9 (3–9) 8 (3–9) .61 Newly diagnosed 3 5 Poorly controlled 4 5

There were no significant differences between the achieving glycemic control as Lente insulin administered Lente (n 5 7) and Glargine (n 5 6) groups with regard to twice daily when used in combination with a high- age, BW, BCS, or sex (Table 2). All cats had subjective protein, low-carbohydrate diet. Cats in both treatment improvement in their clinical signs (eg, polyuria, poly- groups showed significant decreases in serum fructosa- dipsia, polyphagia) throughout the study period. Ten cats mine concentrations and glucose concentrations over the gained weight, 2 cats maintained their weight, and 1 cat 12-week study, but there was no significant difference lost weight. Both groups of cats gained weight, but there between the 2 insulin groups. was no significant difference in weight gain between the 2 A previous study by Marshall and Rand showed that insulin groups (Table 3). There was a slight but non- administration of Glargine (0.5 U/kg q12h) to newly significant increase in insulin dosage during the study, but diagnosed diabetic cats resulted in 100% remission rate there were no differences between groups in the final daily when combined with a high-protein, low-carbohydrate insulin dosage or the change from baseline to week 12. diet.b The current study indicates that once-daily (Table 1). There were significant decreases in the 16-hour administration of Glargine provides a significant blood peak and nadir blood glucose concentrations and the glucose–lowering effect resulting in improved glycemic mean serum fructosamine concentrations over time (P , control over time and can lead to diabetic remission in .001 for both), but there were no differences between the 2 some cats when used in conjunction with a high-protein, insulin groups (Table 3). By the end of the 12-week low-carbohydrate diet. We chose to evaluation once- period, 4 of the 17 cats were in complete remission and no daily insulin glargine rather than twice daily, due to longer required insulin administration. Of the 4 cats in perceived client compliance benefit. A comparison of complete remission (Glargine, n 5 1; Lente, n 5 3), 2 of twice-daily Glargine to twice-daily Lente insulin may the cats were newly diagnosed with diabetes mellitus and have resulted in a different outcome. 2 were previously poorly controlled. Of the cats in This study also shows that it is possible for previously complete remission, previous diets included Eukanuba poorly controlled diabetics to achieve diabetic remission low residueH (n 5 1), typical adult maintenance dry diet when adequate glycemic control is maintained by (n 5 2), and Nutro SeniorH (n 5 1). Time to complete appropriate insulin therapy and feeding a high-protein, remission ranged from 2 to 12 weeks. There was no low-carbohydrate diet. Differences in remission rates significant difference between insulin groups in terms of between insulin groups and between newly diagnosed or the number cats with complete remission of diabetes poorly controlled diabetics were not observed in this mellitus in this study. study. However, we did observe a high remission rate and we recognize that sample size is an important Discussion limiting factor in this study. Additionally, due to study design, cats were monitored very closely. It is important The results of this clinical study suggest that Glargine not to discount the added benefit of frequent evaluations insulin administered once daily is equally effective in and insulin adjustments in the regression of diabetes.

Table 3. Change for measured variables from week 0 to week 12 in the 13 cats that completed the study (median [range]). A negative value indicates that the variable decreased during the study period; a positive variable indicates an increase in the variable.

P Value Comparing Lente (n 5 7) Glargine (n 5 6) Insulin Groups Change in peak glucose concentration over time (mg/dL) 2104 (2180 to 11) 298 (2313 to 99) .83 Change in fructosamine concentration over time (mmol/L) 2110 (2267 to 288) 2142 (2313 to 28) .92 Change in weight from week 0 to week 12 (pounds) 2.0 (20.5 to 3.1) 0.8 (0 to 1.9) .10 Change in absolute insulin dose/day from week 0 to week 12 0.0 (25.0 to 5.0) 2 (23 to 5.0) .16 (units) Change in insulin dose (U/kg/day) 20.2 (21.7 to 1.8) 0.4 (20.4 to 0.9) .20 Once-Daily Glargine in Cats 237

Insulin Glargine administration resulted in relatively of clinical signs. The owners were aware of which stable glycemic control over a 16-hour period with no insulin type their cat was receiving but they were not episodes of . Previous studies have shown told which the investigational insulin was and therefore that once-daily insulin administration in dogs results in we do not feel they were likely to interpret their very high insulin doses with increased risk of hypogly- cat’s clinical signs based on the type of insulin. Client cemia.10 Although there are insulin preparations mar- surveys were not performed to confirm perceptions keted or described for once-daily administration in cats that once daily insulin was preferable to twice-daily (Ultralente), these typically are poorly absorbed, leading administration. A high-protein low-carbohydrate diet to high insulin doses and increased risk of hypoglycemia may be beneficial in the management of cats with or to twice-daily injections to achieve glycemic con- diabetes mellitus.9,b All cats in the study were fed trol.4,11,12 Results from the current study showed that the a commercial high-protein, low-carbohydrate diet, and final dose of insulin was comparable between the 2 this approach also may have contributed to successful groups, indicating that the Glargine group did not treatment. require additional insulin to achieve glycemic control. Glucose nadirs may not have been accurately assessed This has important implications for the treatment of for once-daily insulin administration based on 16-hour diabetes mellitus in cats because once-daily insulin may blood glucose curves. However, in a study by Marshall contribute to improved owner compliance and improved and Rand comparing pharmacokinetic and pharmaco- 24-hour glycemic control, leading to fewer complica- dynamic properties of Glargine, PZI, and Lente insulins, tions such as hypoglycemia and possibly decreased the time to reach glucose nadir for Glargine was 16 6 euthanasia rates. 1.9 hours.a All cats accepted the high-protein, low-carbohydrate Glargine has been shown in people to be a long- diet well, and most cats gained weight as the study acting, peakless insulin more closely mimicking progressed. This weight gain was attributed to a combi- the physiologic profile of basal endogenous insulin nation of both improved glycemic control and the high and leading to improved glycemic control.13 Research calorie content of the diet. This diet, particularly the dry in humans has shown that Glargine is similar or form of the food, is very high in calories and the superior to NPH in achieving control of fasting blood majority of the cats were fed the dry food form in glucose and hemoglobin concentrations, and is associ- unrestricted quantities. It is feasible that improved ated with a decreased incidence of hypoglycemia in glycemic control may have been achieved if BW had humans with type 1 and mellitus.13–17 been reduced in this study, because 10 of the 13 cats Although our study showed that once-daily insulin completing the study exceeded their ideal BCS. Obesity Glargine effectively controls diabetes in cats, more is a known risk factor in the development of type 2 research is necessary to further document its efficacy, diabetes mellitus and can result in insulin antagonism. to determine whether once-daily administration is Therefore it is important to closely monitor BW and preferable over twice-daily administration, and to de- BCS in these patients. For cats that exceed ideal body termine whether Glargine has added benefits over PZI condition, calories should be gradually reduced so that insulin. However, our study supports that once-daily ideal BCS is achieved. administration of insulin Glargine is as effective in Limitations of the study included its small sample achieving glycemic control as Lente insulin administered size, lack of a crossover design, lack of blinding, and twice daily and, as such, once-daily insulin Glargine, the fact that we performed 16-hour blood glucose particularly combined with a high-protein low-carbohy- curves rather than 24-hour curves. Four of the 17 drate diet, is an acceptable strategy for management of cats did not complete the study, which further diabetes in cats. decreased our sample size. A small sample size limits the ability to detect differences between groups, even if present. A crossover design evaluating 1 insulin 1st and then Footnotes the other may have been beneficial in clarifying the a specific roles of the insulin over time. However, we Marshall RD, Rand JS. Comparison of the pharmacokinetics and pharmacodynamics of glargine, protamine zinc and porcine lente noticed a high remission rate and a marked improve- insulin in normal cats. J Vet Intern Med 2002;16(3):373 ment in clinical signs, even in previously poorly b Marshall RD, Rand JS. Insulin glargine and a high protein-low controlled cats, and this finding might make it challeng- carbohydrate diet are associated with a high remission rate in ing to ensure a lack of carryover effect from the original newly diagnosed diabetic cats. J Vet Intern Med 2004;18(3):401 insulin. c Ascensia Elite XL, Bayer Co The investigators and the owners were not blinded to d Systat 10.0, SPSS, Chicago, IL the insulin type being administered to each study participant. This design may have resulted in a bias toward the investigational insulin, but study variable all were objective types of data (eg, BW, serum Acknowledgment fructosamine concentrations, blood glucose concentra- tions) and therefore not subject to bias. One subjective Supported by a grant from Nestle´ Purina PetCare type of data was the owners’ perception of improvement Research. 238 Weaver et al

References 9. Frank G, Anderson W, Pazak H, et al. Use of a high-protein diet in the management of feline diabetes mellitus. Vet Ther 1. Panciera DL, Thomas CB, Eicker S, et al. Epizootiologic 2001;2:238–246. patterns of diabetes mellitus in cats: 333 cases (1980–1986). J Am 10. Hess RS, Ward CR. Effect of insulin dosage on glycemic Vet Med Assoc 1990;197:1504–1508. response in dogs with diabetes mellitus: 221 cases (1993–1998). 2. Rand JS, Fleeman LM, Farrow HA, et al. Canine and feline J Am Vet Med Assoc 2000;216(2):217–221. diabetes mellitus: Nature or nurture? J Nutr 2004;134:2072S– 11. Broussard JD, Peterson ME. Comparison of two Ultralente 2080S. insulin preparations with protamine zinc insulin in clinically 3. Feldman EC, Nelson RW. Diabetes mellitus. In: Feldman normal cats. Am J Vet Res 1994;55(1):127–131. EC, Nelson RW. Canine and Feline Endocrinology and Re- 12. Nelson RW, Feldman EC, DeVries SE. Use of Ultralente production. Philadelphia, PA: WB Saunders; 1996:339–391. insulin in cats with diabetes mellitus. J Am Vet Med Assoc 4. Nelson RW, Lynn RC, Wagner-Mann CC, et al. Efficacy of 1992;200(12):1828–1829. protamine zinc insulin for treatment of diabetes mellitus in cats. 13. Lepore M, Kurzhals R, Pampanelli S, et al. Pharmacoki- J Am Vet Med Assoc 2001;218(1):38–42. netics and dynamics of s.c. injection of the long acting insulin 5. Bertoy EH, Nelson RW, Feldman EC. Effect of lente insulin glargine (HOE901) in TIDM. Diabetes 1999;48(1):A97. for treatment of diabetes mellitus in 12 cats. J Am Vet Med Assoc 14. Pieber TR, Eugene-Jolchine I, Derobert E, et al. Efficacy 1995;206(11):1729–1731. and safety of HOE 901 versus NPH insulin in patients with type 1 6. Goossens MM, Nelson RW, Feldman EC, et al. Response to diabetes. Diabetes Care 2000;23(2):157–162. insulin treatment and survival in 104 cats with diabetes mellitus 15. Rosenstock J, Park G, Zimmerman J. Basal insulin glargine (1985–1995). J Vet Intern Med 1998;12:1–6. (HOE 901) versus NPH insulin in patients with type 1 diabetes on 7. Heinemann L, Linkeschova R, Rare K, et al. Time action multiple daily insulin regimens. Diabetes Care 2000;23(8):1137–1142. profile of the long acting insulin analogue insulin glargine 16. Ratner RE, Hirsch IB, Neifing JL, et al. Less hypoglycemia (HOE901) in comparison with those of NPH insulin, and placebo. with insulin glargine in intensive insulin therapy for type 1 diabetes. Diabetes Care 2000;23:644–649. Diabetes Care 2000;23(5):639–643. 8. McKeage K, Goa KL. Spotlight in insulin glargine in type 1 17. Rosenstock J, Schwartz SL, Clark CM Jr, et al. Basal insulin and 2 diabetes mellitus. Treat Endocrinol 2002;1:55–58. therapy in type 2 diabetes. Diabetes Care 2001;24(4):631–635.