Treatment Strategies

11. Treatment Strategies

Key Issues in Treating Diabetic Cats

Treatment beyond the disappearance of clinical signs (polyuria, polydipsia), which has traditionally been considered sufficient for treating diabetic cats, offers additional benefits. The benefits are linked to the possibility of spontaneous remission of feline DM, i.e. the transition into a subclinical form of DM. Remission of DM is thought to be mainly due to the disappearance of glucotoxicity once hyperglycemia is controlled. The key issues in treating diabetic cats must focus on lowering the blood glucose level into a range of 5 - 15 mmol/L (90 - 270 mg/dl).

Another key issue is that glucose lowering therapy should be initiated as soon as possible after the diagnosis of DM has been established. Early initiation of therapy is warranted because glucotoxic changes in pancreatic islets are at first reversible, but with time will become irreversible (Prentki & Nolan, 2006). Although it has not been unequivocally demonstrated, it is the author’s clinical impression that early intervention leads to a higher percentage of diabetic cats that go into remission.

Overall, the recommendation is to treat early and intensively. Today, this is typically coupled with dietary intervention, especially the use of high-protein (> 50% protein DMB), low-carbohydrate (< 15% DMB) diets (see below).

Insulin As a Glucose Lowering Drug

Insulin therapy is by far the most effective means to achieve good glycemic control in diabetic cats. Feline insulin is not available for therapy, but insulin of animal origin (bovine or porcine), human recombinant insulin and a synthetic analogue of human insulin have been used for the treatment of diabetic cats (Goossens et al., 1998; Marshall & Rand, 2002; Weaver et al., 2006). The different types of insulinthat are currently used are summarized in Table 5.

The only registered insulin preparation for dogs and cats in some countries is lente porcine insulin consisting of 30% amorphous and 70% crystalline Zn-insulin (e.g., Caninsulin®). Insulin therapy typically is initiated with BID injections of this intermediate-type insulin. Dosing in cats typically starts at 1 - 2 U/cat. Recommendations for dose adjustments vary with the type of insulin used. This usually requires serial blood curves which can be either produced at home (home monitoring) or under clinical settings.

A new preparation of human synthetic insulin is now also used in diabetic cats (Marshall & Rand, 2002; Marshall & Rand, 2004; Weaver et al., 2006; Rand, 2006). Glargine insulin is an insulin analogue which is released slowly from subcutaneous depots. It is used in humans to provide a constant, peakless baseline insulin supply. In humans, glargine is often combined with meal associated injections of short acting insulins.

In cats, glargine is thought to result in better glycemic control over an entire 24h-period. In the study by Weaver et al (2006), glargine was shown to provide good glycemic control in cats even if only administered SID. Obviously, this would constitute an important advantage for cat owners, but most cats will require BID injections.

Other Forms of Therapy

Because feline DM is a type of DM corresponding to human type 2 DM, forms of therapy other than insulin have been tested. It should however be clearly stated that by far the best outcome of diabetic therapy is obtained with insulin, complemented by an appropriate diet (see below).

The use of sulfonylurea derivates, which stimulate pancreatic beta-cell secretion (Figure 6) and may improve peripheral insulin sensitivity, is probably the most advanced non-insulin form of therapy. The sulfonylurea of choice is glipizide (Nelson et al., 1993; Feldman et al., 1997). Considering the outcome of various studies, it seems safe to state that at best only 25% of diabetic cats will respond to glipizide treatment. Secondary failures to treat diabetics with sulfonylureas are not uncommon because sulfonylureas not only stimulate insulin but also amylin secretion (Hoenig et al., 2002). The high local amylin concentrations and progressive deposition of pancreatic islet amyloid may be a long-term detrimental sequelae of treatment with these drugs (Hoenig et al., 2002).

Another class of orally available antidiabetic drugs are the thiazolidinediones (glitazones) which are ligands of PPARγ. Glitazones therefore increase insulin sensitivity of insulin target tissues. Darglitazone, one member of this group of compounds, increased insulin sensitivity in obese cats (Hoenig et al., 2003). The usefulness of these drugs in the routine treatment of feline DM, however, remains largely unknown.

Metformin improves insulin sensitivity mainly via inhibition of hepatic gluconeogenesis and glycogenolysis. Even though metformin can have beneficial metabolic effects in diabetic cats, its use for routine treatment was largely questioned: only few of the treated cats improved after treatment. Metformin does not seem to offer any advantage over conventional treatment (Nelson et al., 2004).

Postprandial hyperglycemia is one key feature of DM. Therefore, slowing down postprandial intestinal glucose absorption appears as a viable alternative in diabetic therapy. The competitive inhibitor of pancreatic amylase and glucosidases in the intestinal brush border membrane, acarbose, has been proposed for this purpose (Nelson, 2005). Even though acarbose may slow gastrointestinal glucose absorption, the recommendation of feeding diabetic cats with a high protein diet seems to largely outweigh the benefit of using acarbose.

Future Therapeutic Options

The metabolic effects of amylin and GLP-1 have been described previously in this chapter. Beneficial effects of both amylin and GLP-1 are an inhibition of gastric emptying and of postprandial glucagon release (for amylin, see Figure 16). Not all of these effects have been investigated in cats so far. The amylin analogue pramlintide (Symlin®), which is combined with insulin, and the GLP-1 agonist exendin-4 (Byetta®) are now in clinical use for the treatment of human diabetics. Neither drug has been tested in diabetic cats so far and whether these treatments would constitute considerable advantages over current treatment options with insulin is not clear.

Chemical compounds that activate glucokinase have been considered interesting targets for diabetic therapy (Schermerhorn, 2006). Clinical usefulness of these drugs is unlikely in the foreseeable future.