Pet Health: PZI (Protamine Zinc Insulin)

What is PZI?

PZI (Protamine Zinc Insulin) is insulin combined with zinc and protamine (a protein extracted from salmon testes), which slow the release of the insulin into bodily tissue. Historically, the insulin component of PZI, as well as all other insulin produced for human medical use, was derived from animals, either cows or pigs. Animal-derived insulin is a by-product of slaughtering food animals. The pancreas is ground and transformed into a crystalline powder, which is sold to insulin manufacturers. No animals from countries where BSE (mad-cow disease) exists may be used.

Mass-produced, genetically engineered human insulin has generally replaced animal-derived insulin in use by human diabetics. In the mid-90's in the US, beef-source insulin (including PZI formulations) were phased out by the major producers such as Lilly Pharmaceuticals. Since beef-pork PZI was the insulin most familiar and most recommended for diabetic cats, many were left scrambling (and some were, sadly, unable) to find an effective alternative.

No longer able to obtain beef-pork PZI for their veterinary clients, compounding pharmacists developed a formula substituting human insulin (Lilly markets it as "Humulin") for animal-derived insulin, along with protamine-zinc. Although completely untested in any scientific way, this seems to have been a satisfactory substitute for many feline PZI customers.

PZI sold today by most compounding pharmacies in the US is almost certainly a compound of human “Regular” insulin. Until recently, the only exceptions to this were pharmacists who had hoarded a dwindling supply of one of the discontinued animal-derived insulin. However, in 2000, BCP Veterinary Pharmacy of Houston, Texas succeeded in chemically reproducing Lilly's Iletin I 100% beef PZI (discontinued in 1990), making them the only US source for an all-beef PZI. As for US manufacturers, IDEXX Pharmaceuticals who produces PZI vet doesn't actually have FDA approval for the manufacture. Kellie & chu of the FDMB, contacted the FDA's Center for Veterinary Medicine about this in February 2007. The FDA CVM states that PZI Vet is not FDA approved but is allowed to be marketed under regulatory discretion. PZI Vet is manufactured in a FDA-inspected plant, however. PZI Vet is the first insulin produced for, and tested exclusively for cats rather than humans. Idexx makes the claim that it is "the only insulin scientifically proven to be effective in diabetic cats." That claim is now disputable as more insulin types are now being manufactured and then tested in diabetic cats. You can find more information at the Idexx web site.

Why use PZI?

For a few cats, human insulin does not successfully replace the cat's own insulin, so for them, the source of the insulin is very important to regulation. Bovine (beef) insulin is most similar in molecular structure to feline insulin, and it is thought for this reason, to be most effective for these cats.

In addition, with 2 injections per day, the many cats who do respond to the human forms of insulin, experience better control, consistency and flatter curves with PZI. In some cases, PZI offers longer durations than human insulin (up to 24 hours) allowing one injection per day. Although there is little scientific evidence either way, experientially, among FelineDiabetes.com contributors, there is a strong preference for manufactured beef (or beef-pork) PZI, over the compounded human insulin PZI, which is suspected of sloppy or inconsistent small-scale production, because it deviates from the historical formula for PZI, and has less of a track record.

In the UK, CP Pharmaceuticals has been producing bovine insulin (for humans) for 25 years, and Schering-Plough has recently started to market a veterinary PZI-beef product.

Three forms of PZI sold in the US:

(1) Beef-Pork PZI from IDEXX Pharmaceuticals

Beef-pork insulin from IDEXX Pharmaceuticals (formerly Blue Ridge Pharmaceuticals) is available for sale to veterinarians.

Vets will likely mark up the cost to you, possibly by a lot. Before ordering, ask what your vet will charge you.

IDEXX PZI has a shelf life (unopened) of 3 years from the date of manufacture.

(2) PZI available from US pharmacies

The "PZI" insulin available by prescription from US compounding pharmacists generally consists of "Regular" human insulin (rapid-onset, short-duration) which has been compounded with protamine-zinc to extend its duration. A small number of pharmacists mix insulin from OTHER sources with PZ. They may have sources of discontinued beef-pork from Lilly, Europe, or use pure pork (Lilly Iletin II). You have to ask them, to know for sure what you're getting. Pharmacists combine the insulin with PZ in onsite laboratories, under what should be stringent conditions. Quality controls and checks mandated by the FDA for manufacturers don't apply to compounders. Relatively small batches of insulin may be compounded to order, or monthly, depending on demand. Without strict adherence to procedure, there is a risk of variability between batches and contamination that is greater than when getting insulin from a manufacturer. This is reflected in shorter shelf life recommendations. Some pharmacists, especially those who compound large volumes of PZI, take voluntary measures to ensure a clean, consistent product, such as outside analysis, and incubation to test sterility.

BCP Veterinary Pharmacy is unique as their pharmacists compound PZI with insulin crystals like a manufacturer, although they work in much smaller quantities and under less stringent conditions and specifications. They have chemically reproduced a formula for 100% beef PZI, which Lilly once sold under the name Iletin I. A prescription is required - but unlike IDEXX - there is no minimum order, and they will ship to you directly allowing one to avoid vet markups. As with any compounded formulation, variability between batches may be slightly greater than the stricter tolerances required of manufactured insulin. However, ongoing analysis is conducted by BCP Veterinary Pharmacy to ensure consistent quality control.

Shelf life: Depending on which pharmacist you ask, shelf-life for compounded insulin ranges between 30 and 90 days, which can be less than a manufactured product. They may compensate for this by offering smaller quantities (but they may not charge less). If you test bg's at home, you can judge for yourself if the efficacy is fading. Using sterile techniques and keeping insulin in the refrigerator will prevent or delay bacterial contamination. BCP's shelf life for its regular beef PZI is six months.

(3) 100% Beef PZI from the UK

There are currently 2 manufacturers of 100% beef PZI insulin in the United Kingdom (UK).

CP Pharmaceuticals' Hypurin® is licensed for human use and is therefore sold through pharmacies in the UK (one is listed below), and elsewhere in Europe. The 100% bovine, U100 insulin comes from US cows, and is offered in 4 formulations: PZI, Lente, Isophane (NPH) and Neutral (Regular). Pork insulin (used by some cats), which is structurally identical to dog insulin, and should be similar to human insulin when used in cats, is also offered (in Neutral, Isophane, and 30/70). A prescription is not required when shipping outside the UK. Shelf life once opened is 90 days (refrigerated).

Schering-Plough's Insuvet® is 100%beef, U100, and is approved only for veterinary use in the UK and is available only through vets. It is pure beef, U100 strength, comes in PZI, Lente, and Regular formulations, and has an official shelf life opened and refrigerated, of 28 days.

Import regulations:Good News for US insulin importers. As of November 2006, there is no longer a UDSA permit fee. For those in the US importing foreign insulins (especially beef and pork insulins from CP Pharma) the USDA permit is good for 5 years and the $ 94 permit fee has now been waived for personal importation. Import permits are granted on a case-by-case basis. As soon as USDA updates its website regarding the waiving of the fee, we will provide a link to this new information.

What do the strength numbers (U40, U100) mean?

The vials of what we call insulin actually contain a minute amount of crystalline insulin, which is suspended in a fluid (called diluent) that is mostly water. Pure, crystalline insulin is measured by weight, in international units (iU).

When combined with the other ingredients, insulin strength is expressed as U100, U50, and U40, meaning that there are 100, 50 or 40 international units of insulin per milliliter (ml) of diluent (the fluid). A ml of U40 contains 40iU of crystalline insulin, and therefore a 10ml vial will contain 400iU. The same vial of U100 strength, contains 1000iU of insulin, or 2.5 times as much. Think of U100 as being more concentrated than U40.

IDEXX PZI comes in U40 strength, CP Pharmaceuticals Hypurin® comes in U100 strength, and the compounded human "Regular" PZI's come in a variety of strengths. If your cat takes a very small dose, the more dilute insulin strengths can be easier to measure.

Syringes are designed to be used with a specific strength of insulin. U40 syringes contain a full cc (equivalent to 1ml) and have 40 unit marks. Measuring U40 insulin to the one unit mark in a U40 syringe, will contain 1iU of insulin. U100 syringes are most popular in a 3/10cc size, with 30 marks (100 marks per full cc). Measuring U100 insulin to one mark in a U100 syringe will also contain 1iU of insulin. Note that although the two syringes hold the same amount of active insulin, there's more (2.5 times as much) fluid in the U40 syringe -- it's more dilute.

UIDEXX PZI comes with a supply of U40 syringes. Some people like the U40 syringes for their more widely spaced unit markings, making small increments easier to see. Others feel there are advantages to using U100 (3/10cc capacity) syringes with U40 insulin. One unit of U40 insulin (1/40th of a ml) measures 2.5 units in a U100 syringe, so a very small dose of U40 can be more accurately measured in a U100 syringe, although it takes an eagle eye. U100 needles come in finer gauges (29 or 30 gauge, versus 27g with U40) and come in shorter and longer lengths, versus 1/2" for IDEXX U40. The rubber seal on IDEXX U40 is quite stiff and may bend a few syringes when using finer gauges.

WARNING: IDEXX specifically advises against doing a direct conversion between doses when changing insulin types. They recommend a starting dose of .1-.3 units per pound (or, .22-.66 units per kilogram) regardless of the old dose. For a 10-pound cat, the starting dose range would be 1-3 units (in a U40 syringe), or, multiplying by 2.5, 2.5 - 7.5 units of U40 insulin in a U100 syringe.

For help in converting between U40 and U100, please see our insulin conversion chart.

What about shelf life?

The factors affecting shelf life of a vial that has been opened are, exposure to light, accumulating contaminants from re-used syringes (or even new syringes), mixing with incompatible insulins, lack of refrigeration (loss of sterility), and at some point, chemical instability. Home testing will enable you to determine for yourself whether the insulin is maintaining its effectiveness. You will not be able to tell whether it is still reasonably sterile, or is teeming with bacteria. You should not use insulin that suddenly looks different. PZI is clear (not cloudy) with white sediment (no clumps), that when mixed gently, looks like watery milk. Compounded insulins, as well as user-diluted or mixed insulins have an opened-life of 30 to 90 days.

Which PZI should I get?

It is impossible to predict which insulin will work best for your particular cat. Two diabetic cats in the same household (i.e. same diet and schedule) can respond differently to the same insulin.

If your cat doesn't respond even to large doses of human insulin, meaning that blood sugar consistently stays very high despite doses larger than 1 unit per pound, and assuming there is not another serious problem causing the high blood sugars, it makes good sense to try the bovine PZI.

If your cat responds to human insulin, but bg's (blood glucose values) cannot be maintained within the ideal range of 100-300mg/dl (5.5 - 16.7 mm/ol), by all means consider PZI (either animal or human), but first, review the "lifestyle" suggestions below.

Lifestyles of the diabetic cat

Most people with a newly diagnosed diabetic cat start treatment with human insulins, injected twice a day, since they are widely available, relatively inexpensive, and will work well for many cats. If you're inexperienced (and/or have an inexperienced vet), and the insulin you're using "doesn't work", realize that the insulin is only about half the treatment. There's a great deal that you can learn to do to help the insulin (whatever it is) work longer and better. Even if you've been around the block a few times, if you’re having difficulties, these points are worth reviewing.

Many people turn to PZI because their cat exhibits wide swings in blood sugar levels, from 400+ (or more) to sub-100's, but with extremely variable (unpredictable) readings at all points on the curve. Very often, this is due to giving too much insulin without sufficient testing to see the whole cycle. If this is the case, cutting the dose in half (or more) for several days and more frequent testing will result in a flatter curve AND lower average numbers. Excessive doses of insulin can mean steep roller coaster curves, with peak readings (the insulin's strength is at its peak, and blood sugar is lowest) that vary from being dangerously low, to being higher than desirable. Large doses affect the insulin's duration as well, and may cause excessive overlapping of the next dose (a sign of this is a dinner bg reading much lower than the breakfast reading). If doses are overlapping, changing doses "on the fly" is inadvisable because the effect of the overlap on the next dose will always vary. It is most important where overlap is suspected to find a minimal dose that can be given consistently.

Insulin acts to push blood sugar levels down, diet is a major factor in what pushes blood sugars up. We try to balance the effect of the insulin with the appropriate diet and feeding schedule to obtain a flat curve in the target range (300 to 100mg/dl). With PZI, as with any long-acting insulin, the role of diet cannot be overstated. It is almost impossible to manage a large post-meal surge in blood sugar with a long acting insulin such as PZI (or Ultralente), due to its slow onset, and weak action. Trying to do so usually means excessively large doses, steep curves and widely variable readings at shot time. You can help a weak-acting insulin to control blood sugar by making dietary changes, and you'll get flatter curves and lower numbers overall. To avoid post-meal surges, make sure the diet (even if recommended by your old-school vet) is low in CARBOHYDRATES. Dry cereals (especially diets created for weight-loss) always have significantly more carbohydrates than wet food. When switched to an improved, carbohydrate-restricted, high protein diet, some cats produce enough insulin themselves and no longer need injected insulin. Cats are carnivores, and require no more than 6% carbohydrate (cereals contain as much as 30 or 40%). Purina has done case studies (soon to be made public, 1-800-222-8387 for more info) in which they observed that 93% of cats lower or eliminate insulin requirements when fed their new canned food called Purina CNM DM-Formula (prescription only). It is high in fiber and protein, low in carbohydrates. If you're unable to halt the post-meal surges without large doses, even with a corrected diet, consider trying a combination of a long-acting insulin at 12-hour intervals to provide "fasting" coverage, augmented at mealtimes with a fast-acting, short-duration insulin (use 2 syringes unless you know they're compatible. Usually only a fractional unit of the fast-acting insulin is needed, so you can dilute it.) Caution: substantially reducing carbohydrates in the diet is a POTENT factor in reducing blood sugars and altering bg curves, and it should not be done without also reducing insulin, and careful monitoring.

To get consistent curves, the diet must also be consistent. Caloric intake and schedule should be the same, day to day. If replacing dry food with canned food or "people food", be careful to replace the calories as well; dry foods have 3 or 4 times the calories, by weight. More calories require more insulin, fewer calories require less. Other sources of inconsistency: free feeding in a multi-cat household is not desirable. Canned foods may vary quite a bit in carbs and calories, depending on the "flavor". Detailed nutritional information can be obtained by calling the phone number listed on the can or bag. Be sure to compare equal caloric amounts.

Increasing soluble fiber (metamucil, psillium husks) is thought to slow and even out the process of digestion which may flatten out the insulin's peak (the lowest point on the bg curve) as well as moderate the post-meal rise in blood sugar. Be sure to monitor carefully when adding fiber.

Just enough duration from the previous dose to overlap the new dose while it's gaining strength is desirable. Too much overlap will (sooner or later) drop blood sugar too much. You’re aiming for 12-hour blood sugar values within around 10% of each other. Remember that even before you’ve achieved regulation, you want a gentle curve that gradually gets lower overall as dosage increases. A steep drop from a very high reading, to a good peak cannot achieve regulation in the end. 12-hour readings should be close enough to each other that dosage can remain consistent. If the 12-hour reading is so much lower that you cannot repeat the same dose consistently (assuming that the peak will also be a lot lower), you will have a roller-coaster situation where the affect of duration will always vary. The difference between doses that are "too much" and "too little" can be minute -- as little as a quarter-unit. If your cat is very sensitive to small increments, consider the more dilute PZI from IDEXX (U40 strength) and use a U100 syringe if necessary (see "Strength" discussion below). Unlike other insulin, diluting PZI yourself, is not recommended.

Make sure that you're keeping a consistent injection schedule, so that blood sugars don't get out of control due to an injection given too late, and don't plummet because the injection is given too early. What is "too late" and "too early" will depend on the insulin's duration for your cat.

For various reasons, insulin may be absorbed erratically, and this may affect large doses more than small ones. Avoid using the scruff of the neck for injections, as there is insufficient blood supply to that area. Rotate the injection site to avoid building scar tissue and consequent absorption problems.

Certain conditions render bodily tissue insensitive to insulin, this is called insulin resistance. Obesity is a major cause of insulin resistance. One of the most effective (and most challenging) ways for a fat cat to lower bg levels, and possibly eliminate the need for injected insulin altogether, is by losing excess weight. Exercise, smaller portions of a carb-restricted diet, reduced fat, or restriction or elimination of treats are ways to accomplish weight loss. Note that dry foods sold as low calorie, high fiber, for “Seniors” or weight-loss may be higher in carbohydrates, lower in protein than normal dry food (which is already higher in carbs than wet food), and should not be given to diabetics. Something is wrong if your cat appears to be "starving" -- he or she may have very high, or very low blood sugar at that time -- it is not necessary or desirable to starve your cat. High blood sugar alone is a major cause of insulin resistance -- you will notice that the same dose will have more impact when given at lower bg levels than at high levels.

Other causes for consistently high blood glucose values are, pregnancy, stress, certain medications (corticosteroids), infection (diabetics are especially susceptible to urinary infections) and disease (renal, hyperthyroidism, liver disease and cancer to name a few). These possibilities should be ruled out.

How Much Insulin is Too Much?

The Cornell University Feline Health Center has addressed the topic of high insulin doses in cats. Excessively high insulin doses are those greater than one to two units of insulin per pound per day. Felines who use more insulin than this should be evaluated more intensively. Other diseases may be underlying or complicating the diabetes mellitus and as a result, necessitate high insulin dosages. Problems with insulin injection, poor absorption or too rapid metabolism of insulin, or even insulin overdose are potential causes of an apparently excessive insulin requirement.