Archive | Feline Diabetes

Using glargine intravenously for diabetic ketoacidosis

Diabetic ketoacidosis results from prolonged inadequate insulin activity. The main aims of therapy are to supply exogenous insulin, restore hydration status and manage electrolyte disturbances. Ketoacidotic cats usually present severely dehydrated and as such, have reduced absorption from subcutaneous tissue (from reduced blood flow). Until hydration is restored, insulin must be administered either intravenously or intramuscularly.

For many years, the insulin of choice for treating ketoacidosis has been regular insulin due to its rapid onset, potent glucose lowering effect and predictably short duration of action. Glargine has almost identical properties to that of regular insulin when used intravenously (Scholtz et al, 2003). Its actions are so similar that glargine can simply be substituted for regular insulin (for all your current protocols just draw glargine up instead of regular insulin). There are no reported clinical trials in the human literature assessing glargine administered intravenously as it was accepted to have no benefit over regular insulin. Regular insulin is used solely to treat diabetic ketoacidosis and many veterinary clinics chose not to stock it (or use it well after the expiry date) as the disease is seen so infrequently and most of the vials are wasted. Glargine on the other hand, can be used in DKA as well as maintenance therapy and most clinics have it on hand for diabetic cats. We mix glargine with normal saline, hartmann’s or 2.5% glucose solution. It is uncertain how long it will stay active in these solutions so suggest a new solution is made every 24hrs.

Glargine can be administered to ketoacidotic cats by:

• infusing intravenously at a rate of 0.05-0.1 U/kg/hr and rate adjusted to maintain blood glucose between 10-14mmol/L or
• injected s/c at the normal dose rate (0.25-0.5U/kg) as well as 0.5-1U of glargine injected IM or IV

As soon as I have a diagnosis of DKA, I immediately administer 0.5U/kg subcutaneously as well as 1U into the quadriceps muscles. I often administer glargine before I have discussed the diagnosis and treatment plan with owners. If they decide not to treat the cat,  little has been lost as the syringes and insulin probably cost the clinic less than $1. I have found most cats require 1U of glargine given IM every 2-4hrs based on glucose concentration. The dosing of glargine IM or IV is continued until hydration is restored and appetite returns, which usually occurs in 1-3 days. Glargine is then injected s/c and dosed as for an uncomplicated cat (see Table 1).

Please note When injected s/c, glargine reacts with the tissue and forms micro-precipitates which are slowly absorbed and is responsible for its long duration of action. Mixing or diluting glargine with any solution inhibits micro-precipitates forming and significantly reduces the duration of action. It is only when using intravenously for treating DKA that it can be mixed with other solutions as a long duration of action is not required.

Rhett Marshall BVSc, MANCVSc, PhD
The Cat Clinic
189 Creek Road,
Mt Gravatt, 4122

Basic information

Glargine (Lantus) is readily available from most pharmacies with a script, is not licensed for use in cats.

Glargine must not be diluted or mixed with anything because the prolonged action is dependent on its pH.

Insulin glargine should be kept refrigerated to prolong its life.

Insulin glargine has a shelf-life of 4 weeks once opened and kept at room temperature. We have found that opened vials stored in the refrigerator can be used for up to 6 months.

Discard vial immediately if there is any discoloration. Bacterial contamination and precipitation associated with pH change can cause cloudiness.

If using an insulin pen, the manufacturer recommends that the pen and cartridge be kept at room temperature and not refrigerated. This is to reduce the changes in volume of insulin dispensed associated with changes in temperature.

When performing a blood glucose curve, samples probably only need to be taken every 4hrs over 12 hr in many cats (ie. 0h [before morning insulin], 4h, 8h and 12h after morning insulin).

Dose changes should be made based on pre-insulin glucose concentration, nadir (lowest) glucose concentration, daily water drunk, and urine glucose concentration.

Better glycaemic control is achieved with twice daily dosing rather than once daily.

Some cats that have been treated with other insulin will go into remission, usually within 1-4 months after instituting glargine. Remission in cats that have been treated for more than 2 years is extremely rare.

More accurate dosing may be achieved using 0.3ml U-100 insulin syringes.

Remission is likely to occur if the nadir glucose is in the normal range and pre-insulin blood glucose is less than 12 mmol/l. However, for some cats to achieve remission, the dose needs to be very gradually reduced, tapering off to ½ U SID before being withdrawn. Too rapid withdrawal often requires restabilising at a higher dose for some weeks.

Indications for using glargine

All newly diagnosed diabetic cats (to increase chance of remission)

Poorly controlled or unstable diabetic cats (glargine's long duration of action is likely to benefit these cats)

When SID dosing is desired or demanded (It is important to note that better glycaemic control and higher remission rates will be obtained with BID dosing. SID dosing only provides similar control and remission rates to lente BID)

Ketoacidosis - combined with regular insulin IM or IV

When corticosteroid administration is required in cats in remission. Similarly in cats at high risk of developing clinical signs of diabetes with corticosteroid administration.

Starting a cat on glargine insulin

If BG > 20mmol/L begin glargine at an initial dose of 0.5U/kg ideal body weight q12hrs (BID)

If BG < 20mmol/L begin at 0.25U/kg ideal body weight q12hrs (BID)

Perform a 12hr glucose curve with samples taken every 4hrs. Insulin can be increased daily until normoglycaemia is achieved but careful monitoring is necessary to avoid hypoglycaemia

Decrease dose if biochemical or clinical hypoglycaemia occurs

It is suggested that cats stay in hospital for 3 days to check the initial response to insulin, or home glucose curves are obtained for the first 3 days. Continuous blood glucose monitoring systems are an excellent way of obtaining initial response to therapy and we have great success using the Abbott FreeStyle Libre monitors. These can also be left in place for 2 weeks and allows owners to obtain BG readings without needing to sample blood.

Home glucose monitoring is considered best practice but for owners unable to complete at home then cats should be rechecked at 1, 2, 3 and 4 weeks and then as required.

Ketoacidotic cats may be treated with glargine s/c at the above dose rates in combination with regular insulin IM or IV (we have found 1U regular insulin IM every 2-4hrs based on glucose conc works best). This regime is continued until hydration restored and appetite returns, which usually occurs in 1-3 days.

Monitoring cats receiving glargine insulin

When performing a blood glucose curve, samples probably only need to be taken every 4hrs over 12 hr in many cats (i.e. 0h [before morning insulin], 4h, 8h and 12h after morning insulin).

With the long duration of action of glargine, there should be minimal periods when blood glucose is >14mmol/L for cats treated for more than 2 to 3 weeks, and hence well controlled cats should almost always be 0 or 1+ for urine glucose. A value 2+ or greater likely indicates that an increase in dose is required.

Dose changes should be made based on pre-insulin glucose concentration, nadir (lowest) glucose concentration, daily water drunk, and urine glucose concentration.

Adjusting glargine insulin dose

Once a cat has been stabilised on glargine insulin (i.e. after a week of therapy), the dose may need to be increased or decreased.

1. Indications for increasing the dose of glargine insulin
2. If pre-insulin glucose conc. is > 12mmol/L, then increase dose by 0.25-1.0U/injection

AND/OR

1. If nadir glucose conc. is > 10mmol/L then increase dose by 0.5-1.0U/injection
2. For well controlled cats after several weeks of therapy, an immediate "pre-insulin" glucose measurement > 12 mmol/L suggests that the dose should be increased.
3. Indications for maintaining the same dose of glargine insulin
4. If pre-insulin glucose conc. >10 - <12mmol/L)

AND/OR

1. If nadir glucose conc. 5-9mol/L
2. For well controlled cats after several weeks of therapy, aim for a nadir of 4-7 mmol/L
3. Indications for decreasing the dose of glargine insulin
4. If pre-insulin glucose conc <10 mmol/l decrease 0.5-1.0U
5. If nadir glucose conc <3 mmol/l decrease 0.5-1U
6. If clinical signs of hypoglycaemia develop, then rub honey or golden syrup onto the gums and contact a veterinary clinic immediately.
7. If biochemical hypoglycaemia develops, it can often be managed by feeding the cat, preferably a higher carbohydrate containing food, such as supermarket wet food with gravy.
8. For cats with unexpected biochemical hypoglycaemia (not clinical signs), some owners find that they can manage the hypoglycaemia by delaying the insulin injection until blood glucose increases to 10 mmol/L and then give the same dose (the following dose of insulin may need to be reduced), while others find it best to reduce the dose once glucose is above 10 mmol/L, although this may result in subsequent hyperglycaemia. In some cases, there is a "grey zone" of peak 11 - 14 mmol/L and nadir 3 - 4 mmol/l glucose concentrations. In these cases, the glargine insulin dose may be maintained or decreased depending on the water intake, urine glucose, clinical signs and length of time the cat has been treated with insulin.
9. Insulin dose may be maintained, increased or decreased depending on the water intake, urine glucose, clinical signs and length of time the cat has been treated with insulin.
10. If pre-insulin glucose conc. 11 - 14 mmol/L, or if nadir 3 - 4 mmol/l, clinical parameters are essential for adjustment of insulin dose.

Determining if the cat is in remission

1. Insulin dose should be gradually reduced by 0.25-1 U/cat/injection if nadir blood glucose is in the normal range of 4-7 mmol/L or pre-insulin glucose concentration is < 10 mmol/L. Withdraw insulin SLOWLY until dose is 0.25 - 1 U once daily (SID). Some cats require only small doses of insulin (<1 U/cat BID) and only go into remission if the dose is reduced VERY SLOWLY giving few remaining beta cells a chance to recover.
2. After a minimum of 2 weeks of insulin therapy, if the pre-insulin blood glucose is <10mmol/L and insulin dose is 0.25-1 U SID, insulin should be withheld and a 12hr glucose curve performed. If at the next due dosing time the blood glucose is >12mmol/L, then insulin can be re-administered at 1U BID and then gradually reduced as indicated. If blood glucose is <12mmol/L then continue to withhold insulin and discharge with a follow-up visit in 1 week. Water intake and urine glucose should be closely monitored and insulin reinstituted if glycosuria returns or water intake increases.
3. Some cats may have a pre-insulin glucose concentration <10mmol/L within 2 weeks, but insulin therapy should be maintained for a MINUMUM of 2 weeks to give beta cells a better chance to recover from glucose toxicity. Use 0.5-1U BID or once daily until insulin is withdrawn.
4. Some cats that have been treated with other insulin will go into remission, usually within 1-4 months after instituting glargine. Remission in cats that have been treated for more than 2 years is extremely rare. Remission is MORE likely to occur if the nadir glucose is in the normal range and pre-insulin blood glucose is less than 12 mmol/L. However, for some cats to achieve remission, the dose needs to be very gradually reduced, tapering off to ½ U SID before being withdrawn. Too rapid withdrawal often requires restabilising at a higher dose for some weeks.

Urine Glucose

With the long duration of action of glargine, there should be minimal periods when blood glucose is >14mmol/L for cats treated for more than 2 to 3 weeks, and hence well controlled cats should almost always be 0 or 1+ for urine glucose. A value 2+ or greater likely indicates that an increase in dose is required. This should be confirmed with blood glucose evaluation.

Fructosamine or Glycated Haemoglobin

Urine and blood glucose and water intake (i.e., clinical signs) are usually the easiest way to monitor therapy with glargine insulin. Since many cats go into remission after a few weeks, long-term measures of glycaemic control, such as fructosamine or glycated Hb, are of less value in monitoring patients.

General observations from preliminary use of glargine insulin

Starting doses may be high. Some cats initially require a dose of 5 or 6 U/cat BID to establish glycaemic control. This dose can usually be reduced as insulin sensitivity returns. Cats on these high doses need to be carefully monitored for hypoglycaemia.

Some cats require only small doses of insulin (<1 U/cat BID) and only go into remission if the dose is reduced very slowly giving the few remaining beta cells a chance to recover.

Nadirs can be variable. For many cats, the time at which the nadir (lowest) glucose concentration occurs is often not consistent from day to day, or between cats. Sometimes it occurs somewhere between the two doses, but sometimes the nadir occurs around the time of the next dose. Some cats consistently have their nadir glucose concentration in the evening just before the next insulin injection, and less commonly, it occurs around the time of their morning injection.

BID dosing to start. Better glycaemic control is achieved with twice daily dosing rather than once daily.

To increase the chance of remission, we suggest aiming for perfect control or possibly slightly overdosing during the first 2 months, provided the veterinarian and owner can carefully monitor the cat. There is the potential risk of hypoglycaemia, but we believe this is outweighed by the benefit of diabetic remission to the cat and owner.

Cats requiring intermittent or chronic corticosteroid administration that are either in remission or at risk of developing diabetes can usually safely be placed on 1U SID or BID.

It is a very common observation by owners that when long-term stable diabetic cats are changed over to glargine, usually they do better clinically, even if blood glucose results do not support the clinical improvement.

REFERENCES

Journal Articles

1. Rand JS, Marshall, RD. Diabetes Mellitus in Cats. Vet Clin Small Anim., 2005;35[1]:211-224.
2. Weaver KE, Rozanski EA, Mahony OM, Chan DL, Freeman LM. Use of glargine and lente insulins in cats with diabetes mellitus. J Vet Intern Med. 2006;20(2):234-8.

Proceedings

1. Stenner,V.J., Fleeman,L.M. & Rand,J.S. Comparison of the pharmacodynamics and pharmacokinetics of subcutaneous glargine, protamine zinc and lente insulin preparations in healthy dogs. Proceedings ACVIM 2004.
2. Marshall RD and Rand JS. Treatment with glargine results in higher remission rates than Lente or protamine zinc insulins in newly diagnosed diabetic cats. Proceedings ACVIM 2005.
3. Marshall R, Rand J. Comparison of the Pharmacokinetics and Pharmacodynamics of Glargine, Protamine Zinc and Porcine Lente Insulin in Healthy Cats. Australian College of Veterinary Scientists Science Week, 2003.
4. Marshall R, Rand J. Comparison Of The Pharmacokinetics And Pharmacodynamics Of Once Versus Twice Daily Administration Of Insulin Glargine In Normal Cats. Proceedings ACVIM 2002
5. Marshall R, Rand J. Update on Insulin Glargine Use in Diabetic Cats. Proceedings ACVIM 2005
6. Weaver KE, Rozanski EA, Mahony O, Chan DL, Freeman LM. Comparison of Glargine and Lente Insulins in Cats with Diabetes Mellitus. Proceedings ACVIM 2005

The best method of monitoring response to insulin therapy is measurement of blood glucose concentrations. The vast majority of cats will allow blood collection if they are handled in the right way. Things that help with collecting blood from fractious cats are

• don’t make them wait
• do the collection in a quiet place such as a consulting room
• don’t let them see other cats or dogs
• consider the medial saphenous vein
• use the smallest amount of restraint possible
• use staff that like cats and involve the owner if possible
• if admitted for a blood glucose curve, try housing in a quiet separate location like a spare consult room or the office
• home glucose sampling by staff or owner

Most fractious cats are much better behaved with just their owners present, in a consulting room. I like to sample blood from the jugular vein with the help of the owner. I get owners to stand behind the cat and speak gently to them while petting their head. I slowly but firmly grab hold their heads by placing my thumb under their chin and fingers on top of their head and rotate upwards until vertical. Most cats have a 10 second window of opportunity so without releasing this grip, I use the other hand to shave the skin, swab with alcohol and then direct the owners index finger over the top of the vein and then collect blood using an insulin syringe. Having owners involved like this can be extremely daunting for many veterinarians but with confidence and competence, most fractious cats can have their blood sampled.

Stress induced hyperglycaemia occurs commonly in fractious cats making blood glucose taken under duress or from a stressed cat meaningless so don’t even bother if you have to pin a cat down with force.

Unfortunately, there are times when blood glucose sampling is simply not possible due to the temperament of the cat. What are we to do in such circumstances? Daily water drunk is often overlooked, but is an important tool for monitoring diabetic cats. Blood glucose concentrations above the renal threshold (14 - 16mmol/L in cats) result in glycosuria, osmotic diuresis, and compensatory polydipsia. Measurement of water consumption at home is simpler, cheaper, and less stressful to measure for the owner, cat and practitioner, and correlates better with mean daily glucose concentration than does fructosamine concentration.

Get the owner to start therapy at a dose of 0.25 units/kg of glargine s/c twice daily. Owners then measure the 24hr water intake and record it. Despite seeming obvious, owners must be instructed on how to accurately measure water intake. A measuring cup should be used to pour a known amount of water into the drinking bowl at the start of the period and then to measure it again at the end of the period. Access to alternate drinking sites must be removed and it may be necessary to confine the cat in part of the house if it drinks significantly from a source that can’t be measured, like a pond or swimming pool. Confinement will also be required in multi-pet households so as to be sure of the patients water intake.

Insulin dosage changes are then based on the water intake of the cat with the aim of keeping water intake to around 40mls/kg/day or 200mls per day for an average diabetic cat (normal daily water intake is 20mls/kg if fed wet food only and 70mls/kg if fed dry food only). Insulin dose can be increased weekly by 0.5-1U until water intake is at the desired level.

It is desirable, but not essential, to get pre-insulin blood glucoses in as many of these patients as possible. For some cats that cannot be handled in the clinic a housecall may be worth a try. A pre-insulin glucose of less than 10 mmol/L (on insulin glargine) should trigger a dose reduction.

Another useful tool to help is to get the owners to measure urinary glucose with a dipstick a couple of times a week. Diabetic cats should have some degree of glycosuria. A persistent negative urinary glucose should trigger a dose reduction whereas persistent 4+ urine glucose requires a dose increase. Owners can place paper based litters in a syringe and squeeze urine onto the dipstick with little impact on accuracy.

Management by measuring water intake will not work if there are concurrent factors causing polyuria, eg renal disease, drug therapy with frusemide. Diabetic cats can live many years and many eventually develop renal disease which then makes using water intake invalid for monitoring insulin therapy.

It is imperative to educate owners that this is not the best way of managing the disease and that the risks are increased and the quality of control is likely not as good. However, it provides a method of managing the fractious feline diabetic patient that is stress free to all involved. It can also be useful for those clients that lack the financial resources to manage their diabetic cat more intensively.

How to recognise and approach diabetic remission

Good glycemic control soon after diagnosis reverses glucose toxicity and many newly-diagnosed diabetic cats can have their insulin dose gradually reduced and many can have their insulin completely withdrawn. It is suggested that insulin not be withdrawn completely for at least two weeks after starting insulin therapy to ensure adequate time for beta cells to recover from glucose toxicity.

Insulin dose can be reduced when indicated by low blood glucose parameters listed above. If pre-insulin glucose is below 10mmol/L and insulin dose has been reduced to 1U, insulin should be withheld and blood glucose measured for 12hrs (if the pre-insulin glucose is below 10mmol/L and insulin dose greater than 1U, insulin dose should be reduced to 1U rather than withheld and pre-insulin glucose measured again in 3-7 days). In most cases, if when insulin is withheld the blood glucose concentration

• rises rapidly or significantly over 10mmol/L cats should be discharged on 1U twice daily
• rises slowly towards or just above 10mmol/L, then cats should be discharged on 1U once daily
• remains below 10mmol/L for 12hrs with no insulin, they can be assumed to be non-insulin dependant and cats should be discharged without insulin with their blood glucose monitored every 2-3 days for several weeks. Confirmed non-insulin dependant diabetic cats should have their blood glucose checked weekly for 3 months and then monthly forever.

Some cats may have a pre-insulin glucose concentration below 10mmol/L within 2 weeks, but insulin therapy should be maintained for at least 2 weeks to give beta cells adequate time to recover from glucose toxicity. Use 1U BID or SID until insulin is withdrawn.

What to do with a diabetic cat in remission
Once remission has occurred, it is vital that blood glucose concentration be measured regularly (initially weekly then monthly) to quickly diagnose a relapse. To facilitate the cat remaining in diabetic remission, it is recommended that a low carbohydrate diet is fed, physical activity is increased, calories are restricted to avoid obesity, and that diabetogenic drugs are contraindicated unless a life threatening situation arises.

How to increase the chance of remission occurring
Our study in diabetic cats (Marshall et al, awaiting publication) found better glycaemic control and higher remission rates when newly diagnosed diabetic cats were treated with glargine compared to lente or PZI insulins. This study also showed that, regardless of insulin type, good glycaemic control soon after diagnosis (within 3 weeks) increases the chance of achieving remission.

For reasons that are presently unknown, glargine treated cats appear to tolerate slight overdosing with insulin very well. For this reason, it is suggested that for the first 4-6 weeks of therapy, insulin be slightly overdosed and cats monitored carefully. Slightly overdosing with glargine increases the risk of hypoglycemia but usually results in achieving early good glycemic control which reverses glucose toxicity and results in a non-insulin dependant state. The benefits of remission far outweighs the risks of hypoglycaemia.

To maximise glycaemic control and hence the chance of remission

• select glargine as initial insulin
• administer glargine TWICE daily rather than once daily
• slightly overdose with insulin for the first 4-6 weeks
• use a low carbohydrate diet
• restrict calories if overweight and encourage physical activity

Measurement of blood glucose concentration (BG) is usually the best method of determining the correct insulin dose for diabetic cats. Stress hyperglycaemia occurs commonly when cats visit a veterinary surgery and can result in the wrong dose of insulin being selected. Thus, the stress-free environment at home is the best place to measure a cats BG.

Most human glucometers are very accurate at measuring cat blood. We prefer the Accu-Chek brand which can be purchased from any chemist for approximately $60.

The easiest and safest place for owners to sample blood from is the ear veins. Cats have small veins that run around the outside of their ears and these veins can be easily accessed from the dorsal surface. Blood can be sampled on both the cranial and caudal border of each ear giving a total of 4 sites to sample. Shaving the hair directly over the vein with a scalpel blade allows much better visualisation and with very slow hair regrow, will last for many weeks.

Procedure
1. Turn the glucometer on or insert test strip so the digital display is requesting blood.
2. Hold the edge of the ear between index-middle finger and thumb-fourth finger and firmly pull taut.
3. Quickly prick the vein with an insulin needle so a small drop of blood is produced on the skin surface. Pre-used insulin syringes are fine to use for this.
4. Bring glucometer down to the skin and place the end of the test strip into the blood until it beeps.
5. Read the number on the display and record it.
6. Wipe any excess blood away with a moist tissue.

Cats rarely react to their ears being pricked but topical anaesthetic creams such as EMLA can be applied prior to sampling if required. The most common complaint from owners is spraying of blood around the house if they shake their heads while blood is pooled on the skin. This can be minimised by not releasing the initial grip on the ear until blood has been transferred (with one hand) to the glucometer and a tissue applied to the ear.  Blood glucose samples are best collected just before an insulin dose is due so dose adjustments can be made immediately if required rather than waiting until the next injection.

Selecting insulin dose
à For newly diagnosed diabetic cats (less than 2 months):
If BG is above 12mmol/L then increase insulin dose 0.5 units (half a unit)
If BG is between 6 and 11mmol/L then keep insulin dose the same
If BG is between 3 and 6mmol/L then reduce dose by 0.5 units
If BG is less than 3mmol/L then don’t give insulin and call the clinic to discuss

à For longer-term diabetic cats (more than 2 months of insulin therapy):
If BG is above 25mmol/L then increase insulin dose 1 units
If BG is between 14 and 25mmol/L then increase insulin dose 0.5 units
If BG is between 6 and 13mmol/L then keep insulin dose the same
If BG is between 4 and 6mmol/L then reduce dose by 0.5 units
If BG is less than 4mmol/L then don’t give insulin and either check for remission or call the clinic to discuss.

How often to sample
Ideally, diabetic cats should have BG sampled several times daily (just like humans do) but for many reasons this is not practical. We recommend that newly diagnosed cats should have their BG checked every 2-3 days for the first few weeks and longer-term diabetic cats be sampled every 1-2 weeks. If insulin dose is changed, then a repeat BG should be done 2-3 days afterwards to check the right decision was made, whereas if the insulin dose is kept the same then a repeat BG is probably not required for 1-2 weeks.

Record keeping
A table should be kept which contains the date, current insulin dose, the BG reading and the new insulin dose selected. Initially, this table should be reviewed by a veterinarian in consultation every few weeks. Your veterinarian will assess the BG readings and the decisions you have made and comment as necessary. Most owners rapidly become competent at sampling blood and selecting the correct insulin dose making it unnecessary to consult us for long periods.