Using porcine zinc insulin suspension in the management of canine diabetes mellitus (Sponsored by Intervet/Schering-Plough Animal Health)

Vetsulin (porcine insulin zinc suspension, Figure 1) is the first FDA-approved veterinary product indicated for the reduction of hyperglycemia and hyperglycemia-associated clinical signs in dogs with diabetes mellitus. It is registered in 24 other countries as Caninsulin and has been used since 1990.

Figure 1. Vetsulin (Intervet, a part of Schering-Plough)

Vetsulin is supplied as a sterile injectable suspension in multidose vials containing either 2.5 ml or 10 ml of 40 U/ml (U-40) porcine insulin zinc suspension. Vials are supplied in cartons of one 10-ml vial and cartons of 10 2.5-ml vials and should be kept refrigerated. It is recommended to replace opened vials on a monthly basis.

Pharmacokinetics

Vetsulin is a sterile, aqueous suspension of purified porcine insulin. It contains 40 U/ml, consisting of 30% amorphous and 70% crystalline zinc insulin in a neutral buffer at a pH of 7.35. Vetsulin is a lente, or intermediate-acting, insulin. In dogs, the amorphous fraction has peak activity approximately four hours after subcutaneous administration, and its effects last for about eight hours. Thereafter, the effect is maintained by the crystalline fraction, which has a slower onset of action and peak effects around 11 hours following the injection (Figure 2). Afterward, the effect gradually declines to zero.

Figure 2. Peak activity of Vetsulin

Vetsulin should not be diluted because the amount of soluble insulin is increased by the aqueous diluent used, which results in an alteration of the pharmacokinetics. With a larger aqueous fraction and smaller crystalline fraction, a decrease in the crystalline portion responsible for the second peak of insulin activity would occur.

As porcine insulin, Vetsulin has the same amino acid sequence as canine insulin. This may help decrease the risk of anti-insulin antibody development, which may interfere with the action of the insulin. In a recent study, the presence of anti-insulin antibodies was determined by ELISA in serum samples from 30 diabetic dogs receiving bovine insulin therapy and 30 normoglycemic dogs.1 Twenty of the diabetic dogs had significant reactivity to both bovine (heterologous) and porcine (homologous) insulin compared with control dogs. In contrast, researchers saw no significant difference between the two populations in reactivity to canine distemper virus or canine thyroglobulin. The high degree of correlation between anti-bovine insulin and anti-porcine insulin antibodies suggested cross-reactivity, which was confirmed by performing a competition ELISA, which showed antibody binding to bovine insulin inhibited by pre-incubating serum with porcine insulin.

These data suggest that treatment of diabetic dogs with bovine insulin could lead to anti-insulin antibody production. While anti-insulin antibodies should not develop in newly diagnosed diabetic dogs that are administered Vetsulin, it is possible that dogs initially treated with bovine insulin may have cross-reactivity with the porcine insulin product.

Safety

In the Vetsulin field effectiveness and safety study, 66 dogs were treated with Vetsulin. Sixty-two dogs were included in the assessment of safety. Hypoglycemia with or without associated clinical signs occurred in 35.5% (22/62) of the dogs at various times during the study. If present, clinical signs of hypoglycemia were generally mild in nature (e.g., weakness, lethargy, stumbling, falling down, depression). Disorientation and collapse were reported less frequently and occurred in 16.1% (10/62) of the dogs. Two dogs had a seizure, and one dog died during the seizure. Although never confirmed, the presumptive cause of the seizures was hypoglycemia. In the rest of the dogs, hypoglycemia resolved with appropriate therapy and adjustments in insulin dosage. Seven owners recorded the following observations about the injection site on the home monitoring forms: swollen, painful, sore, and a bleb under the skin.

The following clinical observations occurred in the field study following treatment with Vetsulin: hematuria, vomiting, diarrhea, pancreatitis, nonspecific hepatopathy or pancreatitis, development of cataracts, and urinary tract infections. They may be directly attributed to the drug or may be secondary to the diabetic state or other underlying conditions in the dogs.

During 1995 to 2001, the following adverse reactions in 19 dogs treated with Vetsulin were reported to Intervet: destabilization (defined as lack of adequate regulation), lack of expected efficacy, edema of the head and neck, development of a fibrous lump at the injection site, hypoglycemia, and death following administration of typical doses and overdosage.

Syringe selection

To avoid dosing errors when administering Vetsulin to dogs, it is important to use a U-40 syringe. The use of a syringe other than a U-40 syringe will result in incorrect dosing. Some dog owners may attempt to purchase syringes and insulin from their local human pharmacies, which only carry U-100 syringes and do not stock Vetsulin. Using a U-100 syringe with U-40 insulin would result in a dog receiving 2.5 times less insulin than required. Human insulins are formulated at a concentration of 100 U/ml. If clients use a U-40 syringe with a U-100 insulin preparation, they would be injecting 2.5 times the amount of insulin necessary, which could result in fatal hypoglycemia. Most human pharmacists are not aware of Vetsulin or the U-40 syringes recommended for use with this product. As noted above, any error in product and syringe matching could result in unsuccessful regulation, hypoglycemia, and even death. Therefore, it is strongly advised to educate clients to purchase both Vetsulin and the U-40 syringes from your veterinary clinic.

Dosing

Gently roll the vial to mix Vetsulin before withdrawing the dose from the vial. Using a U-40 insulin syringe, administer the injection subcutaneously at 2 to 5 cm (3/4 to 2 inches) from the dorsal midline, varying from behind the scapulae to the mid-lumbar region and alternating sides.

According to the manufacturer, the initial recommended Vetsulin dose is 0.5 U/kg body weight once daily given concurrently with or right after a meal.

I start the majority of my canine patients on Vetsulin at the same dosage—but given twice a day—and witness few episodes of hypoglycemia.

Once you start initial therapy, reevaluate the dog at appropriate intervals and adjust the dose based on clinical signs, urinalysis results, fructosamine concentrations, and glucose curve results until adequate glycemic control is attained. Glycemic control is considered adequate if the patient achieves an acceptable blood glucose curve (i.e., reduction in hyperglycemia and a nadir of 90 to 125 mg/dl), shows improved clinical signs of hyperglycemia (e.g., polyuria, polydipsia, and ketonuria), and avoids hypoglycemia (i.e., blood glucose <80 mg/dl).

If you transition a dog from other insulin preparations to Vetsulin and deem the patient's pretransition diabetic regulation is adequate, start Vetsulin at 50% to 75% of the dosage used with the previous insulin. If you deem the patient's pretransition diabetic regulation is inadequate and observe persistent hyperglycemia (in the absence of insulin-induced hypoglycemia), start the Vetsulin at 75% to 100% of the dosage used with the previous insulin. This is always more of an art than a science, so close patient monitoring is essential whenever changing the type or dose of insulin used. I normally recommend rechecks in seven days (or sooner, if needed) to assess clinical signs and monitor blood glucose concentrations. Alternatively, pet owners can perform blood glucose curves at home (see Strategies for monitoring diabetes mellitus in dogs).

Frequency of dosing. You should initiate twice-daily therapy if you determine the duration of insulin action to be inadequate. If you initiate twice-daily treatment, the two doses should be 25% less than the once-daily dose required to attain an acceptable nadir. Further dose adjustments may be necessary with changes in the dog's diet, body weight, or concomitant medication or if the dog develops a concurrent infection, inflammation, neoplasia, or an additional endocrine or other medical disorder. Once you establish the maintenance dose and the diabetes appears well regulated, you must implement a long-term management program to minimize variations in the insulin requirement. This includes monitoring to detect insulin underdosage or overdosage and adjustment of dose, if required. Careful monitoring during maintenance will help limit the chronic problems associated with diabetes, including cataracts.

In a study conducted in the United States, researchers treated 53 dogs with Vetsulin for 60 days after an initial dose determination period.2 They determined the means of the blood glucose concentrations during 12-hour glucose curves and the means of the blood glucose nadir concentrations during 12-hour glucose curves for all dogs:

• Before beginning insulin therapy (time 0)

• At the end of the insulin dose determination period (time 1)

• 30 days after time 1 (time 2)

• 60 days after time 1 (time 3).

Researchers also evaluated clinical variables (e.g., results of physical examinations and historic information, including presence or absence of polyuria, polydipsia, and ketonuria) at each time point. They based the adequacy of hyperglycemia control on 12-hour blood glucose curves and improvement in the clinical variables. Safety was evaluated by owner questionnaire and the performance of physical examination, complete blood count, serum chemistry profile, and urinalysis. The means of the blood glucose concentrations during 12-hour glucose curves and the means of the blood glucose nadir concentrations during 12-hour glucose curves for all dogs at times 1, 2, and 3 were significantly lower compared with time 0 (P < .0001). The proportion of dogs with polyuria, polydipsia, and ketonuria reduced 82%, 86%, and 80%, respectively. All the dogs had adequate glycemic control at time 1, 66% at time 2, and 75% at time 3. At time 3, 66% of dogs required insulin injections every 12 hours. Other than hypoglycemia, no important adverse effects of insulin administration were reported.

In my experience, greater than 90% of diabetic dogs require twice-a-day dosing to attain clinical and laboratory evidence of glycemic control. While some pet owners may wish to try once-daily dosing initially, the majority may be dissatisfied as a result of poor control of clinical signs and progression of diabetic cataracts. If glycemic control has not been obtained within four weeks of initiating once-daily dosing, I would encourage the use of Vetsulin twice a day. See Strategies for monitoring diabetes mellitus in dogs for further dosage adjustment recommendations.

References

1. Davison LJ, Ristic JM, Herrtage ME, et al. Anti-insulin antibodies in dogs with naturally occurring diabetes mellitus. Vet Immunol Immunopathol 2003;91:53-60.

2. Monroe WE, Laxton D, Fallin EA, et al. Efficacy and safety of a purified porcine insulin zinc suspension for managing diabetes mellitus in dogs. J Vet Intern Med 2005;19:675-682.

Recommended reading

Behrend EN. Update on drugs used to treat endocrine diseases in small animals. Vet Clin North Am Small Anim Pract 2006;36:1087-1105.

Church DB. The blood glucose response to three prolonged duration insulins in canine diabetes mellitus. J Small Anim Pract 1981;22:301-310.

Feldman EC, Nelson RW. Diabetes Mellitus in Canine and Feline Endocrinology and Reproduction. Feldman EC, Nelson RW, eds. Philadelphia, Pa: WB Saunders, 2004.

Graham P. Prognosis in diabetes mellitus, in Proceedings. Intervet Intl Symp, 6th Annu Congress Eur Soc Vet Intern Med 1996;23-25.

Graham PA, Nash AS, McKellar QA. Pharmacokinetics of porcine insulin zinc suspension in diabetic dogs. J Small Anim Pract 1997;38:434-438.

Hess RS, Ward CR. Effect of insulin dosage on glycemic response in dogs with diabetes mellitus: 221 cases (1993-1998). J Am Vet Med Assoc 2000;216:217-221.

Horn B, Mitten RW. Evaluation of insulin zinc suspension for control of naturally occurring diabetes mellitus in dogs. Aust Vet J 2000;78:831-834.