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Over the last few years a number of new drugs have hit the market for treating diabetes. In this lesson we take a look at some of these. Our goal is to provide information regarding therapeutic options in order to be better capable of serving ourpatients. This lesson provides 1.25 hours of credit (0.125 CEUs), and is intended for pharmacists in all practice settings.
The program ID # for this lesson is 707-000-01-010-H01.
Pharmacists completing this lesson by October 31, 2004 may receive full credit.
To obtain continuing education credit for this lesson, you must answer the questions on the quiz (70% correct required), and return the quiz. Should you score less than 70%, you will be asked to repeat the quiz. Computerized records are maintainedfor each participant.
Upcoming topics for continuous participants: Drug-Food Interactions; Pharmacy Law Update 2002.
If you have any comments, suggestions or questions, contact us at the above address, call 800-323-4305, or email us at info@wfprofessional.com. (In Alaska and Hawaii phone 847-945-8050).
The objectives of this lesson are such that upon completion the Differentiate between Type I and Type II diabetes mellitus.
List complications associated with diabetes mellitus.
Describe the mechanisms of action of oral hypoglycemics.
Discuss the clinical use of oral hypoglycemics.
Comment upon the advantages of the new oral hypoglycemics.
All opinions expressed by the author/authors are strictly their own and are not necessarily approved or endorsed by W-F Professional Associates, Inc. Consult full prescribing information on any drugs or devices discussed.
October, 2001 “New Drug for Diabetes Mellitus” Volume 23, #10
INTRODUCTION
Hypoglycemia (glykys meaning sweet, and hemo meaning blood) is a deficiency of blood sugar.
Hypoglycemics are agents that tend to reduce the concentration of blood sugar. Diabetes mellitus is a disordercharacterized by elevation of blood glucose level caused by absolute absence or deficiency of insulin, a hor-mone secreted by the beta cells of the Isles of Langerhans located in the pancreas. Lack or reduced level ofinsulin leads to low absorption of glucose by body cells, that need it for energy, and by the liver where glucose isnormally stored. The alpha cells of the Isles of Langerhans secrete a hormone known as glucagon in responseto a decline in blood glucose level. Release of glucagon causes glycogenolysis, a process that leads to thebreakdown of glycogen, which is stored in the liver. Glycogenolysis results in increased blood glucose. Gluca-gon triggers insulin secretion, and that in turn stops the release of glucagon. Inhibition of glucagon releaseleads to inhibition of glycogenolysis, which ultimately results in a decline in glucose level. This cycle or feed-back mechanism tends to maintain normal glucose levels.
Diabetes is considered the most common endocrine disorder in the USA, and affects approximately 6% of the population (16 million people). It is a major cause of morbidity and mortality, and contributes to a significantpart of health care costs (approximately $1 in every $7 spent). It has been estimated that this disorder costs over$90 billion annually. Repeated fasting glucose levels of 140 mg/dl indicates the presence of diabetes. Heredityand environmental factors play an important role in causing the disease.
TYPES OF DIABETES MELLITUS
There are two major types of diabetes: 1) insulin-dependent diabetes mellitus (IDDM or Type I) and, 2) non- insulin-dependent diabetes mellitus (NIDDM or Type II.) Type I Diabetes Mellitus: Also known as juvenile-onset diabetes, and ketosis-prone diabetes. In general,
this form develops during childhood or adolescence with the symptoms occurring abruptly. It is characterized byvery little secretion, or absolute deficiency, of insulin, and by susceptibility to ketosis (accumulation of ketonebodies produced during the oxidation of fatty acids including acetoacetic acid, beta-hydroxybutyric acid and ac-etone.) Such deficiency is due to damage or destruction of the beta cells of the Isles of Langerhans. This destruc-tive process is believed to be caused by autoimmunity (development of antibodies directed against the patient’sown pancreatic tissue), viral infections and genetic and environmental factors that may predispose certain per-sons to this type of diabetes.
Type II Diabetes Mellitus (NIDDM) was previously known as maturity-onset diabetes. It often occurs
without symptoms, and patients may become aware of its presence following routine physical or blood examina-tion. It accounts for 90% of all diabetes cases. In this variation, the patient’s pancreatic beta cells are capable ofproducing some insulin, and consequently, the patient is not prone to ketosis as in Type I diabetes. In some cases,the patient may produce adequate amounts of insulin, but the increased blood glucose level is due to the bodycells’ resistance to insulin. This resistance is believed to be caused by :1) reduced binding of insulin to thereceptors, and, 2) reduced receptor responsiveness to insulin. It is most frequently encountered after the age offorty, but may occur at any age. It progresses gradually. The patient usually has a family history of diabetes andis overweight. Diabetics with Type II may not need insulin treatment for survival.
Other less common types of diabetes include gestational diabetes, which is usually discovered during pregnancy, and diabetes associated with disorders such as pancreatic disease, intake of certain drugs and mal-nutrition.
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October, 2001 “New Drug for Diabetes Mellitus” Volume 23, #10
SYMPTOMS
Although Type II diabetes may be asymptomatic in the early stages, the most noticeable symptom to appear is polyuria due to the osmotic diuretic effect of glucose. Continued presence of hyperglycemia leads tothirst, hunger and weight loss. Glucosuria often predisposes female patients to Candida albicans vaginitis, itchingand increased vaginal flow. The excessive loss of fluid causes thirst, and drinking sweet beverages may worsenthis thirst. Since the cells do not receive enough glucose, the patient may feel tired, weak, and find it difficult to getup in the morning. Weight loss in Type 1 diabetes may be caused by the breakdown of fat and muscles to provideenergy. Increased fat breakdown in untreated insulin-dependent patients may result in ketoacidosis, which maylead to anorexia, nausea, vomiting, and, if left untreated, may cause coma and death. Involvement of glomerularcapillaries may lead to renal failure. Likewise, if retinal capillaries are involved, visual loss may follow. Nephropa-thy is indicated by the presence of proteinuria. About 50% of Type I diabetics develop renal failure within 20 to 30years of first diabetic symptoms. Diabetic retinopathy is encountered in 50% of the patients after 10 years. Distalpolyneuropathy, mostly sensory, is a common diabetic neuropathy. Symptoms appear early in the feet, and thepatient may experience tingling in the hands and feet, reduced resistance to infection, and blurred vision due toexcess glucose in the eye fluid. Sexual impotence occurs in 50 to 60 percent of diabetic men, and a gradualdecrease in the firmness of erection begins 6 months to 1 year after the onset of the disease. Absence or irregularmenstrual cycle in women may occur. Diabetics are at a higher risk than nondiabetics for developing atheroscle-rosis, strokes, heart attacks, and high blood pressure. Narrowing of the blood vessels in the feet can causecramps, cold feet, or skin ulcers and even gangrene. Any ulcer or wound that fails to heal within 10 days should betreated by a physician.
COMPLICATIONS
Short-term or acute complications are usually encountered in patients with Type I diabetes. Such persons are prone to hyperglycemia as well as hypoglycemia. A contributing factor to these complications is too great or
too small caloric intake in relation to blood glucose level. Conversely, when insulin dosage is excessive or when
the patient exercises strenuously, hypoglycemia may occur. It is essential, therefore, to establish a proper bal-
ance between exercise and glucose intake. Improper control of hypoglycemia may result in ketoacidosis. Prior to
the use of insulin in the treatment of Type I diabetes, ketoacidosis was the main cause of death in diabetics.
Long-term or chronic complications usually appear many years after the onset of the disease. Approxi- mately 90% of diabetic deaths are due to long-term complications. The most common complications are
macrovascular disease, microvascular disease, retinopathy, nephropathy, neuropathy and gastroparesis.
Atherosclerosis, which appears to be due to changes in lipid metabolism, occurs earlier in diabetics than non-
diabetics and progresses at a faster rate. Atherosclerosis ultimately will lead to hypertension, myocardial infarc-
tion and strokes.
Microvascular disease, or microangiopathy, occurs when the basement membrane of the capillaries
becomes thick, causing a decline in normal blood flow. Reduced circulation in the lower limbs is common and
often leads to skin ulcers. The magnitude and the rate of development of the microvascular complications are
directly related to the degree and duration of the hyperglycemia. Retinopathy, that develops among diabetics, is
the major cause of blindness in the USA. The damage that occurs in the retinal capillaries is due mainly to
microaneurysms followed by scarring, the development of new retinal capillaries, and local ischemia that ulti-
mately reduces visual acuity and causes vision impairment.
Diabetic nephropathy, which is characterized by proteinuria, reduced glomerular filtration, and increased
arterial blood pressure, is the major cause of morbidity and mortality among Type I diabetics. It appears thatdisciplined glycemic control can delay or reverse renal dysfunction.
Neuropathy, or nerve degeneration, frequently appears early in the course of diabetes development, but
may remain asymptomatic for years. Both sensor and motor nerves undergo degeneration causing tinglingsensations in the fingers and toes, suppression of reflexes and loss of sensation.
Diabetic gastroparesis, which includes nausea, vomiting, abdominal distension, and delayed gastric
emptying, occurs in about 20 to 30 percent of diabetics. These complications appear to be caused by damage tothe autonomic nerves that control gastric motility.
October, 2001 “New Drug for Diabetes Mellitus” Volume 23, #10
TREATMENT
Type I diabetes is treated with a combination of controlled diet, exercise and insulin replacement. In the scope of this lesson, the discussion dealing with treatment will focus on the use of new oral hypoglycemics that
are used in treating Type II diabetes. Type II diabetics can be controlled in many cases by diet and exercise. Such
measures can result in significant weight reduction. Dietary measures may result in normalizing insulin release
and reduction of insulin resistance. In addition, exercise helps to promote glucose uptake by muscles. Depending
on weight and height, the allowed caloric intake should range from 800 – 1500 calories daily. To prevent fluctuation
of blood glucose, the patient should eat small portions of carbohydrates at regular intervals. Smoking should be
avoided, as it increases the risk of atherosclerosis. If diet and exercise fail to achieve the intended glucose level,
pharmacotherapy with either oral hypoglycemics or insulin become necessary. Diabetics should remember that
such drugs must be used as a supplement to diet and exercise. It is recommended that patients have their blood
tested regularly, either by do-it-yourself tests or by a physician. Results of these tests will indicate the extent of the
progress in keeping blood sugar at an adequate level.
ORAL HYPOGLYCEMICS
As the name indicates, these are oral medications capable of reducing blood glucose levels. The sulfonylureas were the first group to be utilized as oral hypoglycemics after it was observed that some antibacte-rial sulfonamides had a blood glucose lowering effect. These drugs are used in patients whose pancreas iscapable of producing some insulin, as in the case with Type II diabetes. Usually, oral hypoglycemics are helpful forpatients with Type II diabetes who were diagnosed after the age of 40; a duration of the condition less than 5 to 10years before the start of therapy; a body weight within 110 – 160% of ideal weight; a fasting blood glucose level of180 mg/dl; absence of ketoacidosis episodes; and who require 40 to 50 units of insulin a day. Conversely, Type IIdiabetics who are extremely obese and whose fasting blood glucose level is higher than 200 mg/dl, may not be asuitable candidate for treatment with oral hypoglycemics. In general, the main objective of therapy of Type IIdiabetes is to reduce blood glucose to as close to normal as possible. When therapy is initiated, diet, exercise andweight reduction are essential factors.
Oral hypoglycemics may be used alone or concurrently with insulin. Type II diabetes is progressive, and over time, all treatments show secondary failure. Therefore, initial therapy should be evaluated and revised during
the course of treatment. In general, oral hypoglycemics may be classified into two major groups:
Agents that augment the patient’s supply of insulin.
Agents that improve effectiveness of insulin.
These medications act by a) increasing the secretion of endogenous insulin, if there is sufficient mass of pancre-
atic beta cells, b) binding to parts of a receptor on the surface of the beta cells or, c) by inhibiting enzymes that
breakdown carbohydrate and reduce absorption of glucose. Oral hypoglycemics are ineffective for Type I diabe-
tes. If a particular sulfonylurea does not optimally reduce glucose blood level in Type II diabetes, then it would be
beneficial to switch to another agent or use a combination therapy regimen. Such combinations may increase
both glucose control and lipoprotein metabolism. In cases where these agents fail to produce adequate reduction
of glucose blood level, then discontinuation of therapy with sulfonylurea is advisable.
1. Insulin Augmenting Agents
There are two new long-acting sulfonylureas and one non-sulfonylurea that belong to the insulin-augment- ing agents: glimepiride (Amaryl® Hoechst Marion Roussel), glipizide, and repaglinide (Prandin® Novo Nordisk),respectively.
Glimepiride: this second generation sulfonylurea was approved by the FDA on November 30, 1995. It is
well absorbed from the GI tract and can be taken with food, without any delay in activity. It is metabolized in the liverto both active and inactive metabolites that are excreted mainly through the urine. Like all sulfonylureas, glimepirideis strongly bound to plasma protein, primarily albumin. The protein binding process of glimepiride is mainly non-ionic, and it appears that because of this characteristic, the drug is not likely to be displaced by another drug thatcompetitively binds to protein, as do first generation sulfonylureas. This may be clinically significant, since dis-placement of sulfonylurea from albumin may cause a considerable increase in the hypoglycemic effect. Serumhalf-life is 5 to 9.2 hours following single and multiple doses respectively. Distribution of glimepiride in the milk ofrats is significant, and the offspring of rats receiving high concentrations during pregnancy developed skeletalabnormalities following nursing. As a result, the drug is not recommended to be taken by nursing mothers. Whentransferring patients from sulfonylureas (except for chlorpropamide) to glimepiride, no transitional period is neces-sary. However, when transferring the patient from chlorpropamide, care must be exercised during the first one to October, 2001 “New Drug for Diabetes Mellitus” Volume 23, #10
two weeks because of prolonged retention of chlorpropamide in the body and the potential for overlapping drugeffects and a resultant hypoglycemia. Excessive doses of glimepiride may cause hypoglycemia. Glimepiride,when used alone, can reduce blood glucose concentrations and glycosylated hemoglobin at a dose range of 1 –4 mg once daily. The maximum recommended dose is 8 mg daily. An initial dose of 1 to 2 mg once daily is oftensuggested to be taken at breakfast or the first main meal. The maximum initial dose is 2 mg daily. If bloodconcentration is not controlled significantly with glimepiride alone, or if the drug’s effect begins to decline, theninsulin may be added to glimepiride therapy especially if fasting glucose concentration exceeds 150 mg/dl. Oraltablets of glimepiride are available in 1 mg, 2 mg and 4 mg.
Glipizide: The mechanism of action of glipizide is similar to other sulfonylureas. It is rapidly and com-
pletely absorbed from the GI tract. Food may delay absorption, but has no influence on peak serum concentrationor the extent of absorption. All sulfonylureas can be taken with food, except glipizide. This oral hypoglycemic isavailable in two types of formulations: immediate and extended release. The initial dose of the immediate releasetablets (available in 5 mg and 10 mg) is 5mg/day taken approximately 30 minutes before breakfast to achieve themost efficient reduction in postprandial hyperglycemia. Generally, this drug is administered 30 minutes before ameal. The recommended starting dose is 5 mg before breakfast. (Geriatric patients or those with liver diseasemay be started on 2.5 mg). There is no fixed regimen. Check the current literature for suggestions.
Repaglinide: Repaglinide is indicated for patients with Type II diabetes. It was approved by the FDA on
December 23, 1997. This medication is a non-sulfonylurea, insulin-releasing agent that was developed from thenonsulfonylurea moiety of glyburide. It lowers blood sugar by stimulating the beta cells of the pancreas to secretemore insulin.
The drug is absorbed from the GI tract rapidly and completely. It is highly bound to human serum albumin (over 98%). Repaglinide is metabolized in the liver by oxidative biotransformation. The vast majority of a single
oral dose (90%) is excreted in the feces, and about 8% in the urine. The medication is contraindicated in the
presence of diabetic ketoacidosis. Care must be exercised when giving repaglinide to patients with liver impair-
ment. The adverse reactions of this drug include hypoglycemia, rhinitis, nausea, diarrhea, vomiting, indigestion,
headache and arthralgia. Repaglinide is usually taken within 15 minutes of the meal, but may be taken immedi-
ately or 30 minutes before meals. The initial dose is 0.5 mg. The dose should be adjusted based on responsive-
ness of the patient at least one week after initiation of therapy. The dose may be increased up to 4 mg until
satisfactory results are obtained. Failure of monotherapy with repaglinide may require the addition of metformin
(Glucophage® Bristol-Myers Squibb).
2. Insulin Assisting Agents—These agents improve the effectiveness of insulin.
Acarbose (Precose® Bayer): Acarbose was approved by the FDA on September 6, 1995. This antidia-
betic drug is used as an adjunct to diet and exercise in treating patients with Type II diabetes. Acarbose is an oralalpha-glucosidase inhibitor. It may be used alone or in combination with a sulfonylurea. It is an oligosaccharideobtained from fermentation processes of the microorganism Actinoplanes utahensis. It reduces postprandialblood glucose concentration by competitive, reversible inhibition of pancreatic alpha-amylase, and intestinal al-pha-glycoside hydrolase enzymes. The function of these enzymes is to block hydrolysis of complex starches tooligosaccharide in the small intestine and hydrolysis of oligosaccharides, trisaccharides, and disaccharides toglucose and other monosaccharides in the small intestine. By delaying the digestion of food carbohydrates aswell as the absorption of glucose, it results in a reduced rise in blood glucose level. The resultant reduced bloodglucose levels lead to a reduced level of glycosylated hemoglobin in Type II diabetes. Unlike sulfonylureas, acarbosehas no stimulating effect on the pancreatic beta cells, and when used alone should not cause hypoglycemia.
Because of its mechanism of action, acarbose can be used in combination with sulfonylurea. In addition to theadditive effect of the concurrent use of acarbose and sulfonylurea, acarbose reduces the insulinotropic and weight-increasing effects of sulfonylureas. Acarbose does not inhibit lactose, and consequently, will not induce lactoseintolerance. The delayed absorption of glucose caused by acarbose does not result in loss of calories or weightloss in both healthy or diabetic patients.
Acarbose is not well absorbed from the GI tract. Less than 2% of an orally administered dose is absorbed in the active form. Delayed absorption of about one third of the dose is probably due to the formation of metabo-lites in the GI tract by either intestinal bacteria or by enzymatic hydrolysis. The drug is metabolized in the GI tractmainly by intestinal bacteria and to a lesser extent by digestive enzymes. Excretion of the portion of acarbose thatis absorbed as an unbroken drug, occurs through the kidneys. About 89% of an intravenously injected acarbosedose was excreted in the urine as the active drug. Approximately 51% of an orally administered dose is excreted October, 2001 “New Drug for Diabetes Mellitus” Volume 23, #10
intact in feces within 96 hours after intake. Because the half-life of the drug is approximately 2 hours, drugaccumulation does not occur, when given three times daily. Acarbose is not effective as single therapy in patientswith diabetes complicated by ketoacidosis or coma. Such patients may require the administration of insulin.
When acarbose is used as monotherapy in Type II diabetes, reduction of blood glucose level is usually associatedwith reduction in glycosylated hemoglobin concentration of about 0.4 – 1%. Failure of patients with Type II diabetesto treatment with acarbose may be attributed to variations in the sensitivity of intestinal alpha-glucosidases to thedrug, impaired insulin secretion, severe insulin resistance, or intake of a diet rich in simple sugars. Acarbose maybe used in combination with other oral hyperglycemics that have different mechanisms of action, such assulfonylureas. Combination therapy is useful in patients who are not responsive to monotherapy. Such therapymay delay or avoid the use of insulin. Furthermore, the use of acarbose in patients using insulin may reduce thedaily dose of insulin.
Acarbose is not recommended for patients with renal impairment, and should not be administered to nursing women. It is contraindicated in diabetic ketoacidosis, cirrhosis, inflammatory bowel disease, coloniculceration and partial intestinal obstruction. The most common adverse reactions include abdominal pain, diar-rhea and flatulence.
Dosage regimen of acarbose should be individualized based on effectiveness of the drug and patient’s tolerance, while not exceeding the maximum dose of 100 mg three times daily. The initial dose is 25 mg giventhree times daily at the start of each meal. This dose may be increased to 50 mg three times daily. The mainte-nance dose is usually 50 to 100 mg three times daily.
Miglitol (Glyset® Bayer): Miglitol is one of the alpha-glucosidase enzyme (sucrase, trehalase, glycomylase
and isomaltase) inhibitors that causes a delay in the digestion of complex carbohydrates such as sucrose andstarch into glucose and other monosaccharides in the small intestine. This action causes a smaller elevation ofblood glucose concentration that usually occurs after eating. The competitive binding is reversible. The drug wasapproved by the FDA in 1996 as an adjunct to diet therapy alone, or to diet therapy together with sulfonylurea. Itsuse is for patients with Type II diabetes. Miglitol does not inhibit the activities of lactase and the pancreatic amy-lase, whereas acarbose may have an inhibiting effect on the pancreatic amylase. Unlike the sulfonylureas andthiazolidinediones, it does not promote insulin secretion or increase insulin sensitivity.
Miglitol is absorbed from the GI tract. However, the rate of absorption is dependent on the dosage of the drug, resulting in variable bioavailability. For example, a 25 mg dose of miglitol is completely absorbed, whereasa dose of 100 mg is only 50% to 70% absorbed. The protein binding capability of the drug is negligible. Miglitoldoes not undergo metabolism, and is excreted unchanged in the urine. Caution must be exercised when givingthe medication to persons with renal impairment, as this may cause an increase in plasma concentration of themiglitol. The medication is contraindicated in patients with diabetic ketoacidosis, inflammatory bowel disease,ulcerative colitis and intestinal obstruction. Because of its mechanism of action, miglitol does not cause hypogly-cemia. The adverse effects include skin rash, flatulence, diarrhea and abdominal pain.
The recommended initial dose is 25 mg, three times daily with the start of each meal. It has been sug- gested that certain patients may begin their therapy by taking 25 mg once daily to minimize side effects, andgradually increase the frequency to three times daily. Some patients may benefit if the dose is increased to 100mg, three times daily.
Metformin (Glucophage® Bristol-Myers Squibb): Metformin is a biguanide derived from guanidine that
occurs naturally in Galega officinalis. This antidiabetic agent was approved by the FDA on December 29, 1994.
Its mode of action differs from that of the sulfonylureas or acarbose. The lowering of blood glucose concentrationin Type II diabetics is not due to increased insulin secretion from the pancreatic blood cells. However, to beeffective, some endogenous or exogenous insulin must be present. Metformin does not produce hypoglycemia indiabetics, and does not have influence on normal blood glucose level in nondiabetics. Excessive doses of thedrug do not lower glucose level below normal level. It is recommended for obese patients since, unlike sulfony-lurea, it may cause reduction in body weight.
The mode of action of metformin is believed to be due to decreasing hepatic glucose reduction, decreas- ing intestinal absorption of glucose from the intestine and improving insulin sensitivity, i.e., increase peripheralglucose uptake. When used alone, metformin may be effective in patients who did not receive satisfactory resultsfrom sulfonylurea therapy. Patients who do not respond to monotherapy with metformin may receive synergisticeffects by using metformin in combination with sulfonylurea.
Metformin is absorbed slowly and incompletely from the small intestine. The absolute bioavailability of 500 October, 2001 “New Drug for Diabetes Mellitus” Volume 23, #10
mg of metformin under fasting conditions was reported to be 50 – 60 %. Food appears to decrease and slightlydelays absorption. The drug is excreted intact through the kidneys, and is not metabolized in the liver.
The adverse effects of metformin include GI disturbances such as nausea, vomiting, diarrhea, abdominal bloating, anorexia, and flatulence. Other side effects are headache, dizziness and agitation. It appears that theseside effects are dose related and occur at the start of therapy, but decrease during continued therapy. Lacticacidosis is rare, but can be fatal. Lactic acidosis may occur in 50% of cases, if metformin is allowed to accumu-late during therapy.
There is no specific dosage regimen when using metformin for Type II diabetes. The dosage is deter- mined by tolerance of the patient to the drug and the response to therapy. The dose should not exceed themaximum recommended dose of 2550 mg daily. The drug is recommend to start with a low dose and be given individed doses with meals. The usual initial dose is one 500 mg tablet twice daily given with breakfast and dinner.
Metformin is also available in 850 mg tablets that may be given once daily with breakfast.
Thiazolidinediones: Thiazolidinediones are a group of antidiabetic agents that possess a mechanism of
action unrelated to sulfonylureas, biguanides, and alpha-glucosidase inhibitors. Pioglitazone (Actos® Lilly) and
rosiglitazone (Avandia® Glaxo Smith Kline), which are structurally and pharmacologically related, belong to this
group. Both are used in managing patients with Type II diabetes. The medications act by improving insulin
sensitivity in peripheral tissue sites such as skeletal muscle and adipose tissue. Their activity is dependent on the
presence of endogenous insulin. Unlike sulfonylureas, these drugs do not stimulate insulin release from the
pancreatic beta cells, and, consequently, the risk of causing hypoglycemia is avoided. The addition of
thiazolidinediones to a sulfonylurea produces a synergistic effect because these two groups have different, but
complementary, actions. The first thiazolidinedione to be introduced into the market was troglitazone, which
demonstrated efficacy in monotherapy and combination therapy. However, the drug was withdrawn from the
market due to reports of hepatotoxicity. These drugs should not be used in patients who suffer from chronic heart
failure or hepatic impairment. Edema has been encountered in patients taking those medications, thus should be
used with caution in patients with edema. Body weight gain has been observed in the first year of treatment.
Pioglitazone (Actos® Lilly) is rapidly absorbed from the GI tract without regard to meals. It is highly bound
to serum albumin (99%). The drug is extensively metabolized in the liver, and, consequently, patients who showclinical evidence of liver disease should avoid using the medication. Patients who use the drug should undergoliver enzyme tests. Pioglitazone may be used in monotherapy as well as in combination with insulin, metformin,or sulfonylureas. Patients who use pioglitazone concurrently with insulin or sulfonylureas may be at risk forhypoglycemia. An advantage of the use of pioglitazone is the significant reduction in serum triglyceride and non-esterified fatty acid level at all dosages of the drug (15 to 45 mg daily).
A monotherapy with pioglitazone may be initiated at 15 to 30 mg once daily, with or without meals. The dose may be increased in increments up to 45 mg once daily in cases where adequate response to initial therapywas inadequate. If the patient failed to respond to monotherapy, combination therapy should be considered. Initialdose of 15 or 30 mg of pioglitazone once daily with sulfonylurea may be tried. The same dose should be initiatedwhen used with metformin and insulin. The maximum recommended dose of pioglitazone should not exceed 45mg once daily.
Rosiglitazone (Avandia® Glaxo Smith Kline) is absorbed rapidly from the GI tract. Even though food may
decrease the maximum concentration, the effect does not appear to be clinically significant. It is highly bound toserum albumin, and is metabolized extensively in the liver. In the USA, the drug may be used as monotherapy orin combination with metformin. However, in England and Europe, rosiglitazone is licensed for combination usewith either sulfonylureas or metformin. The initial dose of this medication as monotherapy or in combination withmetformin is 4 mg once daily or in divided doses of 2 mg twice daily in the morning and evening, with or withoutmeals. If the patient does not respond positively to this therapy within three months, the dosage is generallyincreased to 8 mg daily as a single dose or into 2 divided doses daily. The drug should be initiated with caution inpatients with mild hepatic enzyme elevation. Dose dependent reductions in serum fatty acid concentrations mayoccur following rosiglitazone therapy. While serum HDL cholesterol levels are significantly increased withpioglitazone, only a slight increase takes place following the intake of rosiglitazone. Pioglitazone appears to haveno affect on serum LDL cholesterol and total cholesterol levels, whereas rosiglitazone may result in significantincrease in serum LDL cholesterol and total cholesterol.
October, 2001 “New Drug for Diabetes Mellitus” Volume 23, #10
Oral hypoglycemics are the drugs most widely used for the management of Type II diabetes mellitus. In the last several years, new medications were placed on the market that may be used in monotherapy or incombination therapy. These medications possess various mechanisms of action.
References
Riddle, M.D., “Oral Pharmacologic Management of Type 2 Diabetes,” Am. Family Physician, 60, 2613(1999).
Campbell, L.K., “Miglitol: Assessment of Its Role in the Treatment of Patients with Diabetes Mellitus,” theAnn. Pharmacol., 60, 1291 (2000).
Freeman, J.B., Queener, S.F., and Karb, V.B., “Pharmacologic Basis of Nursing Practice,” 5th Ed., Mosby,St. Louis, 1997.
Herfindal, E.T., and Gourley, D.R., “Textbook of Therapeutics: Drug and Disease Management,” 6th Ed.,Williams and Wilkins, Baltimore, 1996.
October, 2001 “New Drug for Diabetes Mellitus” Volume 23, #10
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1. Glucagon is excreted by the pancreatic D. Improves insulin sensitivity in peripheral sites such as skeletal muscle & adipose tissue undergo liver enzyme tests B. They should be used alone & not in 4. The mechanism of action of acarbose is: metformin? 10. Which statement is correct regardingA. It is a biguanide derivative B. It decreases hepatic glucose production & increases peripheral glucose uptake the drug in combination with sulfonylureas D. The drug is excreted intact through the kidneys & is not metabolized in the liver October, 2001 “New Drug for Diabetes Mellitus” Volume 23, #10
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CE PRN® is a publication of W-F Professional Associates, Inc. This program is in printed format.
W-F Professional Associates, Inc. is approved by the American Council on PharmaceuticalEducation (ACPE) as a provider of continuing pharmaceutical education.
Providers who are approved by ACPE are recognized by the following states: Alaska, Arizona,Arkansas, California, Colorado, Connecticut, Delaware, District of Columbia, Florida, Georgia,Idaho, Illinois, Indiana, Iowa, Kansas, Kentucky, Louisiana, Maine, Maryland, Massachusetts,Michigan, Minnesota, Mississippi, Missouri, Montana, Nebraska, Nevada, New Hampshire, NewJersey, New Mexico, New York, North Carolina, North Dakota, Ohio, Oregon, Pennsylvania, PuertoRico, Rhode Island, South Carolina, South Dakota, Tennessee, Texas, Utah, Vermont, Virginia,Washington, West Virginia, Wisconsin and Wyoming.
Pharmacists completing this course by October 31, 2004 may receive full credit.
This program has been approved by the State Boards of Pharmacy in Alabama and Oklahoma.
This lesson furnishes 1.25 hours (0.125 CEUs) of credit.
Program ID #707-000-01-010-H01.

Source: http://www.wfprofessional.com/documents/October2001.pdf