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					  LIFE AFTER LENTE:
CHOOSING FROM AVAILABLE
       INSULINS




  Stacey B. Hoffman, DACVIM
       September 21, 2005
            Origins of insulins
   Historically, beef, pork, or beef/pork origins
   Pork insulinidentical to canine insulin
   Beef insulinone amino acid away from feline
    insulin
   More recently, human recombinant insulins
    available: one amino acid away from canine
    insulin, less similar to feline
             Duration of action
   Short acting: semilente (available only in
    mixtures) and regular
   Intermediate acting: NPH (protamine to
    retard absorption) and lente (combination of
    semilente and ultralente)
   Long acting: PZI (protamine zinc insulin) and
    ultralente
            Upcoming changes
   Eli Lilly discontinuing manufacture of Humulin
    L(lente) and Humulin U(ultralente)-Dec. 2005

   New insulins to consider: Vetsulin (just
    approved in US 2005), PZI (commercially
    manufactured by IDEXX), glargine (new human
    insulin product)
Insulin pharmacokinetics:dogs
       (Stenner et al, 2004 ACVIM Forum, p. 866)

   Comparison of PZI,
    porcine lente, glargine in
    healthy dogs
   Dose: 0.5 U/kg SQ
   Triple cross-over study
        Canine pharmacokinetics
Insulin     Time onset Time nadir       Duration


Lente       0.6+/-0.7hr   2.4+/-1.0hr   10.4+/-1.5hr


PZI         3.1+/-0.7hr   6.4+/-1.0hr   19+/-1.6hr


Glargine    2.2+/-0.9hr   5.7+/-1.2hr   13+/-1.9hr
                 Study results
   Lente insulin: predictable insulin peak with
    shorter onset & duration of action than PZI
   PZI: lowers blood glucose with a prolonged
    duration of action in all dogs
   Glargine: 2/9 dogs did not have significant
    lowering of blood glucose after glargine,
    unpredictable insulin concentration response in
    other dogs
                 Lente insulins
   Human recombinant Humulin L (E. Lilly) off
    market, new pork product (Vetsulin) available
   Absorption controlled by size of zinc insulin
    crystals
     Semilente (30%): small crystals, prompt absorption
     Ultralente (70%): large crystals, extended absorption
             Vetsulin® insulin
   U-40 insulin, porcine origin
   Available in Canada as Caninsulin ®, now FDA
    approved in United States
   Website: www.vetsulin.com
   Lente insulin: 30% amorphous insulin (rapid
    onset), 70% crystalline zinc insulin (longer
    duration) two peaks
           Manufacturer’s dose
Body weight Dose         Supplement   Total

<10 kg      Wt(kg)x 1U   1U           1 U/kg + 1

10-11 kg    Wt(kg)x 1U   2U           1 U/kg + 2

12-20 kg    Wt(kg) x 1 U 3 U          1 U/kg + 3

> 20 kg     Wt(kg) x 1U 4 U           1 U/kg + 4
               Vetsulin study
   53 client owned dogs, 34% controlled with SID
    dosing and 66% BID
   Manufacturer’s recommendation for starting
    dose-1 U/kg plus dose supplementation given
    once daily at meal times
   If changing to Vetsulin BID from human lente
    or NPH, recommend decreasing dose by 25%
    (or 50% if changing to Vetsulin SID)
       Insulin therapy diabetic dogs
                 (Hess, ACVIM Forum 2001)



   >50% of diabetic dogs in retrospective study
    received insulin injections SID (NPH, lente)
   At time of clinical control, only 6% (5/83)
    received SID insulin
   SID insulin administration in dogs associated
    with inadequate glycemic control, insulin
    overdose, hypoglycemia
   Recommend starting lente (Vetsulin) 0.5 U/kg
    BID diabetic dogs
                      Vetsulin
              (Source: Intervet-manufacturer)



   How much $$$ to treat 40 lb dog?
     Once daily
     Twice daily

   Should owner use 2.5 ml or 10 ml vial?
   How long will insulin vial last?
                             Vetsulin
                   (Source: Intervet-manufacturer)

   Cost per ml
       10 ml
            10 ml/vial x 40 U/ml = 400 units per vial
            $30/vial (~pet owner cost)
            $30/vial ÷ 400 units/vial
            7.5 cents per unit
       2.5 ml
            2.5 ml/vial x 40 U/ml = 100 units per vials
            10 vials per box
            $42.80 ÷ 10 vials = $4.28 x 2 + round-up = $8.75 (to ō)
            $8.75/vial ÷ 100 U/vial = 8.8 cents per unit
                       Vetsulin
              (Source: Intervet-manufacturer)

   Cost per syringe
     $19.90 vet cost per box
     ~$25.00 pet owner cost per box

     100 syringes per box

     $25 ÷ 100 = 25 cents per syringe
                     Vetsulin
             (Source: Intervet-manufacturer)


   How long will a 10 ml vial last for this dog?
   How many units per 10 ml vial?
      40 U/ml x 10 ml = 400 U
       400 U ÷ 21 U/day = 19 days
        Vetsulin cost for 40 lb dog
                  (Source: Intervet-manufacturer)

   What is the dosage and the dose?
   For once daily:
     40 lb ÷ 2.2 lb/kg = 18.18 kg
      18 kg x 1U/kg = 18 U
      Plus 3 U (wt-based dose supplement)
      Total of 21 units per day
   Cost of Vetsulin (10 ml) is 7.5 cts/U
       7.5 cts/U x 21 units = $ 1.58 per day
   Cost of syringe is 22 cents each
   Total cost per day is $1.80 per day for 40 lb SID
                                   Vetsulin
                       (Source:Intervet-manufacturer)
   What is the dosage?
   For twice daily:
          Decrease dose by 25%
          Previously 21 units
          21 x .75 = 15.75
          New dose is 15 units, 2 times a day
          Therefore 30 units per day
   Total cost
        Vetsulin: 30 units per day x 7.5 cts/unit = $2.25
        Syringes: 44 cts per day for 2 syringes
        Total = $2.69 per day
        Insulin glargine (Lantus)
   New synthetic (recombinant) human insulin
    analogue
   Clear solution with pH 4.0, microprecipitates
    form when acidic insulin interacts with neutral
    pH subcutaneous tissues following injection
   In human medicine, considered long-lasting
    “peakless” insulin
     Pharmacokinetics study-cats
          (Rand and Marshall, 2005 ACVIM Forum)

   Triple blind cross-over study in normal cats,
    comparing PZI, glargine, and pork lente
   All cats dosed at 0.5 U/kg SQ
   No difference between insulin types w.r.t. onset
    of action and glucose nadir values
   In contrast to results in humans, glargine is not
    “peakless” in cats
          Feline pharmacokinetics
Insulin      Time onset   Time nadir   Duration


Lente        ~2 hrs       4+/-0.5hr    ~12 hrs


PZI          ~2 hrs       6+/-2.3hr    ~16 hrs


Glargine     ~2 hrs       16+/-1.9hr   23+/-0.9hr
         Glargine in diabetic cats
          (Rand and Marshall, 2005 ACVIM, p.483)

   24 newly diagnosed diabetic cats, all fed Purina
    DM (low carb-high protein)
   Received either PZI, porcine lente, glargine
    (0.25 or 0.5 U/kg BID)
   8/8 glargine cats achieved diabetic remission
    within 4 months (reversal of glucose toxicity of
    ß cells), mean remission 13 +/-3 mos.
   5/16 PZI/lente cats remission
              Glargine vs. lente
         (Weaver et al, 2005 ACVIM Forum, p. 863)

   Both newly diagnosed and poorly controlled
    diabetic cats (13 total), all fed Purina DM
   Starting doses: lente 0.5 U/kg BID or glargine
    0.5 U/kg SID
   No difference between groups w.r.t. treatment
    response or remission rates
   4/13 cats achieved complete remission
           Glargine information
   Although 0.5 U/kg SID has significant glucose
    lowering effect, 0.25 U/kg BID has longer effect
   Better glycemic control with BID dosing
   In clinical study (Rand and Marshall), no
    diabetics on glargine showed clinical
    hypoglycemia despite low glucose values
   Starting dose: 0.5 U/kg BID, most cats need
    dose reduction within 2 wks, remission 4 wks
                     PZI insulin
   Beef (90%)/pork (10%)
    origin insulin with longer
    duration of action
   Comes as U-40 insulin,
    so need to use U-40
    insulin syringes (will
    underdose 2.5X if using
    U-100 syringes)
   Commercially available
    from IDEXX
            PZI in diabetic cats
          (Nelson et al 2001, JAVMA 218(1): 38-42)

   Starting doses of PZI: 0.2-0.6 U/kg BID
   Clinical signs of hypoglycemia in 5/67 cats,
    others hypoglycemic w/o signs
   Overlap between doses that cause hypoglycemia,
    control glycemia, don’t control blood glucose
   Recommend starting doses of PZI low (1
    U/injection)
              SID vs. BID PZI
   Historically, PZI often been administered to cats
    once daily (pharmacokinetic data?)
   Variations in PZI absorption: blood glucose
    nadir 1-12 hours post injection, return to
    baseline 8-24 hours post injection
   Could consider once daily PZI in cats that reach
    nadir > 10 hours post insulin, but most cats
    (75%) need BID dosing
         Treatment options: cats
   Insulin glargine: may be best choice in newly
    diagnosed diabetics, possible remission w/diet
   NPH insulin (Humulin or Novolin)
   Lente insulin (Vetsulin): starting doses of 0.25-
    0.5 U/kg BID (short duration of action,
    anectdotal report)
   PZI insulin: start low, BID dosing for most
        Treatment options: dogs
   Humulin or Novolin NPH
   Lente insulin (Vetsulin): use as if using Humulin
    L, rather than manufacturer’s instructions
   PZI: rarely used in dogs
   Glargine: unpredictable concentrations, fails to
    lower glucose in some dogs so probably a poor
    choice
              A few final points
   Remember to use U-40 syringes with U-40
    insulins (Vetsulin, PZI)
   When changing between types of insulin, need
    reduce dose
   Benefits of Purina DM diet in diabetic cats (low
    carb/high protein)
   Clinical judgement (owner and DVM) will still
    play important role in regulation of diabetics

				
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posted:11/11/2011
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