Antidiabetic drugs

Definition

Antidiabetic drugs are drugs that treat diabetes—a condition marked by either failure of insulin production, or reduced sensitivity to insulin,

There are two common forms of diabetes, type 1, which is marked by failure of insulin production, and type 2 which is marked by reduced sensitivity to insulin. Type 1 was formerly called “juvenile” diabetes, because it is most commonly seen in persons under the age of 30. In contrast, type 2 was termed “maturity onset” because it typically appeared after 30 years of age. Type 2 has been associated with obesity , and has been seen with increasing frequency as the weight of the population of developed nations has increased. Type 1 normally requires insulin as the basis of treatment, because the pancreas is unable to produce insulin. Although the treatment of type 2 diabetes should begin with a program of diet and exercise and a focus on weight loss , several different classes of drugs have been developed to treat the condition. These can increase insulin release, help sensitize the cells to insulin, or lower the glucose spikes that occur after meals.

Insulin is a hormone, secreted by the islet cells of the pancreas, which causes other cells to take in glucose. In type 1 diabetes, the islet cells might be insufficient or even absent, and the body might have produced antibodies to these cells. Because the body cannot produce insulin, oral drugs will be ineffective, and the insulin must be replaced by injection. Since the goal is to maintain blood glucose levels within a fairly narrow range, a large number of modified versions of insulin have been developed with different durations of action. Patients requiring insulin must monitor their blood sugar on a regular basis, and use various combinations of insulin in order to maintain appropriate levels.

Oral antihyperglycemic (antidiabetic) drugs may be useful in treatment of patients with type 2 diabetes, although many of these patients may progress to needing insulin. There are no generally recognized protocols for selecting which class of drug to use for initial therapy. For mild cases, physicians will base their judgment on past experience, however, diabetologists conduct detailed testing and base drug selection on the precise mechanism of action of the drug. Although many patients who start on oral drugs eventually progress to needing insulin, a Russian study showed that a regimen of oral therapies resulted in comparable glucose control and less weight gain than a combination of oral drugs and insulin. This was a short term study and the conclusions are not definitive, but further study is indicated.

The sulfonylureas are a group of drugs used in treatment of type 2 diabetes. They are:

• Acetohexamide
• Chlorpropamide
• Tolazamide
• Tolbutamide
• Glipizide
• Glyburide
• Glimepiride

While all these drugs work in a similar manner, acetohexamine, chlorpropamide, tolazamide and tobutamide are termed 1st generation, and have a higher risk of unwanted side effects. Their use in therapy has largely been supplanted by the second generation drugs, glipizide, glyburide and glimiperide. Patients most likely to respond to sulfonylurea therapy are those with type 2 diabetes mellitus who developed diabetes after 40 years of age, a duration of the disease less than 5–10 years before initiation of therapy, a body weight within 110–160% of ideal, a fasting plasma glucose concentration of less than 180, and no history of ketoacidosis (a life-threatening complication of diabetes) and who require less than 40–50 units of insulin daily. Patients who are severely obese or with fasting blood sugar levels in excess of 200 milligrams per deciliter are unlikely to respond well to any of the oral drugs.

Acarbose and miglitol act not by affecting insulin secretion or sensitivity, but by delaying absorption of dietary carbohydrates . This lowers the blood sugar spike that normally follows a meal. These drugs can be used alone, or in combination with other classes of antidiabetic drugs.

Pramlintide acetate injection is used in combination with insulin for either diabetes type 1 or type 2, for patients who cannot control their blood sugar adequately with mealtime insulin injections alone. Pramlintide mimics the effects of amylin which is normally secreted by the pancreas at the same time as insulin. The physiologic effects are to reduce glucagon release (glucagon, stored in the liver, is a stored form of glucose, and its release raises glucose levels), slow the stomach's emptying time to reduce the rate at which carbohydrates are absorbed, and produce a feeling of fullness which reduces overall food intake. This drug is limited to use by patients who are already insulin dependent, although the dosing schedule is different for diabetes type 1 and type 2.

Exenatide is an injection used for patients with type 2 diabetes who are taking one or more oral drugs, but have not achieved adequate glycemic (blood sugar) control. Exenatide mimics the action of the incretins, a group of hormones secreted by the intestinal tract at the time food material enters the intestine. Since approximately 70% of after-meal insulin secretion is stimulated by incretins, the provision of these hormones will stimulate the beta cells of the pancreas to produce more insulin. Glucagon-like peptide-1 (GLP-1) also stimulates the growth of insulin-producing cells and appears to lengthen the survival time of these cells, and slow the time of transit of food through the intestinal tract, which delays absorption of carbohydrates and reduces the after meal blood sugar spike.

Sitagliptin phosphate is a dipeptidyl peptidase-4 (DPP-4) inhibitor that is believed to exert its actions in patients with type 2 diabetes by slowing the inactivation of incretin hormones. The incretins are secreted by the stimulation of the presence of food in the intestine, and they in turn stimulate the beta cells to produce more insulin. DPP-4 inactivates the incretins. By inactivating DPP-4, stigagliptin increases the levels of incretins, leading to increased insulin production. The prolonged incretin level also lowers glucagon secretion from pancreatic alpha cells, leading to reduced glucose production by the liver. Stigaglitin can be use alone or in combination with an insulin sensitizer when diet and exercise alone have not provided adequate control of blood sugar levels.

Metformin can be used alone or in combination with other drugs in the treatment of type 2 diabetes. Metformin decreases glucose production, decreases the intestinal absorption of glucose, and improves insulin sensitivity in the cells of the body. With metformin therapy, insulin secretion remains unchanged, while fasting insulin levels and daylong plasma insulin response might actually decrease. One review of published studies indicated that starting metformin treatment during pre-diabetic states might prevent progression to diabetes.

Repaglinide and nateglinide are the meglitinide group and may be used either alone, or in combination with metformin or one of the drugs in the thiazolidinedione category. In patients whose blood sugar is inadequately controlled with metformin or a thiazolidinedione, a meglitinide may be added to, but not substituted for, those drugs. Meglitinides lower blood glucose levels by stimulating insulin secretion from the pancreas. This action depends upon functioning beta cells in the pancreatic islets.

Pioglitazone and rosiglitazone are the Thiazolidinediones although they are sometimes referred to as the “glitizones.” These drugs decrease insulin resistance in the periphery (the cells of the body) and in the liver. Unlike sulfonylureas, the glitazones do not increase

insulin secretion. They can be used alone or in combination with metformin, insulin, or a sulfonylurea.

Recommended dose

There is no fixed dosage regimen for the management of diabetes mellitus with any hypoglycemic agent. Glycemic or blood sugar control should be monitored with the blood tests hemoglobin A1C or blood glucose levels to determine the minimum effective dose for the patient; to detect primary failure, (i.e., use of the maximum recommended dose of a medication without seeting adequate lowering of the blood glucose, and to detect secondary failure, or the reduction of blood-glucose-lowering response after an initial period of effectiveness. Home blood glucose monitoring can also provide useful information to the patient and physician. Short-term administration of glipizide extended-release tablets can be sufficient during periods of transient loss of control in patients usually controlled on diet.

Precautions

The following warnings are the most significant for anti-diabetic drugs. The absence of an entry in this section does not indicate safety, but that product specific references should be consulted for more detailed information. These warnings are truncated from the official literature—see the full package insert for the complete text.

All sulfonylureas can cause severe hypoglycemia, or low blood sugar. Proper patient selection, dosage, and instructions are important to avoid hypoglycemic episodes. Kidney or liver disease can elevate blood levels of the drug, and liver disease can also reduce the liver's ability to make new glucose (gluconeogenesis). Elderly, debilitated, or malnourished patients, and those with adrenal or pituitary insufficiency are particularly susceptible to the hypoglycemic action of glucose-lowering drugs. Hypoglycemia can be difficult to recognize in the elderly and in patients taking drugs known as beta blockers . Hypoglycemia is more likely to occur when calorie intake is too low, after severe or prolonged exercise, when alcohol is ingested, or when more than 1 glucose-lowering drug is used.

Pramlintide is used with insulin and has been associated with an increased risk of insulin-induced severe hypoglycemia, particularly in patients with type 1 diabetes. When severe hypoglycemia associated with pramlintide use occurs, it is seen within 3 hours following a pramlintide injection. If severe hypoglycemia occurs while operating a motor vehicle, heavy machinery, or while engaging in other high-risk activities, serious injuries can occur. Appropriate patient selection, careful patient instruction, and insulin dose adjustments are critical elements for reducing this risk.

There have been reports of serious allergic and hypersensitivity reactions in patients treated with sitagliptin. These reactions include anaphylaxis (life threatening allergic reaction), angioedema (swelling of the skin and mucousmembranes), and Stevens-Johnson syndrome, an allergic reaction that results in the sloughing of skin. In such cases, promptly stop sitagliptin, assess for other potential causes, monitor and treat, and initiate alternative treatment for diabetes.

Metformin: Lactic acidosis is a rare but serious metabolic complication that can occur because of metformin accumulation during treatment with metformin; when it occurs, it is fatal in approximately 50% of cases. Lactic acidosis may also occur in association with a number of conditions, including diabetes mellitus itself, and whenever there is significant reduction in blood flow and oxygen to the tissues. body temperature, blood pressure and heart rate can drop as the acidosis worsens. the patient and the patient's health care provider must be aware of the possible importance of such symptoms. lactic acidosis is a medical emergency that must be treated in a hospital setting. in a patient with lactic acidosis who is taking metformin, discontinue the drug immediately and promptly institute general supportive measures.

Thiazolidinediones cause or worsen congestive heart failure (CHF) in some patients. After initiation of rosiglitazone and after dose increases, physicians should observe patients carefully for signs and symptoms of heart failure (including excessive, rapid weight gain, shortness of breath and/or edema (swell-ing). If these signs and symptoms develop, the doctor should manage the heart failure appropriately and consider discontinuation or dose reduction of the drug.

The administration of oral hypoglycemic drugs has been reported to be associated with an increased risk of death from heart disease as compared to treatment with diet alone or diet plus insulin. This warning is based on the study conducted by the university group diabetes program (UGDP), a clinical trial designed to whether these drugs reduced heart and vascular disease in diabetics.

As with all drugs, antidiabetic agents should not be used in patients who have shown hypersensitivity to the drug or any of the components.

Side effects

These drugs have been widely used, and a very large number of adverse effects have been ascribed to most of them. Consult specialized references for detailed information.

KEY TERMS

Anemia —A reduction in the number of red blood cells in the blood stream causing too little oxygen to reach tissues and organs.

Carbohydrate —A collective term for sugars and starches that can be broken down to glucose.

Diabetes —A term which, technically may refer to Diabetes Insipidus or Diabetes Mellitus. The common factor is that both conditions cause frequent urination. When used alone, the term refers to Diabetes Mellitus, in which the body cannot control the amount of sugar in the blood. The name derives from the fact that sugar appears in the urine, giving the urine a sweet odor.

Hyponatremia —Reduction in sodium in the blood

Insulin —A hormone produced in the pancreas, which regulates glucose levels in the blood

Pancreas —An organ, located behind the lower part of the stomach. It secretes insulin as well as other enzymes that play a role in food digestion.

Periphery —The part of the body away from the center, the arms and legs

Protocol —A detailed plan for how a disease or condition should be treated, including which drugs should be used first.

Sulfonylureas have been associated with hypoglycemia and possible weight gain.

Metformin has been associated with diarrhea , nausea, gastric pain , vitamin B 12 malabsorption. The drug can increase weight loss.

Thiazolidinediones can cause weight gain, fluid retention and mild anemia .

Alpha-glucosidase inhibitors commonly cause flatulence and bloating at the initiation of treatment, but this often declines over time.

Interactions

See drug specific references.

Clorpropamide may cause hyponatremia and it can also cause flushing after alcohol ingestion.

Caregiver concerns

These drugs should be taken according to a fairly rigid schedule. They must be coordinated with meals.

Patients taking sulfonylureas CAN be subject to hypoglycemia.

Although metformin associated lactic acidosis is extremely rare, caregivers should be familiar with the symptoms and observe patients carefully.

Resources

BOOKS

Davidson MB. “Diabetes Mellitus: Diagnosis and Treatment 4th ed. Philadelphia: Saunders, 1998.

Cowell, JA. “Hot Topics in Diabetes. Philadelphia: Hanley & Belfus, 2003.

PERIODICALS

Davies, MJ, Heller S, Skinner TC et al. “Effectiveness of the diabetes education and self management for ongoing and newly diagnosed (DESMOND) programme for people with newly diagnosed type 2 diabetes: cluster randomised controlled trial.” BMJ. (Mar 1, 2008) 336(7642):491–5

Hornick, T, Aron DC. “Preventing and managing diabetic complications in elderly patients” Cleve Clin J Med.(February 2008) 75(2):153–8.

Salpeter, SR, Buckley NS, Kahn JA. “Meta-analysis: metformin treatment in persons at risk for diabetes mellitus.” Am J Med. (February 2008) 121(2):149–157.e2.

Gaede, P, Lund-Andersen H, ParvingHH, PedersenO. “Effect of a multifactorial intervention on mortality in type 2 diabetes.” N Engl JMed. (Feb 7, 2008) 358(6):580–91.

Malesker, MA. “Optimizingantidiabetic treatmentoptions for patients with type 2 diabetes mellitus and cardiovascular comorbidities.”Pharmacotherapy. (Feb,2008) 28(2):193–206.

Huang, ES. “Appropriate application of evidence to the care of elderly patients with diabetes.” Curr Diabetes Rev. (November 2007) 3(4):260–3.

Jarosz, M, Rychlik E, Respondek W. “Counteraction against obesity—is it possible?” Adv Med Sci. (2007) 52:232–9.

Raz, I, Chen Y, Wu M, Hussain S, et al. “Efficacy and safety of sitagliptin added to ongoing metformin therapy in patients with type 2 diabetes.” Curr Med Res Opin. (February 2008) 24(2):537–50.

Bertoni, AG, Clark JM, Feeney P. “Suboptimal control of glycemia, blood pressure, and LDL cholesterol in overweight adults with diabetes: the Look AHEAD Study.”J Diabetes Complications. (Jan-Feb 2008) 22(1):1–9.

Ushakova, O, Sokolovskaya V, Morozova A, et al. “Comparison of biphasic insulin aspart 30 given three times daily or twice daily in combination with metformin versus oral antidiabetic drugs alone in patients with poorly controlled type 2 diabetes: a 16-week, randomized, open-label, parallel-group trial conducted in Russia.

” Clin Ther. (November 2007) 29(11):2374–84.

Chien, HH, Chang CT, Chu NF, et al. “Effect of glyburide-metformin combination tablet in patients with type 2 diabetes.” J Chin Med Assoc. (November 2007) 70(11):473–80.

Klonoff, DC, Buse JB, Nielsen LL. “Exenatide effects on diabetes, obesity, cardiovascular risk factors and hepatic biomarkers in patients with type 2 diabetes treated for at least 3 years.” Curr Med Res Opin.(January 2008) 24(1):275–86.

Ober, SK, Watts S, Lawrence RH. “Insulin use in elderly diabetic patients.” Clin Interv Aging. (2006) 1(2):107‐13.

OTHER

http://www.nlm.nih.gov/medlineplus/druginfo/medmaster/a684060.html

http://www.nlm.nih.gov/medlineplus/news/fullstory_62714.html

http://www.pfizer.com/products/products_result.jsp?productconditionselect=Diabetes%20Mellitus

http://www.nlm.nih.gov/medlineplus/diabetes.html

http://www.bayerdiabetes.com/

http://www.medmatrix.org/

http://care.diabetesjournals.org/

http://www.drugs.com/diabetes-treatment.html

http://www.januvia.com/sitagliptin/januvia/hcp/pi/index.jsp

http://www.mayoclinic.com/health/diabetes/DA99999

http://www.fda.gov/

http://www.merck.com/mmpe/sec12/ch158/ch158b.html#CIHGADAI

ORGANIZATIONS

American Diabetes Association, 1701 North Beauregard Street, Alexandria, VA, 22311, 1–800-DIABETES (1–800–342–2383), [email protected]>, http://www.diabetes.org.

International Diabetes Federation (IDF), Avenue Emile De Mot 19, Brussels, Belgium, +32–2–5385511, +32–2–5385114, [email protected], http://www.idf.org.

National Diabetes Information Clearinghouse (NDIC), 1 Information Way, Bethesda, MD, 20892–3560, 1–800–860–8747, 703–738–4929, [email protected], www.diabetes.niddk.nih.gov.

Sam Uretsky PharmD

Antidiabetic Drugs

Definition

Antidiabetic drugs are medicines that help control blood sugar levels in people with diabetes mellitus (sugar diabetes).

Purpose

Diabetes may be divided into type I and type II, formerly termed juvenile onset or insulin-dependent, and maturity onset or non insulin-dependent. Type I is caused by a deficiency of insulin production, while type II is characterized by insulin resistance.

Treatment of type I diabetes is limited to insulin replacement, while type II diabetes is treatable by a number of therapeutic approaches. Many cases of insulin resistance are asymptomatic due to normal increases in insulin secretion, and others may be controlled by diet and exercise. Drug therapy may be directed toward increasing insulin secretion, increasing insulin sensitivity, or increasing insulin penetration of the cells.

Description

Antidiabetic drugs may be subdivided into six groups: insulin, sufonylureas, alpha-glucosidase inhibitors, biguanides, meglitinides, and thiazolidinediones.

KEY TERMS

Blood sugar— The concentration of glucose in the blood.

Glucose— A simple sugar that serves as the body's main source of energy.

Hormone— A substance that is produced in one part of the body, then travels through the bloodstream to another part of the body where it has its effect.

Metabolism— All the physical and chemical changes that occur in cells to allow growth and maintain body functions. These include processes that break down substances to yield energy and processes that build up other substances necessary for life.

Pregnancy category— A system of classifying drugs according to their established risks for use during pregnancy. Category A: Controlled human studies have demonstrated no fetal risk. Category B: Animal studies indicate no fetal risk, but no human studies; or adverse effects in animals, but not in well-controlled human studies. Category C: No adequate human or animal studies; or adverse fetal effects in animal studies, but no available human data. Category D: Evidence of fetal risk, but benefits outweigh risks. Category X: Evidence of fetal risk. Risks outweigh any benefits.

Salicylates— A group of drugs that includes aspirin and related compounds. Salicylates are used to relieve pain, reduce inflammation, and lower fever.

Seizure— A sudden attack, spasm, or convulsion.

Insulin (Humulin, Novolin) is the hormone responsible for glucose utilization. It is effective in both types of diabetes, since, even in insulin resistance, some sensitivity remains and the condition can be treated with larger doses of insulin. Most insulins are now produced by recombinant DNA techniques, and are chemically identical to natural human insulin. Isophane insulin suspension, insulin zinc suspension, and other formulations are intended to extend the duration of insulin action, and permit glucose control over longer periods of time. In 2003, research suggested that inhaled forms of insulin offered advantages to injected types, but further study was needed on its long-term effects on the lungs and cost-effectiveness.

Sulfonylureas (chlorpropamide [Diabinese], tolazamide [Tolinase], glipizide [Glucotrol] and others) act by increasing insulin release from the beta cells of the pancrease. Glimepiride (Amaryl), a member of this class, appears to have a useful secondary action in increasing insulin sensitivity in peripheral cells.

Alpha-glucosidase inhibitors (acarbose [Precose], miglitol [Glyset]) do not enhance insulin secretion. Rather, they inhibit the conversion of disaccharides and complex carbohydrates to glucose. This mechanism does not prevent conversion, but only delays it, reducing the peak blood glucose levels. Alpha-glucosidase inhibitors are useful for either monotherapy or in combination therapy with sulfonylureas or other hypoglycemic agents.

Metformin (Glucophage) is the only available member of the biguanide class. Metformin decreases hepatic (liver) glucose production, decreases intestinal absorption of glucose and increases peripheral glucose uptake and use. Metformin may be used as monotherapy (alone), or in combination therapy with a sulfonylurea.

There are two members of the meglitinide class: repaglinide (Prandin) and nateglitinide (Starlix). The mechanism of action of the meglitinides is to stimulate insulin production. This activity is both dose dependent and dependent on the presence of glucose, so that the drugs have reduced effectiveness in the presence of low blood glucose levels. The meglitinides may be used alone, or in combination with metformin. The manufacturer warns that nateglitinide should not be used in combination with other drugs that enhance insulin secretion.

Rosiglitazone (Avandia) and pioglitazone (Actos) are members of the thiazolidinedione class. They act by both reducing glucose production in the liver, and increasing insulin dependent glucose uptake in muscle cells. They do not increase insulin production. These drugs may be used in combination with metformin or a sulfonylurea.

Recommended dosage

Dosage must be highly individualized for all antidiabetic agents and is based on blood glucose levels which must be taken regularly. Patients should review specific literature that comes with antidiabetic medications for complete dosage information.

Precautions

Insulin. The greatest short term risk of insulin is hypoglycemia, which may be the result of either a direct overdose or an imbalance between insulin injection and level of exercise and diet. This also may occur in the presence of other conditions which reduce the glucose load, such as illness with vomiting and diarrhea. Treatment is with glucose in the form of glucose tablets or liquid, although severe cases may require intravenous therapy. Allergic reactions and skin reactions also may occur. Insulin is classified as category B in pregnancy, and is considered the drug of choice for glucose control during pregnancy. Insulin glargine (Lantus), an insulin analog which is suitable for once-daily dosing, is classified as category C, because there have been reported changes in the hearts of newborns in animal studies of this drug. The reports are essentially anecdotal, and no cause and effect relationship has been determined. Insulin is not recommended during breast feeding because either low or high doses of insulin may inhibit milk production. Insulin administered orally is destroyed in the GI tract, and represents no risk to the newborn.

Sulonylureas. All sulfonylurea drugs may cause hypoglycemia. Most patients become resistant to these drugs over time, and may require either dose adjustments or a switch to insulin. The list of adverse reactions is extensive, and includes central nervous system problems and skin reactions, among others. Hematologic reactions, although rare, may be severe and include aplastic anemia and hemolytic anemia. The administration of oral hypoglycemic drugs has been associated with increased cardiovascular mortality as compared with treatment with diet alone or diet plus insulin. The sulfonylureas are classified as category C during pregnancy, based on animal studies, although glyburide has not shown any harm to the fetus and is classified as category B. Because there may be significant alterations in blood glucose levels during pregnancy, it is recommended that patients be switched to insulin. These drugs have not been fully studied during breast feeding, but it is recommended that because their presence in breast milk might cause hypoglycemia in the newborn, breast feeding be avoided while taking sulfonylureas.

Alpha-glucosidase inhibitors are generally well tolerated, and do not cause hypoglycemia. The most common adverse effects are gastrointestinal problems, including flatulence, diarrhea, and abdominal pain. These drugs are classified as category B in pregnancy. Although there is no evidence that the drugs are harmful to the fetus, it is important that rigid blood glucose control be maintained during pregnancy, and pregnant women should be switched to insulin. Alphaglucosidase inhibitors may be excreted in small amounts in breast milk, and it is recommended that the drugs not be administered to nursing mothers.

Metformin causes gastrointestinal (stomach and digestive) reactions in about a third of patients. A rare, but very serious, reaction to metformin is lactic acidosis, which is fatal in about 50% of cases. Lactic acidosis occurs in patients with multiple medical problems, including renal (kidney-related) insufficiency. The risk may be reduced with careful renal monitoring, and careful dose adjustments to metformin. Metformin is category B during pregnancy. There have been no carefully controlled studies of the drug during pregnancy, but there is no evidence of fetal harm from animal studies. It is important that rigid blood glucose control be maintained during pregnancy, and pregnant women should be switched to insulin. Animal studies show that metformin is excreted in milk. It is recommended that metformin not be administered to nursing mothers.

Meglitinides. These drugs are generally well tolerated, with an adverse event profile similar to placebo. The drugs are classified as category C during pregnancy, based on fetal abnormalities in rabbits given about 40 times the normal human dose. It is important that rigid blood glucose control be maintained during pregnancy, and pregnant women should be switched to insulin. It is not known whether the meglitinides are excreted in human milk, but it is recommended that these drugs not be given to nursing mothers.

Thiazolidinediones. These drugs were generally well tolerated in early trials, but they are structurally related to an earlier drug, troglitazone, which was associated with liver function problems. However, in 2003, researchers reported that these drugs, which are used by more than 6 million Americans, may lead to serious side effects. Research showed that after one to 16 months of therapy with pioglitazone or rosiglitazone, some patients developed serious edema and signs of congestive heart failure. Additional studies were underway in late 2003 to determine how these drugs caused fluid build-up and if the symptoms occurred more frequently in certain age groups. The mean age of patients in the 2003 study was 69 years.

It is strongly recommended that all patients treated with pioglitazone or rosiglitazone have regular liver function monitoring. The drugs are classified as pregnancy category C, based on evidence of inhibition of fetal growth in rats given more than four times the normal human dose. It is important that rigid blood glucose control be maintained during pregnancy, and pregnant women should be switched to insulin. It is not known whether the thiazolidinediones are excreted in human milk, however they have been identified in the milk of lactating rats. It is recommended that these drugs not be administered to nursing mothers.

Interactions

The sulfonylureas have a particularly long list of drug interactions, several of which may be severe. Patients should review specific literature for these drugs.

The actions of oral hypoglycemic agents may be strengthened by highly protein bound drugs, including NSAIDs, salicylates, sulfonamides, chloramphenicol, coumarins, probenecid, MAOIs, and beta blockers.

The literature that accompanies each medication should list possible drug-drug or food-drug interactions.

Resources

PERIODICALS

"Inhaled Insulin Means Better Quality of Life." Health & Medicine Week (September 16, 2003): 189.

"Two Common Diabetes Drugs May Cause Heart Failure and Fluid Buildup." Cardiovascular Week (September 29, 2003): 26.

ORGANIZATIONS

American Diabetes Association. ADA National Service Center, 1660 Duke Street, Alexandria, VA 22314. (800)232-3472. 〈http://www.diabetes.org〉.

National Diabetes Information Clearinghouse. 1 Information Way, Bethesda, MD 20892-3560. (301)654-3327. [email protected].

OTHER

National Institute of Diabetes and Digestive and Kidney Diseases. 〈http://www.niddk.nih.gov〉.

Antidiabetic Drugs

Definition

Antidiabetic drugs are medicines that help control blood sugar levels in people with diabetes mellitus (sugar diabetes).

Purpose

Diabetes may be divided into type I and type II, formerly termed juvenile onset or insulin-dependent, and maturity onset or non insulin-dependent. Type I is caused by a deficiency of insulin production, while type II is characterized by insulin resistance.

Treatment of type I diabetes is limited to insulin replacement, while type II diabetes is treatable by a number of therapeutic approaches. Many cases of insulin resistance are asymptomatic due to normal increases in insulin secretion, and others may be controlled by diet and exercise. Drug therapy may be directed towards increasing insulin secretion, increasing insulin sensitivity, or increasing insulin penetration of the cells.

Description

Antidiabetic drugs may be subdivided into six groups: insulin, sufonylureas, alpha-glucosidase inhibitors, biguanides, meglitinides, and thiazolidinediones.

Insulin (Humulin, Novolin) is the hormone responsible for glucose utilization. It is effective in both types of diabetes, since, even in insulin resistance, some sensitivity remains and the condition can be treated with larger doses of insulin. Most insulins are now produced by recombinant DNA techniques, and are chemically identical to natural human insulin. Isophane insulin suspension, insulin zinc suspension, and other formulations are intended to extend the duration of action of insulin, and permit glucose control over longer periods of time.

Sulfonylureas (chlorpropamide [Diabinese], tolazamide [Tolinase], glipizide [Glucotrol], and others) act by increasing insulin release from the beta cells of the pancrease. Glimepiride (Amaryl), a member of this class, appears to have a useful secondary action in increasing insulin sensitivity in peripheral cells.

Alpha-glucosidase inhibitors (acarbose [Precose], miglitol [Glyset]) do not enhance insulin secretion. Rather, they inhibit the conversion of disaccharides and complex carbohydrates to glucose. This mechanism does not prevent conversion, but only delays it, reducing the peak blood glucose levels. Alphaglucosidase inhibitors are useful for either monotherapy or in combination therapy with sulfonylureas or other hypoglycemic agents.

Metformin (Glucophage) is the only available member of the biguanide class. Metformin decreases hepatic glucose production, decreases intestinal absorption of glucose and increases peripheral glucose uptake and utilization. Metformin may be used as monotherapy, or in combination therapy with a sulfonylurea.

There are two members of the meglitinide class: repaglinide (Prandin) and nateglitinide (Starlix). The mechanism of action of the meglitinides is to stimulate insulin production. This activity is both dose dependent and dependent on the presence of glucose, so that the drugs have reduced effectiveness in the presence of low blood glucose levels. The meglitinides may be used alone, or in combination with metformin. The manufacturer warns that nateglitinide should not be used in combination with other drugs which enhance insulin secretion.

Rosiglitazone (Avandia) and pioglitazone (Actos) and the members of the thiazolidinedione class. They act by both reducing glucose production in the liver, and increasing insulin dependent glucose uptake in muscle cells. They do not increase insulin production. These drugs may be used in combination with metoformin or a sulfonylurea.

Recommended dosage

Dosage must be highly individualized for all antidiabetic agents and is based on blood glucose levels which must be taken regularly. Review specific literature.

Precautions

The greatest short term risk of insulin is hypoglycemia, which may be the result of either a direct overdose or an imbalance between insulin injection and level of exercise and diet. This may also occur in the presence of other conditions which reduce the glucose load, such as illness with vomiting and diarrhea. Treatment is with glucose in the form of glucose tablets or liquid, although severe cases may require intravenous therapy. Allergic reactions and skin reactions may also occur. Insulin is classified as category B in pregnancy, and is considered the drug of choice for glucose control during pregnancy. Insulin glargine (Lantus), an insulin analog which is suitable for once-daily dosing, is classified as category C, because there have been reported changes in the hearts of newborns in animal studies of this drug. The reports are essentially anecdotal, and no cause and effect relationship has been determined. Insulin is not recommended during breast feeding because either low of high doses of insulin may inhibit milk production. Insulin administered orally is destroyed in the GI tract, and represents no risk to the newborn.

All sulfonylurea drugs may cause hypoglycemia. Most patients become resistant to these drugs over time, and may require either dose adjustments or a switch to insulin. The list of adverse reactions is extensive, and includes central nervous system problems and skin reactions, among others. Hematologic reactions, although rare, may be severe and include aplastic anemia and hemolytic anemia. The administration of oral hypoglycemic drugs has been associated with increased cardiovascular mortality as compared with treatment with diet alone or diet plus insulin. The sulfonylureas are classified as category C during pregnancy, based on animal studies, although glyburide has not shown any harm to the fetus and is classified as category B. Because there may be significant alterations in blood glucose levels during pregnancy, it is recommended that patients be switch to insulin. These drugs have not been fully studied during breast feeding, but it is recommended that because their presence in breast milk might cause hypoglycemia in the newborn, breast feeding be avoided while taking sulfonylureas.

Alpha-glucosidase inhibitors are generally well tolerated, and do not cause hypoglycemia. The most common adverse effects are gastrointestinal problems, including flatulence, diarrhea, and abdominal pain. These drugs are classified as category B in pregnancy. Although there is no evidence that the drugs are harmful to the fetus, it is important that rigid blood glucose control be maintained during pregnancy, and pregnant women should be switched to insulin. Alphaglucosidase inhibitors may be excreted in small amounts in breast milk, and it is recommended that the drugs not be administered to nursing mothers.

Metformin causes gastrointestinal reactions in about a third of patients. A rare, but very serious, reaction to metformin is lactic acidosis, which is fatal in about 50% of cases. Lactic acidosis occurs in patients with multiple medical problems, including renal insufficiency. The risk may be reduced with careful renal monitoring, and careful dose adjustments to metformin. Metformin is category B during pregnancy. There have been no carefully controlled studies of the drug during pregnancy, but there is no evidence of fetal harm from animal studies. It is important that rigid blood glucose control be maintained during pregnancy, and pregnant women should be switched to insulin. Animal studies show that metformin is excreted in milk. It is recommended that metformin not be administered to nursing mothers.

Meglitinides are generally well tolerated, with an adverse event profile similar to placebo. The drugs are classified as category C during pregnancy, based on fetal abnormalities in rabbits given about 40 times the normal human dose. It is important that rigid blood glucose control be maintained during pregnancy, and pregnant women should be switched to insulin. It is not known whether the meglitinides are excreted in human milk, but it is recommended that these drugs not be given to nursing mothers.

Thiazolidinediones are generally well tolerated, however they are structurally related to an earlier drug, troglitazone, which was associated with liver function problems. It is strongly recommended that all patients treated with pioglitazone or rosiglitazone have regular liver function monitoring. The drugs are classified as pregnancy category C, based on evidence of inhibition of fetal growth in rats given more than four times the normal human dose. It is important that rigid blood glucose control be maintained during pregnancy, and pregnant women should be switched to insulin. It is not known whether the thiazolidinediones are excreted in human milk, however they have been identified in the milk of lactating rats. It is recommended that these drugs not be administered to nursing mothers.

Interactions

The sulfonylureas have a particularly long list of drug interactions, several of which may be severe. Review specific literature for these drugs.

The actions of oral hypoglycemic agents may be strengthened by highly protein bound drugs, including NSAIDs, salicylates, sulfonamides, chloramphenicol, coumarins, probenecid, MAOIs, and beta blockers.

Review the specific literature of each drugs for possible drug-drug or food-drug interactions.

KEY TERMS

Blood sugar— The concentration of glucose in the blood.

Glucose— A simple sugar that serves as the body's main source of energy.

Hormone— A substance that is produced in one part of the body, then travels through the bloodstream to another part of the body where it has its effect.

Metabolism— All the physical and chemical changes that occur in cells to allow growth and maintain body functions. These include processes that break down substances to yield energy and processes that build up other substances necessary for life.

Pregnancy category— A system of classifying drugs according to their established risks for use during pregnancy. Category A: Controlled human studies have demonstrated no fetal risk. Category B: Animal studies indicate no fetal risk, but no human studies; or adverse effects in animals, but not in well-controlled human studies. Category C: No adequate human or animal studies; or adverse fetal effects in animal studies, but no available human data. Category D: Evidence of fetal risk, but benefits outweigh risks. Category X: Evidence of fetal risk. Risks outweigh any benefits.

Salicylates— A group of drugs that includes aspirin and related compounds. Salicylates are used to relieve pain, reduce inflammation, and lower fever.

Seizure— A sudden attack, spasm, or convulsion.

Resources

PERIODICALS

Hingley, Audrey. "Diabetes Demands a Trial of Treatments." FDA Consumer 31 (May-June 1997): 33.

ORGANIZATIONS

American Diabetes Association. ADA National Service Center, 1660 Duke Street, Alexandria, VA 22314. 800-232-3472. 〈http://www.diabetes.org〉.

National Diabetes Information Clearinghouse. 1 Information Way, Bethesda, MD 20892-3560. 301-654-3327. [email protected].

OTHER

National Institute of Diabetes and Digestive and Kidney Diseases. 〈http://www.niddk.nih.gov〉.

antidiabetic drugs (anti-dy-ă-bet-ik) pl. n. drugs used to control diabetes mellitus. Type 1 diabetes is treated with the wide range of formulations of insulin. Type 2 diabetes is treated mainly with oral hypoglycaemic drugs but in some cases insulin may be required.