Feline Diabetes Mellitus - Treatment
The aim of therapy is to eliminate the symptoms, prevent short-term complications (e.g. hypoglycaemia, ketoacidosis) and thereby enable a good quality of life. Contrary to the canine situation, diabetic cats have a relatively high chance of remission with appropriate treatment. This is defined as normalization of blood glucose and fructosamine levels and resolution of clinical signs and glucosuria without further need of anti-diabetic therapy, and may occur in up to 50% of cats, usually within the first 3 months of therapy. Good glycemic control reverses the effect of glucose toxicity; treatment initiated as soon as the diagnosis is made increases the chance of remission. Clinical signs are well controlled if blood glucose concentrations are kept between 5-15mmol/L - 90-270 mg/dL throughout the day. Owners may find it difficult to treat their cats; it is therefore essential to supply detailed information on all relevant technical aspects of the disease and to ensure ready access to veterinary support whenever needed. Treatment should follow a precise and comprehensible protocol (Table 1), and written instructions are of great value.
Oral Hypoglycaemic Agents
Since 80% of cats suffer type 2 diabetes, in theory these drugs can be used. Currently, there are 7 distinct classes of oral hypoglycaemics available but other than sulfonylureas they have either not been investigated or have shown only limited efficacy in cats. Sulfonylureas, of which glipizide is the drug most often used in cats, stimulate insulin secretion and some β-cell function is required for the drug to be effective. Glipizide should only be used in diabetic patients who are in good physical condition, are non-ketotic and have only moderate severity of symptoms. The starting dose is 2.5 mg/cat BID, increased to 5 mg/cat BID after 2 weeks if no adverse effects are noted and hyperglycaemia is still present. However, treatment success is only ~ 30% and the drug may negatively affect islets, leading to accelerated loss of remaining β-cells. Since glipizide offers no medical advantage over insulin it should only be used in cases in which the owner is unable to inject insulin.
Administration of insulin and dietary management are the mainstays of treatment in diabetic cats. The insulins of first choice in cats with uncomplicated diabetes are the intermediate-acting compounds. Availability of preparations varies, but porcine-derived lente-type insulin is licensed for feline use in many countries. Note that in some cats this insulin lasts for less than 12h, and in fact the problem of short action is well recognized in cats and applies not only to lente-type but also various other kinds of insulin. An additional issue is that insulin absorption may be inconsistent, causing erratic blood glucose concentrations. In human diabetes the same problem exists and has led to the recent development of insulin analogues; currently the most frequently-used compound is a substance known as insulin glargine. Recently this drug has gained a lot of popularity among owners of diabetic cats; its duration of action is longer than for lente-type insulins but is usually <24h and glycemic control is better when injected BID instead of SID. Glargine may be a suitable alternative for cats in which duration of action of lente-type insulin is too short for metabolic control and it has been postulated that the remission rate is higher in cats treated with glargine than with other types of insulin (7). However, the number of published cases is still small and therefore a definitive conclusion is not possible.
The author’s preference is to start treatment with either lente insulin or glargine; although a PZI insulin is also a good first choice (8) this preparation is difficult to obtain in many countries. Frequency of administration is always BID, the initial dose in cats weighing <4 kg is 1 U/cat BID, and in cats >4 kg it is usually 1.5-2.0 U/cat BID. In cats with a blood glucose concentration <20 mmol/L - 360 mg/dL at the time of diagnosis, no more than 1 U/cat BID is given, independent of the body weight. At diagnosis the cat may be hospitalized for 1-2 days to complete the work-up. During this time, blood glucose concentration should be measured 3-4 times daily and the insulin dosage reduced if hypoglycemia (<5 mmol/L - 90 mg/dL) is detected. If the blood glucose remains high the dose should not be adjusted immediately, as it takes a few days for full insulin action to develop (so-called equilibration). Adjustments in dosage are made on subsequent evaluations. The initial work-up and start of treatment may also be done on an outpatient basis. One of the most important periods in the owner’s care of a diabetic pet is when the veterinarian discusses the technical aspects of the treatment. The owner should be able to mix the insulin correctly (rolling the bottle gently, avoiding shaking; note glargine is a clear solution that does not require rolling), load a syringe without air bubbles, and inject the insulin subcutaneously over the lateral chest wall. The owner should understand potential problems (e.g. pain, bleeding, injection into the fur), know how to deal with these problems, and know when to consult the hospital (signs of hypoglycaemia, recurrence of PU/PD, symptoms of diabetic ketoacidosis). The owner should be advised not to heat or freeze the insulin, and although insulin is not inactivated at room temperature, it should be stored in the refrigerator. In the author’s experience, insulin maintains its activity for several months when handled correctly and a bottle should only need replacing when there is unexplainable worsening of glycemic control. The owner must also understand the differences between U-40 and U-100/mL insulins and that use of the correct size of syringe is imperative. The use of non-matching syringes should be avoided because the risk of confusion is high.
The cat is a true carnivore which distinguishes it clearly from the omnivorous dog. The natural diet of wild felids, e.g. mice and birds, contains less than 10% of carbohydrates on a dry matter basis. This is very different from many commercial cat foods which have a high carbohydrate percentage. Several studies indicate that using low-carb, high protein diet results in better clinical control and increased rates of diabetic remission (9,10). These findings are in concert with the AAHA diabetes mellitus guidelines (11) which recommend feeding a high-protein diet (>45% protein metabolisable energy) and the lowest amount of carbohydrate levels the cat will eat. Canned foods may be preferred over dry food due to their lower carbohydrate levels and lower caloric density; this also allows easy portion control and assists with additional water intake (11). Since obesity-induced insulin resistance is almost completely reversible, and even slight to moderate weight loss improves metabolic control, weight reduction should be strongly encouraged in overweight cats (approximately 1% per week). However, the veterinarian should always evaluate the nutrient content of the diet on a calorie basis (g/1000 kcal) as not all canned diets are low in carbohydrate, and similarly, not all dry diets are high in carbohydrates. Furthermore, some high protein, low carbohydrate diets are also very energy dense, which can be counterproductive to successful weight management control. A recent study (12) noted that physical inactivity and indoor confinement may be independent risk factors for the development of diabetes in cats. Timing of feeding relative to insulin administration does not seem to be critical; the quality of metabolic control in cats receiving their meal along with the insulin injection does not differ from cats fed 45 minutes after insulin administration (13). Re-evaluations are essential during long-term management. In cats close supervision is of particular importance during the first months because diabetic remission is possible; if this goes unnoticed and insulin administration is continued serious hypoglycaemia may result. Most cats go into remission during the first 3 months of therapy, however, remissions after one year or longer are possible.
Re-evaluations are initially scheduled at short intervals (Table 1) and include assessment of the owner’s observations with regard to the clinical signs, measurement of body weight, and determination of blood glucose and fructosamine levels. Fructosamine concentrations increase when glycaemic control worsens and decrease when glycaemic control improves. Since even well controlled diabetic cats are slightly to moderately hyperglycaemic throughout the day, fructosamine will not usually become completely normal during therapy. In contrast, a normal fructosamine level (especially if in the lower half of the reference range) should raise concerns about prolonged periods of hypoglycaemia, e.g. due to diabetic remission. Fructosamine levels between 350-450 μmol/L usually suggest good control, levels between 450-550 μmol/L moderate control and >550-600 μmol/L poor metabolic control. Single glucose measurements are usually insufficient to assess metabolic control, and the generation of serial blood glucose curves (BGC), where blood glucose is measured every 2h over approximately 12h, is recommended. Normally insulin and food is given at home and the BGC initiated (either at home or at the hospital) as soon as possible thereafter. The most important parameters to assess with a BGC are glucose nadir and duration of effect (Figure 4).
• The glucose nadir should ideally range between 5-8 mmol/L - 90/144 mg/dL. A lower nadir can be seen with insulin overdosage, excessive overlap of insulin actions, lack of food intake and strenuous exercise. If the nadir is >9 mmol/L insulin underdosage, stress, the counter-regulatory phase of the Somogyi phenomenon, and technical problems should be considered. If the animal is already on high insulin doses, insulin resistance is also possible. It is very important to identify the exact cause, because treatment decisions will vary with the cause.
• The duration of effect is defined as the time from insulin injection through the glucose nadir until the blood glucose concentration exceeds 12-15 mmol/L - 216-270 mg/dL. If the duration is less than 8-10h animals usually show clinical signs of diabetes, if the duration is >14h the risk of developing hypoglycaemia or the Somogyi phenomenon increases. Duration of action may improve with dietary manipulation, but if this is not successful changing to an insulin with a different action profile is indicated. Stress hyperglycaemia may make BGC interpretation difficult. This can be overcome by the owner performing BGC at home, sometimes called home-monitoring (HM) (Figures 5 and 6). Owners are introduced to HM approximately 3 weeks after starting therapy, determining fasting blood glucose twice weekly (to practice blood sampling as well as to detect hypoglycaemia) and a BGC is recommended at least monthly. Many owners are able and willing to perform HM on a long-term basis and in a recent survey all owners pointed out that HM had raised their self-confidence with regard to their ability to manage the disease in their pets (14). Note some variability is also seen in BGCs performed at home, and therefore a single curve may be misleading. In complicated cases, more than one curve can be performed before any treatment decision is made (15,16).
Difficulties Associated with the Regulation of Diabetes
Most cats can be adequately stabilized within the first three months of therapy. However, it is normal that after this phase adjustments will be needed, for example due to further β-cell loss or a change in insulin sensitivity due to concurrent disease. Where clinical signs persist despite therapy a stepwise approach to the problem is recommended.
1. Ensure that work-up and previous treatment has been done according to protocol. Increase insulin dosage every 5-7 days until the cat receives a dose of 1.0-1.5 U/kg BID (lente-insulin).
2. Check if insulin used by the owner is outdated, has been shaken, diluted, frozen or heated, and check if appropriate syringes are used. Verify the owner’s method of mixing, drawing up and injecting insulin, and review the dietary regimen. This part of the problem-solving protocol is often omitted, but technical errors are frequently the cause of poor diabetes regulation.
3. Perform BGCs to identify any Somogyi phenomenon or short duration of insulin effect. HM should be considered, enabling frequent sampling without the stress of the hospital visit.
4. If no problem is identified, a work-up for diseases causing insulin resistance should be pursued. In principle any other concurrent disease (e.g. inflammatory, infectious, neoplastic) may cause insulin resistance. The most relevant problems are pancreatitis, pancreatic neoplasia, HC, hypersomatotropism, infection of oral cavity or urinary tract, chronic kidney disease, or obesity. HC and hypersomatotropism (Figure 7) have the potential to cause the most severe insulin resistance. Clinical signs may range from mild to severe and concurrent disease may not be suspected until it becomes evident that the diabetes is difficult to regulate.
Prompt diagnosis of diabetes in cats should allow satisfactory treatment of the patient in most cases. However initial assessment should not only clarify severity of the disease (e.g. ketoacidosis) but also search for any concurrent disease or other contributing factors (e.g. obesity, diabetogenic drugs). Treatment should be initiated immediately after diagnosis and most cats can be adequately stabilized within the first 3 months of therapy, but note that remission occurs in up to 50% of cats. Periodic re-evaluations are essential and should include assessment of clinical signs and body weight, generation of a BGC and fructosamine measurement. If clinical signs persist despite therapy a stepwise work-up is recommended.
This article was kindly provided by Royal Canin, makers of Diabetic diet for cats. For the full range please visit www.RoyalCanin.co.uk or speak to your Veterinary Business Manager:
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