Pharmacodynamics of Insulin Detemir and Insulin Glargine Assessed by an Isoglycemic Clamp Method in Healthy Cats

Abstract

Background: Insulin detemir and insulin glargine are synthetic long-acting insulin analogs. In people, insulin glargine is longer acting and has a relatively flat time-action profile, while insulin detemir has significantly less within-subject variability. Insulin detemir is also associated with less undesired weight gain and decreased frequency of hypoglycemic events.Objectives: To compare the pharmacodynamics of insulin detemir and insulin glargine in healthy cats. Animals: Ten young, healthy, neutered, purpose-bred cats. Methods: Randomized, cross-over design. Pharmacodynamics of insulin detemir and insulin glargine were determined by the isoglycemic clamp method after a 0.5 U/kg SC injection.Results: The only significant difference in the pharmacodynamics of insulin detemir and insulin glargine was onset of action (1.8 AE 0.8 and 1.3 AE 0.5 hours for insulin detemir and insulin glargine, respectively, P 5 .03). End of action of insulin detemir was reached at 13.5 AE 3.5 hours and for insulin glargine at 11.3 AE 4.5 hours (P 5 .18). Time-to-peak action of insulin detemir was reached at 6.9 AE 3.1 hours and for insulin glargine at 5.3 AE 3.8 hours (P 5 .7). The time-action curves of both insulin analogs varied between relatively flat curves in some cats and peaked curves in others.Conclusion and Clinical Importance: Insulin detemir and insulin glargine have shorter durations of action than in people when assessed by the clamp method, but in some cats these insulin analogs could be useful as once-a-day drugs. Peak effects of both insulin analogs are pronounced in some cats.

Update on insulin treatment of dogs and cats with non-complicated diabetes mellitus

“…In the acidic (pH: 4) commercially available solution, insulin glargine is water soluble but after its injection into SC tissues, where pH is neutral, insulin crystals precipitate thus delaying absorption that remains steady over time (Mori et al, 2008;Gilor et al, 2010;. The pH-dependency is the reason why dilution or mixing with other insulin preparations is not allowed and also explains why insulin glargine acts like shortacting regular insulin if administered intravenously or intramuscularly (Zerrenner et al, 2007;Marshall et al, 2008;.…”

“…These molecular changes result in a slowly absorbed and highly albumin-bound molecule with long duration of action and increased the duration of action was found to be 24h in normal dogs and the blood glucose lowering-effect is similar or slightly lower compared to insulin NPH (Mori et al, 2008;Sako et al, 2011). In cats pharmacokinetics and pharmacodynamics vary between patients so that a clear nadir of blood glucose concentration may or may not be seen; onset of action occurs after approximately 1-2h, glucose nadir may be seen any time between 2.5 and 16h, sometimes a biphasic action with an early and a late nadir is noticed and the duration of action varies between 7h and 24h but in most cats it exceeds 12h Rios and Ward, 2008;Gilor et al, 2010;Smith et al, 2012). Also, potency (blood glucose lowering effect) of insulin glargin is generally similar but is some cats it may be lower than that of insulin lente, NPH and PZI Ford and Lynch, 2013;.…”

“…On the contrary, in diabetic cats insulin glargine treatment is clearly superior and carries an increased potential for diabetic remission (see later) compared to insulin lente and PZI (Marshall et al, 2009;) which explains why, despite its recent introduction into the market and lack of a veterinary formulation, it is the preferred insulin for treatment of feline DM for more than 25% of the veterinarians in the U.S.A. (Smith et al, 2012). However, a recent analysis did not demonstrate a benefit of insulin glargine over insulin lente of porcine origin in terms of the duration of survival of diabetic cats (Callegari et al, 2013) Insulin detemir (Levemir ® , 100 U ml -1 , Novo Nordisk) is also a recombinant human insulin analogue where threonine has been removed from the C-terminal of B chain and myristic acid has been bound to the lysine which is 29 th amino acid of the same chain (Gilor et al, 2010;Sako et al, 2011;. These molecular changes result in a slowly absorbed and highly albumin-bound molecule with long duration of action and increased the duration of action was found to be 24h in normal dogs and the blood glucose lowering-effect is similar or slightly lower compared to insulin NPH (Mori et al, 2008;Sako et al, 2011).…”

“…For cats with DM insulin glargine treatment is started at 0.25-0.5 U kg -1 BID (the upper end of the dosing regimen is used when blood glucose concentration exceeds 360 mg dl -1 ) or at 1-2 U per cat BID depending on the ideal body weight (1 U if ≤4 kg and 1.5-2 U if >4 kg) (Cook, 2007;Rios and Ward, 2008;Hall et al, 2009;Marshall et al, 2009;Tschuor et al, 2011). Some investigators advocate to adjust the initial dose by hospitalizing cats and performing serial J HELLENIC , 67(2) ΠΕΚΕ 2016 liver penetration (Gilor et al, 2010;Sako et al, 2011; which is also very stable and can be used for up to 6 weeks after opening if kept at room temperature and up to 6 months if refrigerated . In normal dogs peak activity is witnessed at 8-10h and the duration of action is more than 24h (Sako et al, 2011), whereas the respective figures in cats are 5-9h (average: 7h) and 9-14h (average: 12h) (Gilor et al, 2010).…”

“…Insulin glargine (Lantus ® , 100 U ml -1 , SanofiAventis) is a recombinant human insulin analogue: asparagine has been replaced by glycine at the 23 rd amino acid position of the A chain and two arginine amino acids have been added at the C-terminus of the B chain (Zerrenner et al, 2007;Gilor et al, 2010;. In the acidic (pH: 4) commercially available solution, insulin glargine is water soluble but after its injection into SC tissues, where pH is neutral, insulin crystals precipitate thus delaying absorption that remains steady over time (Mori et al, 2008;Gilor et al, 2010;.…”