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Oral Antidiabetic Drugs for Cats - VetLearn.com

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Vol. 23, No. 7 July 2001 633

Article #2 (1.5 contact hours)

Refereed Peer Review

KEY FACTS

■ Glipizide is the only antidiabetic

agent whose mechanism of

action is directed at the endocrine

pancreas.

■ Acarbose does not reverse any

pathophysiologic derangements

in patients with diabetes. In fact,

the drug is not systemically

absorbed.

■ Of the oral antidiabetic drugs

available for cats, glipizide and

acarbose appear to have the

most efficacy and the least

potential for toxicity.

Oral Antidiabetic

Drugs for Cats

University of Tennessee

Sara M. Cowan, DVM

North Carolina State University

Susan E. Bunch, DVM, PhD, DACVIM

Email comments/questions to

compendium@medimedia.com

or fax 800-556-3288

ABSTRACT: Diabetes mellitus (DM) is commonly diagnosed in cats. In humans, treatment

regimens for non–insulin-dependent DM include various combinations of dietary modification,

exercise, insulin administration, and one or more oral antidiabetic drugs, which have been extensively

evaluated in humans but not in cats. Glucose toxicity is a phenomenon of chronic hyperglycemia

and must be understood before interpreting response to any antidiabetic therapy.

This article provides a critical review of the oral antidiabetic drugs glipizide, metformin, troglitazone,

and acarbose.

Diabetes mellitus (DM) is a common endocrine disorder in cats. It is estimated

to affect 1 in 300 cats, 1 with both forms of the disease defined by

the ability of pancreatic beta cells to secrete insulin. 2 Type I DM is characterized

by the destruction of insulin-producing beta cells in the islets of

Langerhans. Type I DM is always insulin dependent; therefore, the treatment of

choice is insulin. Type II DM is characterized by defects in glucose-stimulated

insulin secretion by the pancreas and in peripheral tissue sensitivity to and use of

insulin. 3–5 Initially, type II DM is non–insulin-dependent because of the ability

of beta cells to produce some insulin. However, the progression of disease usually

results in insulin dependence. 6

In humans, treatment options for type II DM include various combinations

of dietary modification, exercise, and administration of one or more oral antidiabetic

drugs with or without insulin. The treatment options for type II DM in

cats are not as diverse as those for humans for the following reasons:

■ It is difficult to discern in cats whether DM is insulin dependent, and most

cats are treated as insulin-dependent diabetics.

■ Diabetic cats with finicky appetites may be difficult to manage with dietary

changes.

Oral antidiabetic drugs have not been extensively evaluated in cats. (Nevertheless,

understanding their possible role in treating feline diabetics is important

for veterinarians. Use of these drugs in cats may become more commonplace,

and clients often have questions regarding their use.)


634 Small Animal/Exotics Compendium July 2001

(A) Glipizide

K +

(B)

K +

K +

K +

K +

Closes ATP – K + channel

I

(E) Exocytosis of vesicles

Insulin leaves the pancreas to portal vein

In general, oral antidiabetic drugs act by stimulating

insulin secretion, decreasing hepatic gluconeogenesis,

or improving muscle and adipose tissue sensitivity to

insulin. Because type II DM is a progressive disease 7

that ultimately requires insulin injections and/or multiple

drug therapies, careful patient selection is essential

for these drugs to be used successfully.

Due to the high incidence of diabetes, diabetic complications,

problems with long-term insulin use, and

the hospital time and resources spent on managing diabetes

in humans, 8 diabetologists have studied alternatives

to insulin over the past 30 years. Similar investigations

are needed in cats in light of the high euthanasia

rate of diabetic cats (30% to 40%) and the knowledge

gained in humans on the effects of diet, exercise, and

antihyperglycemic drugs on glycemic control.

The following factors are used to evaluate the efficacy

of antidiabetic drugs 9–12 :

■ The difference between pretreatment and posttreatment

fasting blood glucose (FBG) and postprandial

blood glucose (PPBG) concentrations

■ Similar differences in glycosylated hemoglobin (Hb

A 1c) or serum fructosamine concentrations

■ Pretreatment factors serving as positive predictors of

response to therapy

■ Causes of failure to respond

SULFONYLUREAS (GLIPIZIDE)

Sulfonylureas were found to have the potential to

K +

(C) Cell membrane

depolarization

(D)

Ca ++

Ca ++

Ca ++

Figure 1—Mechanism of action of glipizide at the pancreatic

beta cell. Glipizide (A) binds to a receptor on the ATP–

potassium (K + ) channel, which closes it, resulting in reduced

potassium efflux from the cell. An increase in extracellular

potassium (B) causes cell membrane depolarization

(C) and calcium (Ca ++ ) influx (D). An increase in intracellular

calcium is the direct stimulus for exocytosis of insulincontaining

vesicles (E).

I

I

treat diabetes over 50 years ago when researchers were

studying their antibiotic effects. 9 Sulfonylureas are

highly protein-bound derivatives of the sulfa antibiotics.

Glipizide is a second-generation sulfonylurea;

first-generation drugs of this class have less potency

and higher polarity, are less lipid soluble, and have not

been examined for use in cats. Sulfonylureas are well

absorbed from the gastrointestinal (GI) tract. There

are some weakly active or inactive metabolites produced

in the liver. The liver and kidney clear sulfonylureas;

hepatic inactivation is the primary route of

clearance. 10

The sulfonylureas are the only class of antihyperglycemic

drug with a direct mechanism of action at the

pancreatic beta cell. 11 The insulinotropic effect of sulfonylureas

is depicted in Figure 1.

Other effects of sulfonylureas have also been described.

13 There is in vitro evidence for a decrease in

hepatic gluconeogenesis, an increased number of insulin

receptors in tissues of action, and increased

postinsulin receptor activity. 12

Efficacy

Humans

In humans with type II diabetes, glipizide decreases

the FBG level by 60 to 70 mg/dl and the Hb A 1c by

1.5% to 2%, 12 which is similar to the efficacy of insulin.

7 In humans, factors that predict a positive response

to sulfonylureas include diabetes diagnosed

within the past 5 years, hyperglycemia in the range of

220 to 240 mg/dl, adequate beta-cell function as measured

by a high fasting C-peptide level, and no history

of exogenous insulin treatment. 10,14 The likelihood of

response to glipizide treatment is inversely correlated

with the degree of blood glucose elevation at the start

of therapy. 7 Therefore, carefully selecting patients with

mildly to moderately elevated fasting and postprandial

glucose levels for glipizide therapy is recommended and

may improve efficacy.

Failure of humans to respond to therapy as evidenced

by an unacceptably minimal decrease in glucose

concentrations after 3 months of therapy is related

to patient factors (noncompliance, coexisting

disease), drug factors (use of medications that antagonize

insulin action or secretion, inadequate drug

dosage), and disease progression. 12 A 6-year follow-up

of humans treated with sulfonylureas showed that only

5% (33 of 660) maintained normoglycemia. This attests

to the nature of type II DM as a progressive disease

and the eventual need for multidrug therapy, including

insulin. 7


Compendium July 2001 Small Animal/Exotics 635

Cats

The data on efficacy of glipizide in cats is complicated

by the uncertainty of the underlying diabetic state

(type II versus type I DM) and the absence of blinded,

placebo-controlled prospective clinical trials. The first

study of glipizide in cats examined its effect on serum

insulin and glucose concentrations in 10 healthy cats. 15

Mean serum insulin concentration increased for 1 hour

after glipizide administration, and mean serum glucose

concentration decreased within 15 minutes of glipizide

administration, with the lowest concentration at 60

minutes and duration of effect up to 120 minutes. In a

1993 study of 20 cats, Nelson and colleagues found improved

clinical signs and blood glucose concentrations

in 65% (13 of 20) of cats with DM that were treated

with glipizide. 16a This included five cats that were considered

complete responders based on resolution of

clinical and laboratory indices of diabetes by the fourth

week of therapy. Eight cats considered to be partial responders

did have resolution of clinical signs but remained

hyperglycemic (greater than 200 mg/dl) and

glucosuric.

In 1997, Feldman and coworkers monitored glycemic

control in feline diabetics treated with only glipizide for

50 weeks. 16b Glycemic control was achieved in 44% (22

of 50) of cats. These cats were further classified as complete

responders (14%), partial responders (12%), transient

diabetics (12%), and transient responders (6%).

However, three of these cats had long-term treatment

failure, reducing the overall success rate to 38%. Results

of long-term follow-up in a number of these diabetic

cats supported the presence of type II DM and its progressive

nature. The relationship between the degree and

duration of hyperglycemia prior to therapy and the likelihood

of response to glipizide in cats is unknown. Other

predictive factors for determining response to therapy

in cats are also unknown. Therefore, conservative patient

selection promotes a better success rate when using

glipizide in cats. Guidelines for patient selection as well

as therapeutic protocols have been described. 10,17–19

Side Effects

Humans

In humans, adverse effects of sulfonylureas are typically

mild and reversible upon discontinuation of drug

administration. The most important side effect of therapy

is hypoglycemia, which is estimated to occur in 2%

to 4% of humans treated for type II DM with a sulfonylurea.

For comparison, the incidence of hypoglycemia

due to insulin therapy is the same. 12 Other

common side effects include cutaneous rashes and GI

disturbance, while less common side effects include

mild thrombocytopenia, mild hemolytic anemia, and

high liver enzyme activity. 20

Risk factors that predispose humans to adverse effects

include decreased glomerular filtration rate, hepatic

insufficiency, mild DM (mean serum glucose concentration

of 140 mg/dl), and the simultaneous use of

drugs that interact with the pharmacokinetics of sulfonylureas

(e.g., aspirin, trimethoprim, H 2-blockers,

warfarin, β-adrenergic blockers, sympatholytic drugs,

thiazides, loop diuretics, corticosteroids). 12,20–22

Cats

The incidence of side effects due to glipizide in cats

was 16% in 50 cats treated for 50 weeks. 16 Commonly

reported side effects are high liver enzyme activity, hepatotoxicity,

anorexia, and vomiting, all of which may

resolve with temporary discontinuation of the drug.

Liver enzyme activity may return to normal despite

continued administration of glipizide, suggesting that

elevated liver enzyme activity may be seen with or

without underlying hepatotoxicity. GI side effects resolve

or improve by administering the drug with food.

Based on current information, the incidence of hypoglycemia

(usually asymptomatic) ranges between 12%

to 15%. 7,16b The incidence of mild hypoglycemia may

be underestimated due to the subtle clinical signs associated

with its occurrence. 10

BIGUANIDES (METFORMIN)

Metformin is a biguanide antihyperglycemic agent.

The active component, guanidine, is found naturally in

animal and plant material and explains the medieval

European practice of administering components of the

French lilac flower (Galega officinalis) to diabetic patients.

23 Unlike glipizide, it is not highly protein bound

or metabolized. To date, there are two reports of metformin

pharmacokinetics in cats. The mean oral

bioavailability in six healthy adult cats was found to be

48%. 24 The peak plasma concentration occurs between

1 and 3 hours after oral administration. 24,25 Ninety percent

of the drug is excreted in the urine within 12

hours of administration. 26

Because metformin improves insulin sensitivity in peripheral

tissues, it is not effective in the absence of insulin.

27 Whereas glipizide results in an increase in

serum insulin concentration to lower blood glucose,

metformin results in a decrease in serum insulin concentration.

In humans and rats, therapeutic concentrations of

metformin in the liver result in improved insulin-induced

suppression of hepatic gluconeogenesis, which

correlates with decreases in FBG concentrations. 12,26


636 Small Animal/Exotics Compendium July 2001

Also, glucagon-induced gluconeogenesis is reduced. In

myocytes, metformin increases the activity of the insulin

receptor tyrosine kinase and enhances the number

and activity of the glucose-transporter-4. Uptake of

glucose by muscle, muscle glycogen formation, and

glucose oxidation are all increased. 28 In adipose tissue,

metformin increases the uptake and oxidation of glucose

and increases the binding of insulin to its receptors.

26 The antilipolytic action of insulin is thereby reduced,

causing weight loss even when diet and exercise

are held constant. 27 This benefit in obese patients is in

contrast to insulin and glipizide therapy, which increases

insulin concentrations. 28 Metformin has no effect

on insulin production or secretion at the pancreatic

beta cell.

Efficacy

Humans

When used as monotherapy in humans, the FBG level

decreases by a mean of 60 to 70 mg/dl and the Hb

A 1c concentration by a mean of 3%. 7,12,24,26–30 When

compared with other therapies (insulin, glipizide), metformin

causes a greater decrease in the PPBG concentration

compared with the FBG concentration.

When used in combination therapy with a sulfonylurea

in humans, the FBG decreases by 63 mg/dl more

than with sulfonylurea alone. 7,31 When patients with

poorly controlled type II DM on insulin were treated

with metformin, Hb A 1c concentrations were significantly

lower compared with placebo and there was improved

glycemic control with the use of 30% less insulin.

10,30 This indicates that the hypoglycemic effect of

metformin is additive to that of sulfonylureas and insulin

in humans, a concept that has not been studied in

cats.

Primary treatment failure, defined as failure to

achieve glycemic control at the onset of therapy, occurs

at an overall incidence of 12% in humans. 7,10 As with

most patients, the incidence of secondary treatment

failure (failure to maintain target glycemic levels after

an initial positive response) with metformin increases

with duration of therapy because of the progressive nature

of type II DM.

Cats

Recently, 25 five newly diagnosed diabetic cats and one

acromegalic diabetic cat that was on insulin therapy

were given metformin (10 mg sid to 50 mg bid PO).

Clinical signs, blood glucose, serum fructosamine, and

Hb A 1c values did not improve after 7 weeks in three

cats. There was no improvement in the cat with diabetes

and acromegaly. One cat developed ketoacidosis, and

one was found dead (cause unknown) 2 weeks after ini-

BOX 1

Chronic Hyperglycemia: A Brief Review

Chronic hyperglycemia causes pancreatic beta cells

to be desensitized to glucose, resulting in impaired

insulin secretion. In addition, there is relative insulin

resistance in peripheral tissues. Insulin receptors can

move beneath the cell membrane as a result of chronic

hyperglycemia, and the glucose transport systems

become dysfunctional. 4 The end result is a low serum

insulin concentration with hyperglycemia (this is in

contrast to insulin resistance, characterized by a

very high insulin concentration accompanying

hyperglycemia). Glucose-induced desensitization

of the pancreas and peripheral tissues is reversible.

Glucose toxicity is the term used for an irreversible

state of beta-cell dysfunction and resembles type I

DM because the pancreas becomes unresponsive after

stimulation by insulin secretagogues despite its ability

to produce insulin. Therefore, results of insulin

secretory tests to distinguish type I from type II DM

in cats are inconsistent partly because of the effects of

glucose-induced desensitization and glucose toxicity. 3

A clinically useful way of distinguishing type I from

type II DM in cats may be to evaluate response to

treatment with antidiabetic drugs.

tiating metformin administration. One cat achieved improved

glycemic control for 5 months and then developed

acute pancreatitis and loss of glycemic control.

There are no other published data on the efficacy of

metformin in cats. It has been speculated that many cats

suffer from glucose toxicity as a result of chronic hyperglycemia

(Box 1); therefore, improving insulin sensitivity

in peripheral tissues by using metformin may provide

little benefit in cats with glucose toxicity.

Side Effects

Humans

The overall incidence of adverse effects of metformin

treatment in humans is 20% to 30%. The most common

effects are diarrhea, nausea, abdominal pain, and a

metallic taste. 28 Side effects can be minimized by taking

metformin with food and by slowly increasing the dose

in small increments once therapy is initiated. 10,27

Hypoglycemia is a rare occurrence in humans treated

with metformin alone because the drug does not increase

insulin secretion. An uncommon yet potentially

fatal adverse effect of metformin therapy documented

in humans is lactic acidosis, with an estimated incidence

of 0.027 to 0.06 cases per 1000 patient-years. 12,28

Metformin precipitates lactic acidosis by promoting the


Compendium July 2001 Small Animal/Exotics 637

conversion of ingested carbohydrate to lactate by the

intestinal mucosa, which is subsequently absorbed and

metabolized by the liver. 10 Incriminating metformin as

the sole cause of all lactate elevations is complicated because

obesity and diabetes also slightly raise blood lactate

concentrations. 26

In most patients suffering from metformin-associated

lactic acidosis, predisposing factors include concurrent

renal insufficiency, liver disease, or other major illness

causing tissue hypoperfusion or hypoxia. 10,12,26 The

risk of death from metformin-induced lactic acidosis

(50%) is similar to that of severe hypoglycemia in sulfonylurea-treated

patients. 26

There are infrequent reports of drug interactions

with metformin. In humans, cimetidine causes an elevation

of plasma metformin by competition for renal

tubular secretion. 28

Cats

There is little information on the adverse effects of

metformin in cats. In cats, the drug appears to be excreted

primarily by glomerular filtration. 24 The effects

of cimetidine on plasma metformin concentration in

cats are unknown.

In one study, six healthy male cats received metformin

(25 mg sid for 7 days, then 25 mg bid for 14

days) and two cats received placebo. All six cats receiving

metformin, but neither cat receiving the placebo,

developed a combination of inappetence, weight loss,

and/or intermittent vomiting. 25 In another study, six

healthy adult cats were given 25 mg metformin IV and

PO. There was no mention of adverse effects (e.g.,

vomiting). 24

THIAZOLIDINEDIONES (TROGLITAZONE)

Thiazolidinediones were discovered by Japanese scientists

almost 2 decades ago as they were studying compounds

to serve as hypolipidemic drugs. 32 One analogue,

troglitazone, was approved for human use by the

FDA in 1997. Troglitazone is rapidly absorbed (its

bioavailability is 40% to 50%), and food increases the

absorption. 33 In humans, troglitazone undergoes

metabolism by sulfation, glucuronidation, and oxidation

into active conjugates. Hepatic impairment causes

plasma concentrations of troglitazone to increase. 33 Despite

proven efficacy, its suitability as a first-line drug to

treat type II DM has been questioned because of the

risk of severe liver dysfunction. 34,35

Like metformin, troglitazone enhances peripheral insulin

sensitivity and thereby lowers both glucose and

insulin levels. Troglitazone reduces the expression of

specific genes responsible for producing the regulatory

enzymes of hepatic gluconeogenesis, thereby slowing

the rate of hepatic gluconeogenesis. 36 In muscle and fat,

thiazolidinediones cause an increase in intracellular glucose

transport, which increases glucose metabolism and

decreases peripheral demand for insulin. 10,12,37 Troglitazone

has no effect on insulin production or secretion at

the pancreatic beta cell.

Efficacy

Humans

Clinical trials show that troglitazone achieves longterm

(up to 2 years) glycemic control in humans. 32,33,35,37

To date, six trials examining troglitazone as the sole

agent for treating type II DM showed a mean decrease

in FBG of 34 mg/dl and in Hb A 1c of 0.6%. 12 Therefore,

troglitazone is not as efficacious as monotherapy

when compared with other classes of antidiabetic drugs.

Primary treatment failure occurs in 25% of humans

with type II DM treated with troglitazone alone. 12,35

Troglitazone is more effective in patients with the syndrome

of insulin resistance, where serum insulin concentrations

are very high. This is in keeping with the

described mechanism of action in peripheral tissues

(enhancing insulin sensitivity). Combination therapy

with metformin is not recommended because troglitazone

and metformin have similar mechanisms of action

and do not show complementary effects as do metformin

and a sulfonylurea or troglitazone and a sulfonylurea.

Cats

There is no published information on the efficacy of

troglitazone in cats.

Side Effects

Humans

Troglitazone-related adverse effects occurred in one

fourth of patients using troglitazone either as monotherapy

or in combination with a sulfonylurea. 34,35–38

Liver-related death occurs in 1 of 100,000 humans. 35

This has raised questions regarding the role of troglitazone

in the repertoire of antidiabetic drugs; therefore,

troglitazone is no longer recommended by the FDA as

monotherapy. 12 The causative mechanism of hepatotoxicity

is unknown but may represent idiosyncratic injury

as a result of aberrant metabolism, resulting in the accumulation

of hepatotoxic metabolites. 39

Troglitazone may cause expansion of the plasma volume;

5% of patients receiving the drug experience edema.

Its use is contraindicated in patients with New

York Heart Association class III or IV cardiac status. 12,38


638 Small Animal/Exotics Compendium July 2001

Cats

There are no published data on adverse effects of

troglitazone in cats.

α-GLUCOSIDASE INHIBITORS (ACARBOSE)

α-Glucosidase inhibitors delay glucose absorption

from the GI tract. Acarbose, an α-glucosidase inhibitor,

is an oligosaccharide extracted from the bacterium

Actinomyces. It was first developed as a starch blocker

for obesity. Acarbose was introduced in the United

States in 1995 and has recently been studied for use in

domestic animals. 40,41

Dietary control of blood glucose through stringent

dietary regimens has been the proposed foundation of

early therapy for human diabetes, but noncompliance

with eating small, frequent meals is high. 7,10 Similarly,

owners of diabetic cats are often unable to provide

small, frequent meals. Appropriate dietary therapy for

diabetic cats is outlined elsewhere. 19

Acarbose inhibits the α-glucosidases, which include

enzymes produced in the brush border of the small intestine.

Sucrase, maltase, isomaltase, glucoamylase, lactase,

and others function to digest oligosaccharides and

disaccharides (complex carbohydrates) into monosaccharides

(glucose), which are subsequently absorbed

through the small intestine. 42 Acarbose competitively

and reversibly inhibits these enzymes, delaying the hydrolysis

of complex carbohydrates without affecting the

absorption of the glucose molecule. 10 Carbohydrate absorption

then shifts to more distal parts of the intestines.

43 Carbohydrates that reach the large intestine

are metabolized by colonic bacteria into fatty acids for

absorption.

Acarbose does not cause a malabsorptive state; rather,

it slows the digestive and absorptive processes. The end

result is a blunted entry of glucose into the systemic

circulation, thus reaching the pancreatic beta cell at

lower blood concentrations. 44,45 Acarbose does not decrease

hepatic glucose output or reverse any pathophysiologic

derangements in patients with diabetes. In fact,

the drug is not systemically absorbed.

Efficacy

Humans

Human studies with acarbose have documented a

decrease in PPBG concentrations and glucosuria for

up to 3 years irrespective of concomitant therapy.

10,42,44–48 This occurs in both insulin- and non–insulin-dependent

DM, which may have implications

for veterinary medicine because discriminating between

type I and type II DM would not be a factor in

deciding whether or when to prescribe the drug. When

used alone in humans, acarbose decreased the FBG

level by only 25 to 30 mg/dl, the PPBG level by 40 to

50 mg/dl, and the Hb A 1c concentration by 0.5% to

1.2%. 49–51 Although less potent than insulin, glipizide,

or metformin, acarbose is prescribed as initial and adjunctive

therapy in obese patients. Acarbose does not

affect the absorption of other antidiabetic drugs. It is

not recommended for patients with normal or decreased

body condition. 50

Cats

The efficacy of acarbose in cats is not established. Because

acarbose works by interfering with starch digestion

and absorption, its effectiveness needs to be studied

in cats in light of their low carbohydrate intake

when compared with humans. 12 Recently, seven obese

diabetic cats (five on insulin therapy) were evaluated for

the effects of acarbose (12.5 mg PO bid with meals)

and a high-protein diet on glycemic control. Insulin administration

was discontinued in four of five cats during

the course of the 4-month study. Improved serum

fructosamine and FBG concentrations as well as improved

attitude compared with pretreatment values

were noted in six cats. 41

Side Effects

Humans/Dogs

Up to 30% of humans experience mild and transient

GI side effects from acarbose that diminish despite continued

drug use. Bloating with abdominal discomfort,

flatulence, and diarrhea have been reported. 45,52–55 In

five healthy dogs fed a high-fiber diet and given 200

mg acarbose daily, four dogs developed soft to watery

stools and two dogs lost weight during the study. 40

To minimize the incidence of GI side effects, acarbose

therapy should be initiated with a low dose and

gradually increased to reach the minimally effective

dose. 48 Food must be present in the bowel with acarbose

for the drug to have its effect, but side effects may

occur regardless of the presence or absence of food.

Other adverse effects are dose dependent and include

high liver enzyme activities and abnormal results of liver

function tests. These abnormalities resolve when the

drug is discontinued. Hypoglycemia does not occur as a

direct result of acarbose therapy. However, if hypoglycemia

occurs due to concurrent administration of

other antidiabetic drugs (insulin, glipizide), pure glucose

should be ingested. 52–55

Cats

The appropriate dose for cats has not been established.


Compendium July 2001 Small Animal/Exotics 639

CONCLUSION

The mechanism of action, efficacy, and side effects of

the oral antidiabetic drugs glipizide, metformin, troglitazone,

and acarbose have been extensively studied in

humans but not in cats. On the basis of limited data,

glipizide and acarbose appear to have the most efficacy

and the least potential for toxicity when compared with

metformin and troglitazone. Careful patient selection is

important. Oral antidiabetic drugs may be appropriate

for cats that are in good overall health with early or

mild clinical signs of diabetes and those with owners

who are unwilling or unable to administer insulin injections.

There are complications 56 and many uncertainties

regarding the current use of oral antidiabetic

agents in cats. They should not be used in cats with evidence

of diabetic complications (e.g., ketoacidosis, infection,

any concurrent disease).

Although the difficulty in differentiating between

type I and II DM in cats complicates the ideal treatment

plan for each patient, it is clear that not every

newly diagnosed diabetic cat requires exogenous insulin.

Hyperglycemia in cats with type II DM may be a

reflection of impaired insulin secretion from the pancreas,

increased hepatic glucose output, decreased peripheral

insulin sensitivity, and intestinal glucose ab-

sorption. If so, therapy would ideally revolve around

correcting these abnormalities by the use of dietary

changes, oral antidiabetic agents, insulin, or a combination

of these treatments. 4,10,12,18,32,57–59

Some cats that are exquisitely sensitive to insulin may

benefit from a diet change and the use of an oral agent

without insulin. Other cats that are well maintained

with insulin and then become unregulated may represent

the progressive nature of type II diabetes; these cats

may also benefit from the addition of drugs (e.g., glipizide

or acarbose alone or with insulin). More information

is needed on the use of combination therapy in

cats and the efficacy and/or toxicity of metformin and

troglitazone. Initial observations have not been encouraging.

The reason for the apparent lack of efficacy compared

with that in humans remains unknown but may

be related to low serum insulin concentrations associated

with glucose toxicity.

Improving recognition of type II DM in cats and further

study of oral antidiabetic agents are important for

managing the unique characteristics of feline diabetes.

To date, clinical trial data are insufficient in both human

and veterinary medicine for determining the optimal

insulin formulation and optimal combinations and

dosages of oral agents. 59 We hope that future research


640 Small Animal/Exotics Compendium July 2001

will provide clues to the many unanswered questions

regarding glycemic control in cats.

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ARTICLE

CE

#2 CE TEST

The article you have read qualifies for 1.5 contact

hours of Continuing Education Credit from

the Auburn University College of Veterinary

Medicine. Choose the best answer to each of the fol-

lowing questions; then mark your answers on the

postage-paid envelope inserted in Compendium.

1. Which of the following is not a result of glucose toxicity?

a. desensitization of the pancreatic beta cell to glucose

b. dysfunctional glucose transport systems in peripheral

tissues

c. movement of peripheral insulin receptors beneath

the cell membrane

d. low serum insulin concentration

e. depletion of liver glycogen stores

2. Insulin resistance is characterized by _____ serum insulin

concentration and _____ blood glucose.

a. high; low

b. high; high

c. low; high

d. low; normal

e. low; low

3. The direct physiologic stimulus for insulin secretion

by the pancreatic beta cell is

a. closing of the ATP–potassium channel.

b. hypoglycemia.

c. intracellular calcium influx.

d. intracellular potassium influx.

e. opening of the ATP–potassium channel.

4. In humans, the likelihood of response to glipizide is

improved by selecting patients with

a. mild to moderate hyperglycemia.

b. marked hyperglycemia.

c. insulin resistance.

d. a history of ketoacidosis.

e. ketonuria.

5. All of the following are reported adverse effects of glipizide

therapy in cats except

a. jaundice.

b. vomiting.

c. hypoglycemia.

d. constipation.

e. high liver enzyme activity.

6. To which class of drugs does metformin belong?

a. α-glucosidase inhibitors

b. biguanides


642 Small Animal/Exotics Compendium July 2001

c. sulfonylureas

d. thiazolidinediones

e. glycosylated proteins

7. Which of the following are mechanisms by which

metformin lowers the blood glucose concentration?

a. improved insulin-induced suppression of hepatic

gluconeogenesis

b. increased stimulation of insulin secretion by the

pancreas

c. enhanced number and activity of glucose transporters

into myocytes

d. increased uptake and oxidation of glucose in adipose

tissue

e. a, c, and d

8. Troglitazone is not commonly used in cats because

a. clinical trials have shown that it does not lower

blood glucose concentrations in cats as it does in

humans.

b. it causes profound hypoglycemia in cats.

c. it causes renal toxicity in cats.

d. its efficacy and toxicity in cats is unknown.

e. it cannot be used concomitantly with insulin.

9. In a study of seven obese diabetic cats evaluated for the

effects of acarbose,

a. insulin administration could not be discontinued in

any of the cats due to refractory hyperglycemia during

acarbose administration.

b. the cats did not tolerate acarbose administration

due to the metallic taste reported in humans.

c. serum fructosamine and FBG concentrations were

improved compared with pretreatment values in

most of the cats.

d. the drug resulted in complete resolution of clinical

signs of DM in all seven cats.

e. long-term follow up on all seven cats showed

glycemic control on acarbose alone after 1 year.

10. Which of the following statements regarding acarbose

administration is true?

a. Acarbose must be taken on an empty stomach in

order to have an affect.

b. Compared with glipizide, metformin, and troglitazone,

acarbose has the most profound effect in lowering

the blood glucose concentration.

c. The use of acarbose is not suitable for insulin-dependent

DM (type I).

d. Therapeutic serum concentrations of acarbose are

met by tid administration.

e. GI side effects in humans are usually transient and

diminish despite continued use.

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