Proceedings of the World Small Animal Veterinary Association Sydney, Australia 2007

Transcription

1 Proceedings of the World Small Animal Veterinary Association Sydney, Australia 2007 Hosted by: Australian Small Animal Veterinary Association (ASAVA) Australian Small Animal Veterinary Association (ASAVA) Australian Small Animal Veterinary Association (ASAVA) Next WSAVA Congress

2 DIABETES WHAT S NEW AND WHAT WORKS Richard W. Nelson, DVM, Diplomate ACVIM School of Veterinary Medicine, University of California, Davis The basic objective of treating diabetic dogs and cats is to control clinical signs of diabetes while avoiding common complications such as hypoglycemia, recurring ketosis, peripheral neuropathy in cats, and recurring problems with lethargy, polyphagia, polyuria, polydipsia, weight loss or a combination of these problems. Most of the devastating chronic complications of human diabetes (e.g., nephropathy, vasculopathy, coronary artery disease) require decades to develop and are uncommon in diabetic dogs and cats; the exception is peripheral neuropathy. The need to establish near normal blood glucose concentrations is not necessary in diabetic dogs and cats. Most owners are happy and most dogs and cats are healthy and relatively asymptomatic if most blood glucose concentrations are kept between 5 and 15 mmol/l. Most treatment strategies involve a combination of insulin, diet, exercise, and correction of insulin resistance. What is ultimately effective varies between individual diabetic dogs and cats and is often unpredictable at the start of treatment. The initial approach to treatment should be based on what has historically worked best for you and subsequent therapy is adjusted as needed to attain control of the diabetic state. The following is a synopsis of my approach to the initial management of the newly-diagnosed diabetic dog and cat. Insulin Insulin is the cornerstone of therapy for diabetes mellitus. Newly-diagnosed diabetic dogs should be considered insulin-dependent and insulin therapy should be started at the time diabetes is diagnosed. Reversion to a subclinical diabetic state is rare in diabetic dogs; the exception is the older intact female dog that develops diabetes during diestrus. Ovariohysterectomy may result in resolution of an insulin-requiring diabetic state in these dogs. In contrast, the severity of pancreatic islet destruction is variable at the time diabetes is diagnosed in cats. Cats with severe loss of beta cells need insulin to control hyperglycemia. Cats with partial loss of beta cells and concurrent insulin resistance may or may not be insulin dependent. Adjustments in diet and correction of insulin resistance may correct hyperglycemia in some diabetic cats while others initially require insulin to control hyperglycemia before reverting to a non-insulin-requiring state. The decision to treat a newlydiagnosed diabetic cat with insulin and diet versus diet alone is dependent on many factors, including the overall health of the cat, presence of ketosis, identification and ease of correction of insulin resistance, wishes of the owner, and instinct of the veterinarian. When in doubt, I always initiate insulin therapy and let the cat s clinical response dictate future insulin requirements. Diabetic dogs are reasonably predictable in their response to exogenous insulin. In my opinion, recombinant human NPH and porcine lente insulin are the initial choices for treating newly-diagnosed diabetic dogs. My starting dosage for both types of insulin is approximately 0.25 U/kg and I prefer to start with twice a day insulin administration because the overwhelming majority of

3 diabetic dogs require NPH or lente insulin twice a day. Establishing control of glycemia is easier and problems with hypoglycemia and the Somogyi response are less likely when twice a day insulin therapy is initiated while the insulin dose is low, i.e., at the time insulin treatment is initiated. My experience with insulin glargine in diabetic dogs has been mixed and somewhat disappointing. Currently, I use insulin glargine in poorly-controlled diabetic dogs when NPH and lente insulin are ineffective because of problems with short duration of insulin effect. I rarely use beef/pork-source PZI insulin in dogs because of the potential for development of insulin antibodies that may create problems with diabetic control. Diabetic cats are notoriously unpredictable in their response to exogenous insulin. There is no single type of insulin which is routinely effective in maintaining control of glycemia, even with twice a day administration. Commonly used insulin preparations for managing diabetic cats include NPH, lente, PZI, and insulin glargine. All have potential problems in diabetic cats. Although lente and NPH insulin are consistently and rapidly absorbed following subcutaneous administration, the duration of effect of lente and especially NPH insulin can be considerably shorter than 12 hours, resulting in inadequate control of glycemia despite twice a day administration. Although PZI is a longer acting insulin, the timing of the glucose nadir is quite variable and occurs within 9 hours of PZI administration in greater than 80% of treated diabetic cats. Insulin glargine is the longest acting commercially available insulin for treatment of diabetes in humans and is currently a popular initial choice by veterinarians for the treatment of diabetes in cats. A preliminary study identified better glycemic control and a higher diabetes remission rate in newly-diagnosed diabetic cats treated with glargine twice a day, compared with lente or PZI administered twice a day. 1 Another study found no difference in glycemic control in diabetic cats treated with insulin glargine once a day versus diabetic cats treated with recombinant human lente insulin twice a day, and a higher diabetes remission rate in diabetic cats treated with recombinant human lente insulin. 2 In my experience, the duration of effect of insulin glargine is quite variable, with the glucose nadir occurring as soon as 4 hours and as late as 20 hours after administration. Insulin glargine works well when given once or twice a day in some diabetic cats and does not work very well in others. Problems are usually related to duration of effect. Currently, my personal preference for the initial treatment of newly-diagnosed diabetes in cats is PZI at an initial dose of 1 U per cat administered twice a day. Because the majority of diabetic cats require PZI insulin twice a day, I prefer to start with twice a day insulin therapy while the insulin dose is low to avoid problems with hypoglycemia and the Somogyi response. I switch to porcine lente insulin given twice a day if problems with prolonged duration of PZI effect develop and glycemic control can not be maintained with once a day PZI. I switch to insulin glargine given twice a day if problems with short duration of PZI effect develop. When using insulin glargine for the treatment of newly-diagnosed diabetic cats, I use an initial dose of 1 unit per cat administered once a day and switch to twice a day therapy if subsequent blood glucose evaluations support a duration of effect of 12 hours or less.

4 Diet Diet plays an integral role in the successful management of the diabetic dog or cat. Correction of obesity is one of the cornerstones of dietary therapy. Obesity is especially common in diabetic cats and results from excessive caloric intake typically caused by free-choice feeding of dry cat food. Obesity causes reversible insulin resistance which resolves as obesity is corrected. Improved sensitivity of tissues to insulin leads to improved control of the diabetic state. Diabetic cats may revert to a non-insulin-requiring diabetic state following weight reduction. Successful weight reduction requires a combination of restriction of caloric intake, feeding low calorie-dense diets, and increasing caloric expenditure through exercise. Unfortunately, correction of obesity is difficult in cats because it requires restriction of daily caloric intake with a minimal corresponding increase in caloric expenditure (i.e., exercise). There are several diets specifically formulated for weight reduction in dogs and cats. Diets containing increased amounts of fiber should be used in diabetic dogs and diets containing high protein and low carbohydrate or high fiber and moderate carbohydrate should be used in diabetic cats. Diets containing increased fiber content improve hyperglycemia in some but not all diabetic dogs. Viscous soluble fibers (e.g., guar gum, pectin) are more effective in slowing intestinal glucose absorption than insoluble fibers (e.g., peanut hulls, powdered cellulose). Most commercial fiber diets contain insoluble fiber although diets containing mixtures of soluble and insoluble fiber are becoming available. The amount of fiber varies considerably among products, ranging from 3% to 25% of dry matter (normal diets contain less than 2% fiber on a dry matter basis). In general, diets containing 12% or more insoluble fiber or 8% or more of a mixture of soluble and insoluble fiber are most likely to be effective in improving hyperglycemia in diabetic dogs. Diets containing increased fiber and moderate carbohydrate content, increased protein and decreased carbohydrate content, and increased fat and decreased carbohydrate content by itself and in conjunction with administration of the alpha-glucosidase inhibitor acarbose improve hyperglycemia in some but not all diabetic cats. The central theme in these dietary studies has been restriction of carbohydrate absorption by the gastrointestinal tract, either by inhibiting starch digestion (acarbose), inhibiting intestinal glucose absorption (fiber), or decreasing carbohydrate ingestion (low carbohydrate-containing diets). Intuitively, the most effective means to minimize gastrointestinal absorption of carbohydrate in diabetic cats is to feed diets that contain minimal amounts of carbohydrate. Currently, I initially use diets containing high protein and low carbohydrate content, unless renal insufficiency also exists. I consider switching to a fiber-containing diet if palatability, adverse effects, or inability to correct obesity become an issue with the high protein, low carbohydrate diets or poor control of glycemia persists despite adjustments in insulin therapy. Exercise

5 Exercise helps improve control of glycemia by promoting weight loss and by eliminating the insulin resistance induced by obesity. Exercise also has a glucose-lowering effect by increasing mobilization of insulin from its injection site, increasing blood flow (and therefore insulin delivery) to exercising muscles, and stimulating translocation (i.e., upregulation) of glucose transporters in muscle cells. The daily routine for diabetic dogs should include exercise, preferably at the same time each day. Strenuous and sporadic exercise can cause hypoglycemia and should be avoided. Insulin Resistance Concurrent disease and medications such as prednisone and megesterol acetate cause insulin resistance and interfere with the effectiveness of insulin therapy. The severity of insulin resistance varies from mild to severe. Excess glucocorticoids, growth hormone and progestagens cause severe insulin resistance and sustained and marked hyperglycemia regardless of the type or dose of insulin administered. In contrast, inflammation such as chronic pancreatitis and gingivitis, infection, obesity, hyper- and hypothyroidism, and organ dysfunction such as renal or cardiac insufficiency cause insulin resistance which is usually mild, often fluctuates in severity, and is relatively easily overcome by increasing the dosage of insulin. Disorders causing mild insulin resistance have a significant negative impact on control of the diabetic state, in part because of the fluctuating nature of the insulin resistance. Recognition and correction of insulin resistance, regardless of its severity, is critical for the successful management of the diabetic dog and cat. A thorough diagnostic evaluation of the newly-diagnosed diabetic dog or cat is always indicated, including a CBC, serum biochemical panel, urinalysis with bacterial culture, serum T 4 concentration, and serum progesterone concentration in an intact female dog, regardless of her cycling history. Pancreatitis is a common concurrent disorder in diabetic dogs and cats. Measurement of plasma lipase immunoreactivity and performance of abdominal ultrasound to assess the pancreas should also be done. Monitoring Diabetic Control The most important initial parameters for assessing diabetic control are the owner's subjective opinion of severity of clinical signs and overall health of their pet, findings on physical examination, and stability of body weight. If the owner is happy with results of treatment, the physical examination is supportive of good glycemic control, clinical signs of hypoglycemia have not been observed and the body weight is stable, the diabetic dog or cat is usually adequately controlled. Determination of serum fructosamine concentration may provide further evidence for good control. A serial blood glucose curve is only indicated when poor control of the diabetic state is suspected after reviewing the history, physical examination and body weight, not when the history, physical exam and body weight support good control. Problems with stress-induced hyperglycemia are caused by frequent visits to the veterinary hospital for blood samplings. Once stress-induced hyperglycemia develops it is a perpetual problem and blood glucose measurements can no longer be considered accurate. Generation of a serial blood glucose curve should be

6 reserved for newly-diagnosed and poorly-controlled diabetic dogs and cats. The serial blood glucose curve provides guidelines for making rational adjustments in insulin therapy. Lack of consistency in results of serial blood glucose curves creates frustration for many veterinarians. It is important to remember that this lack of consistency is a direct reflection of all the variables that affect the blood glucose concentration in diabetics. The purpose of serial blood glucose measurements is to obtain a glimpse at the actions of insulin in that diabetic animal and hopefully identify a reason that could explain why the diabetic dog or cat is poorly controlled. Reliance on history, physical examination, body weight, and serum fructosamine concentration to determine when a blood glucose curve is needed helps reduce the frequency of performing blood glucose curves, minimize the animal s aversion to these evaluations, and improve the chances of obtaining meaningful results when a blood glucose curve is needed. References 1. Marshall RD, Rand JS. Treatment with glargine results in higher remission rates than lente or protamine zinc insulins in newly diagnosed diabetic cats. J Vet Intern Med 2005;19:425 (abstr). 2. Weaver KE, Rozanski EA, Mahony OM, et al. Use of glargine and lente insulins in cats with diabetes mellitus. J Vet Intern Med 2006;20: