Oral Antidiabetic Agents: A Comparative Review

Transcription

1 / KOSKI ORAL ANTIDIABETIC AGENTS ARTICLE Oral Antidiabetic Agents: A Comparative Review Renee R. Koski, PharmD Type 2 diabetes mellitus is a chronic disease characterized by insulin resistance, impaired insulin secretion, and/or increased hepatic glucose production. The mainstays of drug treatment are the oral antidiabetic agents. Insulin is usually reserved for patients who do not achieve fasting plasma glucose or A1C goals with or cannot tolerate the oral antidiabetic agents. There are 5 classes of oral antidiabetic agents KEY WORDS: Diabetes, treatment, pharmacology, efficacy, safety. available in the United States: sulfonylureas, biguanides, alpha-glucosidase inhibitors, thiazolidinediones, and nonsulfonylurea secretagogues. They have differences and similarities with respect to their pharmacology and role in diabetes. This article reviews the pharmacology, efficacy, safety, and selection of the oral agents used to treat type 2 diabetes mellitus. ORAL DRUG TREATMENT OF TYPE 2 DIABETES MELLITUS Type 2 diabetes mellitus, previously referred to as non insulin-dependent diabetes or adult-onset diabetes, refers to a condition in which patients usually have insulin resistance, impaired insulin secretion, and/or increased hepatic glucose production. 1 Most patients with this form of diabetes are obese, and this contributes to the insulin resistance. Hyperglycemia develops gradually in type 2 diabetes compared to that in type 1 diabetes, and so ketoacidosis rarely occurs in type 2 diabetes patients. The gradual development of hyperglycemia usually results in the late detection of diabetes, which increases the patient s risk for microvascular and macrovascular complications. The United Kingdom Prospective Diabetes Study (UKPDS) has provided strong evidence that tight control of hyperglycemia in type 2 diabetes decreases the morbidity and mortality of the disease by decreasing its chronic complications. Tight glycemic control decreases morbidity and mortality of microvascular complications. Blood pressure control in diabetes decreases morbidity and mortality of macrovascular complications as it does in those without diabetes. 2 The mainstay of treatment for patients with type 2 diabetes who fail diet therapy are the oral antidiabetic agents. Because of the inconvenience of insulin, it is usually reserved for patients who do not achieve fasting plasma glucose or A1C (formerly HbA1C or hemoglobin A1C) goals with the oral antidiabetic agents or cannot tolerate the oral antidiabetic agents. This article focuses on the oral antidiabetic agents. MECHANISM OF ACTION/EFFECT ON LIPIDS The oral antidiabetic drug classes differ in their sites and mechanisms of action to lower plasma glucose. The sulfonylureas and nonsulfonylurea (non-su) secretagogues primarily work in the pancreas to stimulate insulin release. The biguanides primarily work in the liver to decrease glucose production. The alphaglucosidase inhibitors primarily work in the small intestine to slow carbohydrate absorption. The thiazolidinediones (TZDs) primarily work in the peripheral tissues and act as insulin sensitizers. 3 Table 1 lists the mechanism and site of action for each class of drugs. The oral antidiabetic agents also differ in their effects on the patient s lipid profile., non- SU secretagogues, and alpha-glucosidase inhibitors do To whom correspondence should be addressed: Renee R. Koski, PharmD, 1655 S. Westwood Circle, Ishpeming, MI 49849; rkoski@mgh.org. Renee R. Koski, PharmD, associate professor, pharmacy practice, Ferris State University, UPHEC, 418 West Magnetic Street, Marquette, MI JOURNAL OF PHARMACY PRACTICE ;1: Sage Publications DOI: /

2 KOSKI Table 1 Mechanism and Site of Action for Oral Antidiabetic Agents 22 Primary Drug Class Mechanism of Action Site of Action insulin release Pancreas hepatic glucose production; Liver; peripheral tissues insulin sensitivity in hepatic and peripheral tissues Alpha-glucosidase inhibitors carbohydrate absorption Small intestines Thiazolidinediones Nonsulfonylurea secretagogues not appreciably affect the lipid profile. can improve the complete lipid profile, whereas TZDs can improve some lipid levels while adversely affecting others. 3 Table 2 lists the effects the oral antidiabetic agents have on lipid profiles. insulin sensitivity in peripheral tissues; hepatic glucose production insulin release Peripheral tissues; liver Pancreas are classified as first- and second-generation agents based on when they became available. The generations differ in their potency, pharmacokinetics, and safety. The second-generation agents are more potent and in general have better pharmacokinetic and safety profiles. The first-generation agents include acetohexamide, chlorpropamide, tolazamide, and tolbutamide. The second-generation agents include glimepiride, glipizide, and glyburide. It is well known that sulfonylureas (available since 1954) lower plasma glucose primarily by increasing the release of insulin from functioning pancreatic β-cells. They bind to the sulfonylurea receptor on β-cells. This causes the closure of adenosine triphosphate dependent potassium channels, which results in cell membrane depolarization and leads to calcium influx and release of stored insulin from secretory granules within the cell. This mechanism only works if there is insulin present to be released from the β-cells. display a more pronounced action in the presence of glucose. The increased insulin flows into the portal veins to suppress the elevated basal rate of hepatic glucose production. One concern with these agents is the loss of efficacy over time, which may be related to the potential Table 2 Efficacy of Oral Antidiabetic Agents in Improving Lipid Levels 3 Low-density High-density Drug Class Lipoproteins Lipoproteins Triglycerides No effect No effect Slight Slight Alpha-glucosidase No effect No effect No effect inhibitors Thiazolidinediones Nonsulfonylurea secretagogues No effect No effect Slight to exhaust β-cell function. Because these agents increase plasma levels of insulin, they may cause hypoglycemia. The addition of other antidiabetic agents can further increase the risk of hypoglycemia. 3 Glimepiride has also been shown to increase insulin sensitivity of peripheral tissues to insulin. Results of a long-term, randomized, placebo-controlled trial showed that glimepiride improved postprandial insulin and C-peptide responses and overall glycemic control without producing clinically meaningful increases in fasting insulin or C-peptide levels. In fact, glimepiride may decrease insulin levels. 4 do not have a clinically significant effect on the lipid profile. 3 Metformin (available since 1995) is the only biguanide available in the United States. It is in the same class of drugs as phenformin, which was available but was removed from the United States and European markets in the 1970s because of its association with lactic acidosis. 3 Metformin has several mechanisms of action, but its primary mechanism for lowering plasma glucose is to decrease hepatic gluconeogenesis. To a smaller extent, it also improves insulin sensitivity of peripheral tissues. It does this by increasing insulin-stimulated uptake and use of glucose. This is shown by a reduction in fasting plasma glucose and insulin concentrations. It is not effective in the absence of insulin. 5 Metformin also decreases intestinal absorption of glucose. It does not affect insulin secretion, so it is not associated with hypoglycemia when used alone. Metformin s effect may diminish over time. It is unclear why this may occur. Metformin has been shown to decrease the low-density lipoprotein (LDL) levels and triglycerides (TGL) by about 10% to 15% and may slightly increase the high-density lipoprotein (HDL) levels JOURNAL OF PHARMACY PRACTICE 2004(17.1)

3 ORAL ANTIDIABETIC AGENTS Alpha-glucosidase Inhibitors The alpha-glucosidase inhibitors (available since 1996) include acarbose and miglitol. These agents decrease the rate of ingested carbohydrate absorption in the small intestine. They act as competitive, reversible inhibitors of alpha-glucosidases (hydrolase enzymes found in the brush border of the small intestine), and alpha-amylase (found in the pancreas). Alpha-amylase hydrolyzes complex starches. Alpha-glucosidases convert nonabsorbable dietary starch and sucrose into absorbable glucose. Inhibition of these enzymes slows digestion of carbohydrates, which results in slower absorption and a reduction in postprandial plasma glucose levels. 3 These drugs bind to the carbohydratebinding region of alpha-glucosidase enzymes. Therefore, they compete with the binding of oligosaccharides to the enzymes and interfere with their hydrolyzing into monosaccharides. 6 There are several alphaglucosidase enzymes. The primary ones involved are glucoamylase, sucrase, maltase, and isomaltase. Lactase is not involved, so lactose absorption is not affected (ie, they do not induce lactose intolerance). These agents do not affect insulin levels, so they do not cause hypoglycemia when used alone. If they are used in combination with another agent and hypoglycemia occurs, the hypoglycemia needs to be reversed by administering glucose (tablets or gels) to the patient, not complex carbohydrates. Complex carbohydrates would be slowly broken down by the alphaglucosidase inhibitor and thus would not be effective in quickly relieving the hypoglycemia. Alphaglucosidase inhibitors have no effect on the lipid profile. 3 TZDs TZDs (available since 1997) include pioglitazone and rosiglitazone. These agents act primarily to improve insulin sensitivity of muscle and adipose tissue. To a lesser extent, these agents decrease hepatic glucose production. TZDs are selective and potent agonists for the peroxisome proliferator-activated receptor-gamma (PPARγ) nuclear receptors. PPARγ receptors are located in adipose tissue, skeletal muscle, and the liver. Activation of these receptors regulates the transcription of insulin-responsive genes involved in the control of production, transport, and use of glucose. The action of these agents requires the presence of insulin. 7 It has been postulated that TZDs may improve β-cell function by reducing free fatty acids. It has been shown in rodent studies that free fatty acids play a role in β-cell death. 8 A study by Porter et al found rosiglitazone to decrease the proinsulin insulin ratio in patients with type 2 diabetes mellitus, indicating an improvement in β-cell function. 9 These agents do not directly affect insulin secretion, so they are not associated with hypoglycemia when used alone. TZDs can decrease TGL by 10% to 20% and increase HDL levels by 5% to 10%, but they may increase LDL levels by 10% to 15%. Pioglitazone may lower TGL more than rosiglitazone. It also may not elevate LDL levels as much as rosiglitazone. 3 Both agents may reduce the level of small, dense LDL cholesterol, which is thought to be the most atherogenic lipoprotein component in patients with diabetes. 10 Non-SU Secretagogues The non-su secretagogues include repaglinide (which is a member of the meglitinide family) and nateglinide (which is a derivative of δ-phenylalanine). Like the sulfonylureas, the non-su secretagogues (available since 1998) lower plasma glucose by increasing the release of insulin from functioning pancreatic β-cells. The mechanism is exactly the same as the sulfonylureas, except the non-su secretagogues bind to different receptors on the β-cells. Unlike sulfonylureas, non-su secretagogues have a very short half-life and duration of action, so they stimulate insulin secretion for brief episodes. Therefore, they are dosed with meals and are most helpful in decreasing postprandial hyperglycemia. Because non-su secretagogues stimulate insulin release from the pancreas, they have the risk of hypoglycemia. The quick on and off helps to decrease the incidence of hypoglycemia compared to sulfonylureas. 1 Like sulfonylureas, non-su secretagogues have no appreciable effect on the lipid profile. 3 EFFICACY All 5 classes of oral antidiabetic agents lower fasting plasma glucose and A1C, but they do so to different extents. Table 3 lists the efficacy in lowering fasting plasma glucose and A1C for the 5 classes of antidiabetic agents. In general, sulfonylureas, biguanides, and non-su secretagogues lower fasting plasma glucose and A1C to a similar extent. TZDs and alphaglucosidase inhibitors lower fasting plasma glucose and A1C to a lesser extent than the other 3 classes of agents. Although the reduction in these clinical end points differs between drug classes, comparative clinical trials have shown most of these agents to be equally efficacious because of the various doses used. 7 The only oral antidiabetic agents that have been involved in JOURNAL OF PHARMACY PRACTICE 2004(17.1) 41

4 KOSKI clinical trials looking at a reduction in cardiovascular complications are the sulfonylureas and metformin (ie, UKPDS). The TZDs are currently being studied in several diabetes trials involving cardiac outcomes (ie, Action to Control Cardiovascular Risk in Diabetes, Prospective Actos Clinical Trial in Macrovascular Events, Rosiglitazone Evaluated for Cardiac Outcomes and Regulation of Glycemia in Diabetes, etc). 11 have been shown in several placebocontrolled trials to reduce fasting plasma glucose by 60 to70mg/dlanda1cby1.5%to2.0%whenmaximal doses are used. The higher the fasting plasma glucose, the greater the magnitude of effect is seen with sulfonylureas. In comparative trials, sulfonylureas have been shown to be equivalent with each other. 3 In the UKPDS, the efficacy of sulfonylureas was similar to that of insulin and metformin and better than diet therapy in reducing A1C. In this large trial, sulfonylureas were associated with a decrease in microvascular events compared to diet treatment, but there was no significant difference in mortality or macrovascular events. It is postulated that the lack of benefit of sulfonylureas on cardiovascular complications is related to the fact that they cause hyperinsulinemia, which is associated with the metabolic syndrome. 2 Most studies that compared sulfonylureas with metformin found the 2 classes to have equal efficacy in lowering A1C. 7 A European study by Campbell et al found metformin (up to 3000 mg daily) to be significantly more efficacious than glipizide (up to 30 mg daily) in reducing A1C ( 2.6% versus 1.9%, respectively). 12 In comparative trials, low-dose sulfonylureas have been found to have equivalent or more efficacy than alpha-glucosidase inhibitors. 13,14 In a study by Hoffman et al, glibenclamide (equivalent to glyburide, available in Europe) 3.5 mg 1, 2, or 3 times daily lowered A1C similarly to acarbose 100 mg 3 times daily ( 0.9% versus 1.1%, respectively). 13 In a study by Segal et al, glibenclamide 3.5 mg daily or twice daily lowered A1C by 1.01%, compared to miglitol 50 to 100 mg 3 times daily, which lowered it by 0.75%. Fasting plasma glucose decreased slightly and postprandial plasma decreased significantly in both groups compared to placebo. 14 have been found to have similar effects on A1C with the non-su secretagogues. 15 A study by Wolffenbuttel and Landgraf showed a decrease in A1C in the first 6 months for patients in both the glyburide ( mg daily) and repaglinide (0.5-4 mg 3 times daily) treatment arms. In the second 6 months, the A1C slightly increased in both groups. They have also been found to have equivalent effects on A1C and fasting plasma glucose with TZDs. 16 Table 3 Efficacy of Oral Antidiabetic Agents in Reducing Fasting Plasma Glucose and A1C 3 Reduction in Fasting Plasma Glucose Reduction Drug Class (mg/dl) in A1C (%) Alpha-glucosidase inhibitors Thiazolidinediones Nonsulfonylurea secretagogues Metformin has been shown in placebo-controlled trials to reduce fasting plasma glucose by approximately 60 to 70 mg/dl and A1C by 1.5% to 2.0%. Like the sulfonylureas, the higher the fasting plasma glucose, the greater the magnitude of effect seen with metformin. 3 As previously mentioned, most studies comparing metformin with sulfonylureas found them to have equivalent efficacy in lowering A1C. 7 One study found metformin to be more efficacious in decreasing A1C than glipizide. 12 Metformin has also been compared to alpha-glucosidase inhibitors. In a study by Hoffmann and Spengler, metformin 850 mg twice daily was compared to acarbose 100 mg 3 times daily. Acarbose lowered A1C by 1.1%, metformin decreased it by 1.0%, and placebo increased it by 0.4%. Both metformin and acarbose decreased fasting and postprandial plasma glucose. Even though metformin was found to have equivalent efficacy to acarbose, the dose of metformin used was less than maximal (850 mg twice daily). 17 In comparative trials, metformin has been shown to have equivalent efficacy to TZDs. A study by Inzucchi et al found metformin 1000 mg twice daily and troglitazone 400 mg daily to lower both fasting (by 20%) and postprandial (by 25%) plasma glucose levels similarly. 18 Metformin has also been compared to non-su secretagogues. A study by Moses et al found usual doses of metformin to be equally efficacious in decreasing A1C to usual doses of repaglinide ( 0.3% versus 0.4%, respectively). 19 A study by Horton et al found metformin 500 mg 3 times orally daily to be slightly more effective than 42 JOURNAL OF PHARMACY PRACTICE 2004(17.1)

5 ORAL ANTIDIABETIC AGENTS nateglinide 120 mg 3 times daily in lowering A1C ( 0.8% versus 0.5%, respectively). 20 In the UKPDS, there was a reduction in diabetes-related end points, deaths, and myocardial infarctions with metformin compared to diet therapy. This benefit was not seen in the treatment arm that received combination therapy with a sulfonylurea and metformin. These patients had an increase in the risk of death compared to patients on sulfonylureas alone. The investigators are uncertain why these results occurred. 2 It may be due to selection bias, as the patients in the treatment arm who required combination therapy had longstanding, poorly controlled diabetes, which necessitated the combination therapy. Until another trial can be completed to prove or disprove these findings, the American Diabetes Association does not recommend changing the current guidelines for the use of metformin as monotherapy or in combination with a sulfonylurea. 2 Alpha-glucosidase Inhibitors Alpha-glucosidase inhibitors have been shown in placebo-controlled trials to reduce fasting plasma glucose by 25 to 30 mg/dl and A1C by 0.7% to 1.0%. 3 These agents have been found to have equivalent or less efficacy than low-dose sulfonylureas in comparative trials 13,14 and have been found to be equally efficacious to low-dose metformin. 17 Alpha-glucosidase inhibitors are more effective in lowering postprandial glucose levels than preprandial glucose levels because they are dosed with meals and have a short onset/offset. They can decrease postprandial glucose levels by 40 to 50 mg/dl compared to placebo. 3 TZDs TZDs have been shown in placebo-controlled trials to reduce fasting plasma glucose by 35 to 40 mg/dl and A1Cby0.7%to1.0%. 3 As stated above, they have been shown to have equivalent efficacy to sulfonylureas and metformin in comparative studies. 16,18 A study by Raskin et al found repaglinide 0.5 to 4.0 mg with meals to be more effective than troglitazone 200 to 600 mg orally daily at reducing A1C ( 0.8 versus 0.4%, respectively). 21 Non-SU Secretagogues Repaglinide has been shown in placebo-controlled trials to reduce fasting plasma glucose by 60 to 70 mg/ dl and A1C by 1.5% to 2.0%. 3 Nateglinide may have a little less efficacy, as it has been shown to lower A1C by 0.5% to 1%. 7,11 As stated above, they have been shown to be equally effective to sulfonylureas and more effective than troglitazone in comparative trials. 14,20 As stated above, a study found repaglinide to be equally efficacious to metformin, and another study found nateglinide to be less efficacious than metformin. 19,20 These agents may have a more important role in lowering postprandial hyperglycemia. 11 SAFETY The 5 classes of oral antidiabetic agents have some similar and different side effects, contraindications, and drug interactions. All oral antidiabetic agents can have their effects increased by drugs that can decrease blood glucose, such as nonsteroidal anti-inflammatory drugs, nonselective β-blockers, and monoamine oxidase inhibitors. Drugs that can increase blood glucose, such as corticosteroids, thiazide diuretics, and thyroid preparations, can decrease their effect. 22 Tables 4 and 5 compare the oral antidiabetic agents with respect to safety. are generally well tolerated. About 2% to 5% of patients report side effects with sulfonylureas. 3 Hypoglycemia and weight gain (typically 2 to 5 kg) are the major adverse effects. 3,7 The incidence of hypoglycemia varies somewhat among the agents. Hypoglycemia is especially a problem with the first-generation agents with long half-lives, in the elderly, in patients who frequently skip meals, and in patients who perform frequent intense exercise. Because of the presence of the sulfonyl component in their chemical structures, hypersensitivity can occur in patients with sulfa allergies. Patients with a sulfa allergy should use caution when taking sulfonylureas. 22 The cardiovascular risk found to be associated with tolbutamide in the University Group Diabetes Study in the 1970s has been questioned because of methodological problems in the study. The UKPDS did not find a higher rate of cardiovascular events in the sulfonylurea group compared to the control group. 3 are associated with many drug interactions. Calcium channel blockers, estrogen, isoniazid, niacin, oral contraceptives, phenytoin, and many other drugs can decrease the effect of sulfonylureas through various mechanisms (including decreased insulin re- JOURNAL OF PHARMACY PRACTICE 2004(17.1) 43

6 KOSKI Table 4 Side Effects and Contraindications/Warnings Associated With Oral Antidiabetic Agents 22 Contraindications/ Drug Class Side Effects Warnings Alpha-glucosidase inhibitors Thiazolidinediones Nonsulfonylurea secretagogues Hypoglycemia; weight gain; rash GI; vitamin B12 levels; lactic acidosis GI Edema/weight gain; increase liver enzymes; induce ovulation Hypoglycemia DKA; severe sulfa allergy Renal/hepatic disease; congestive heart failure; metabolic acidosis Cirrhosis; DKA; inflammatory bowel disease; renal impairment Class III or IV heart failure; DKA; liver disease DKA Note: GI = gastrointestinal side effects; DKA = diabetic ketoacidosis. Table 5 Drug Interactions Associated With Oral Antidiabetic Agents 22 Drug Class Drug Interaction Many Alcohol ( risk of lactic acidosis) Alpha-glucosidase inhibitors Thiazolidinediones effect by CYP 450 2C8 and 2C9 inhibitor-gemfibrozil Nonsulfonylurea secretagogues effect by CYP 450 3A4 inhibitors; effect by CYP 450 3A4 inducers Note: CYP = cytochrome p450 enzyme. lease, increased renal excretion, and increased hepatic metabolism). Azole antifungals, histamine-2 receptor antagonists, tricyclic antidepressants, and many other drugs can increase the effect of sulfonylureas through various mechanisms (including decreased hepatic metabolism, inhibition of renal excretion, displacement from protein binding sites, and decreased blood glucose). 22 Glimepiride is a cytochrome p450 2C9 substrate, so inhibitors of that enzyme (ie, amiodarone, cimetidine, fluoxetine, etc) will increase its effect, whereas inducers (ie, carbamazepine, phenobarbital, rifampin, etc) will decrease its effect. Glyburide is a cytochrome p450 3A4 substrate, so inhibitors of that enzyme (ie, erythromycin, clarithromycin, itraconazole, etc) will increase its effect, whereas inducers (ie, carbamazepine, phenobarbital, rifampin, etc) will decrease its effect. 22 Although the sulfonylureas are associated with many drug interactions, it is up to the clinician to decide which are clinically significant. About 20% to 30% of patients on metformin experience gastrointestinal (GI) side effects, such as nausea, abdominal discomfort, and diarrhea. These adverse effects can be minimized by titrating the dose up slowly. 3 There is a modest weight loss associated with the use of metformin. There are several proposed mechanisms for the weight loss. The weight loss has been attributed to a reduction in net caloric intake due to appetite suppression. The reduction in hyperinsulinemia related to insulin resistance may also contribute to weight loss in obese diabetics with insulin resistance. 23 The incidence of lactic acidosis that has been reported with metformin is 0.03 per 1000 patient-years of use. It is usually fatal in 30% to 50% of cases. 23 Any condition that predisposes a patient to hypoxia may increase the risk of lactic acidosis. Risk factors for lactic acidosis include renal (serum creatinine 1.5 mg/dl in men or 1.4 mg/dl in women) or hepatic impairment, respiratory insufficiency, severe infection, alcohol abuse, and heart failure. Metformin is contraindicated in patients with any of these risk factors. Metformin should also be used with caution in elderly patients (especially those older than 80 years of age) with reduced lean body mass, as their low serum creatinine concentrations would fail to detect a decrease in the glomerular filtration rate. It is recommended to monitor renal function before initiating metformin and at least annually thereafter. 24 Metformin should be withheld 48 hours before a patient receives radiocontrast dye for a procedure (ie, intravenous pyelogram), as these patients are more at risk of developing renal failure and lactic acidosis while on metformin. It should also be withheld for surgical procedures. It can be restarted 48 hours after a procedure if the patient s renal function is normal and his or her condition is stable. 3 Metformin may interfere with vitamin B12 absorption and may lower serum vitamin B12 concentrations. It is rarely associated with anemia. It was observed in 7% of patients in controlled clinical trials. It appears to be rapidly reversible with discontinuation of metformin. It is recommended to monitor hematologic parameters at baseline and at least annually thereafter. The mechanism for this interaction is unknown. 13 Alpha-glucosidase Inhibitors Alpha-glucosidase inhibitors are associated with GI side effects, such as abdominal discomfort (11%-21%), diarrhea (28%-33%), and flatulence (41%-77%), in many patients who take these agents. The effects tend to decrease with continued drug use and can be mini- 44 JOURNAL OF PHARMACY PRACTICE 2004(17.1)

7 ORAL ANTIDIABETIC AGENTS mized by titrating the dose up slowly. The GI symptoms are related to the presence of undigested carbohydrates in the lower GI tract. These agents are contraindicated in patients with inflammatory bowel disease, intestinal obstruction, or predisposition to obstruction, cirrhosis, and renal impairment (serum creatinine > 2 mg/dl). 25,26 TZDs TZDs are associated with edema and weight gain (about 2 kg), and they are contraindicated in patients with New York Heart Association class III or IV heart failure. Due to the expansion of extracellular fluid space, dose-related dilutional anemia (decreased hemoglobin about 1g/dL, hematocrit about 3.3%) can be seen. 3 TZDs have been shown to induce ovulation in patients with polycystic ovary syndrome. 22 Premenopausal and perimenopausal women must be made aware of this possibility. Pioglitazone and rosiglitazone have been associated with an increase in aspartate aminotransferase and alanine aminotransferase greater than 3 times the upper limit of normal at an incidence similar to placebo (0.25%). They should be used with caution in patients with hepatic impairment. Troglitazone was taken off of the U.S. market in 2000 (2 years after it was approved in the United States) due to reports of idiosyncratic hepatocellular injury (560 reports of hepatotoxicity in the first 6 months in the United States). Pioglitazone and rosiglitazone do not share the hepatotoxic profile of troglitazone. It may be because the structures of these agents differ from troglitazone. Troglitazone has a unique tocopherol side chain that may have contributed to its hepatotoxic effects. Also, troglitazone is the only TZD that induces cytochrome P450 3A4, so it has been postulated that patients with a polymorphism in these enzymes are more at risk for hepatotoxicity. 27 Patients on a TZD should have their liver enzymes monitored before initiation of therapy, every 2 months for the first year, and periodically after that. These agents should be discontinued if alanine aminotransferase levels remain elevated above 3 times the upper limit of normal. 28,29 Non-SU Secretagogues Like sulfonylureas, non-su secretagogues can cause hypoglycemia. Unlike sulfonylureas, non-su secretagogues do not have a sulfonyl component, and so there is no risk of allergic reactions in patients with a sulfa allergy. Repaglinide is metabolized by cytochrome p450 3A4, and nateglinide is metabolized by both cytochrome p450 2C9 and 3A4. Inhibitors of those enzymes will increase their effect, whereas inducers will decrease their effect. 30,31 DOSING The recommended dose ranges for the oral antidiabetic agents and their average wholesale prices are listed in Table 6. The recommended doses for the various sulfonylureas differ. The first-generation agents have a lower binding affinity to the receptor on the β-cells, so they must be given in higher doses than the secondgeneration agents, which have a higher binding affinity. should be started at low doses and titrated up every 1 to 4 weeks. 3 The majority of the hypoglycemic action of sulfonylureas is usually observed with half of the maximum daily dose. 7 The significance of dosing oral antidiabetic agents up to their maximally effective dose (not their maximum daily dose) is for cost savings, avoidance of prolonged therapy that may not work, and more timely addition of another agent. The starting dose for metformin is 500 mg orally twice daily. 24 It should be taken with the two largest meals of the day to minimize the GI effects. The antihyperglycemic effects start to occur in less than a week. The dose should be increased by 500 mg orally daily every 2 weeks, up to a maximum daily dose of 2550 mg. Many physicians titrate the daily dose up to a maximum of 2000 mg, as the antihyperglycemic action of this agent plateaus at that dose. 3 Metformin XR should be started at a dose of 500 mg orally once daily with the evening meal. It can be titrated every 2 weeks up to 2000 mg daily. 24 Alpha-glucosidase Inhibitors To minimize the GI adverse effects, both acarbose and miglitol should be initiated at low doses (25 mg once or twice orally daily) and titrated up every 2 to 4 weeks to a maximum dose of 100 mg 3 times daily. 25,26 These agents only work in the presence of food, especially foods containing sucrose or starch. They should be taken with the first bite of a meal because they need to be present with food in the small intestines to work. JOURNAL OF PHARMACY PRACTICE 2004(17.1) 45

8 KOSKI Table 6 Doses and Costs Associated with Oral Antidiabetic Agents 22 Drug Dose a Price for 1-Month Supply (Generic) Low doses Acetohexamide (Dymelor ) mg QD (QD-BID) 250 mg BID; no data Chlorpropamide (Diabinese ) mg QD 250 mg QD $27.50 ($9.00) Tolazamide (Tolnase ) mg QD (QD-BID) 250 mg QD $34.00 ($6.00) Tolbutamide (Orinase ) mg QD (BID-TID) 500 mg BID $23.73 ($14.99) Glimepiride b (Amaryl ) 1-8 mg QD 2 mg QD $16.99 Glipizide b (Glucotrol mg QD (BID) 5 mg BID $26.99 ($9.99) Glucotrol XL ) 5-20 mg QD 10 mg QD $24.99 Glyburide b (Diabeta mg QD (BID) 2.5 mg BID $26.70 Micronase ) QD mg (BID) 2.5 mg BID $41.98 ($15.98) Micronized Glyburide b (Glynase ) mg QD 3 mg QD $25.00 ($10.50) Metformin (Glucophage mg QD (BID-TID) 500 mg TID $70.49 ($50.99) Glucophage XR ) mg QD 1500 mg QD $67.49 Alpha-glucosidase inhibitors Acarbose (Precose ) mg with meals 25 mg TID $56.99 Miglitol (Glyset ) mg with meals 25 mg TID $51.99 Thiazolidinediones Pioglitazone (Actos ) mg QD 15 mg QD $90.99 Rosiglitazone (Avandia ) 4-8 mg QD (QD-BID) 2 mg BID $ Nonsulfonylurea secretagogues Nateglinide (Starlix ) mg with meals 60 or 120 mg TID $86.00 Repaglinide (Prandin ) mg with meals 0.5, 1, or 2 mg TID $80.99 Combinations Glyburide/metformin (Glucovance ) 1.25/250 mg QD; 10/1000 mg BID All strengths $52.99 Glipizide/metformin (Metaglip ) 2.5/250; 10/2000 mg QD (BID) All strengths $59.99 Rosiglitazone/metformin (Avandamet ) 1/500; 8/2000 mg QD (BID) 1/500 mg BID $61.99; 4/500 mg BID $ Note: Average wholesale prices were retrieved August 1, 2003, from QD = once a day; BID = 2 times a day; TID = three times a day. a. Total daily dose is listed, but the dose interval in parentheses represents the preferred interval at which the daily dose should be given. b. Second-generation sulfonylureas. If a meal is skipped (or added), the alpha-glucosidase inhibitor dose for that meal should be skipped (or added). 3 TZDs Pioglitazone should be initiated at 15 mg orally daily and titrated every 3 to 4 weeks up to a maximum dose of 45 mg orally daily. Rosiglitazone should be initiated at 4 mg once daily orally (or 2 mg twice daily orally) and titrated every 3 to 4 weeks up to a maximum daily dose of 8 mg. 3 The maximum daily doses listed for these agents are also the maximally effective doses. These agents have a relatively slow onset of action, so the full effect may not be seen for up to 4 months. 10 Non-SU Secretagogues Repaglinide should be initiated at 0.5 mg 3 times daily orally with meals and titrated up to a maximum daily dose of 16 mg. 30 The majority of the hypoglycemic effect is achieved with 1 mg 3 times daily. 3 Nateglinide should be initiated at a dose of 60 mg 3 times daily orally and titrated up to a maximum daily dose of 360 mg. If a meal is skipped (or added), the dose for that meal should be skipped (or added). The dose should be taken 1 to 30 minutes prior to meals. 31 INITIAL DRUG SELECTION Considerations for selecting an initial oral antidiabetic agent for a patient include the patient s age, body weight, comorbidities, compliance, and target goals and each drug s Food and Drug Administration approved indications, adverse effects, contraindications, drug interactions, and cost. Table 7 lists the Food and Drug Administration-approved indications for the oral antidiabetic agents. The UKPDS provides strong evidence for the use of sulfonylureas and metformin as first-line agents. 2 Factors that predict a good response 46 JOURNAL OF PHARMACY PRACTICE 2004(17.1)

9 ORAL ANTIDIABETIC AGENTS to sulfonylureas include recently diagnosed diabetes, mild to moderate fasting hyperglycemia, good β-cell function as reflected by a high-fasting C-peptide level, no history of insulin therapy, and absence of islet cell or glutamic acid antibodies. 4 Metformin would be a reasonable first choice for patients with type 2 diabetes who are overweight (or normal weight) or have lipid profile abnormalities. Because alpha-glucosidase have only modest efficacy in reducing fasting plasma glucose (~30 mg/dl), they would be appropriate agents for patients with mild diabetes or those taking other oral antidiabetic agents who continue to experience significantly elevated postprandial glucose levels. Non-SU secretagogues would be appropriate for patients with contraindications to the sulfonylureas, with erratic lifestyles (at risk of hypoglycemia from longer acting sulfonylureas), or with significant postprandial hyperglycemia. TZDs would be appropriate for patients who should start with an insulin sensitizer because of known insulin resistance. Drug Table 7 Food and Drug Administration (FDA) approved Indications for Oral Antidiabetic Agents 22 (Metformin) Alpha-glucosidase inhibitors Thiazolidinediones Nonsulfonylurea secretagogues Glucovance Metaglip Avandamet FDA-approved Indications Monotherapy or with metformin, alphaglucosidase inhibitors, thiazolidinediones, or insulin Monotherapy or with sulfonylurea or insulin Monotherapy or with sulfonylurea, metformin, or insulin (Miglitol only approved for use with sulfonylurea) Monotherapy or with sulfonylurea, metformin, or insulin (Rosiglitazone not approved for use with insulin) Monotherapy or with metformin Monotherapy or in combination with a thiazolidinedione Monotherapy Monotherapy COMBINATION THERAPY If a patient fails to achieve the target fasting plasma glucose and A1C levels with monotherapy, combination therapy can be used. Most combinations of the oral antidiabetic agents have been studied. Most of the trials found the reduction in A1C to be additive. 7 There are several reasons patients may fail monotherapy for their type 2 diabetes. First, results from the UKPDS have shown that sulfonylureas and metformin have a duration of action of about 5 years, after which patients require a change or addition in their diabetes therapy. 32 At 3 years, 50% of the patients in the UKPDS achieved the glycemic goals with monotherapy. At 9 years, only 25% of the patients were at goal with monotherapy. The conclusion was that because diabetes is a progressive disease, the majority of patients need multiple therapies to attain the target glycemic levels. 33 Second, patients may fail monotherapy due to noncompliance with their therapy. This may be due to adverse effects, cost of obtaining the medicine, or other reasons. The choice of which oral antidiabetic agent to add depends on which agent was first initiated and individual patient characteristics. Most oral antidiabetic agents can be combined with other oral antidiabetic agents. It is best to combine two agents with different mechanisms of action. It would not make sense to combine a sulfonylurea with a non-su secretagogue because they have similar mechanisms of action. There are combination pills available, including glyburide and metformin (Glucovance ), glipizide and metformin (Metaglip ), and rosiglitazone and metformin (Avandamet ). 22 These agents have limited dosage options, but they may be convenient for the patient. At higher doses, they may not offer convenience for the patient, as multiple tablets would need to be given twice a day. The oral agents can also be used in combination with insulin. 7 Some patients may be on 3 oral agents before being transitioned to insulin, although there are no published randomized trials to support this therapy. 10 CONCLUSION Type 2 diabetes is a chronic disease that usually requires drug therapy. Oral drug therapy should be tried before starting insulin. All of the available oral antidiabetic agents are effective in lowering plasma glucose and A1C levels. Choosing the agent that best fits the individual diabetic patient will enhance efficacy, safety, and compliance with therapy. REFERENCES 1. Mayerson AB, Inzucchi SE. Type 2 diabetes therapy: a pathophysiologically based approach. Postgrad Med. 2002;111: American Diabetes Association. Implications of the United Kingdom Prospective Diabetes Study. Diabetes Care. 2003;26(suppl 1):S28-S DeFronzo RA. Pharmacologic therapy for type 2 diabetes mellitus. AnnInternMed. 1999;131: JOURNAL OF PHARMACY PRACTICE 2004(17.1) 47

10 KOSKI 4. Amaryl. Physicians Desk Reference. 57th ed. Montvale, NJ: 5. Bailey CJ, Turner RC. Metformin. N Engl J Med. 1996;334: Lebovitz HE. Alpha-glucosidase inhibitors. Endocrinol Metab Clin North Am. 1997;26: Inzucchi SE. Oral antihyperglycemic therapy for type 2 diabetes. JAMA. 2002;287: Shimabukuro M, Zhou Y-T, Lee Y, et al. Troglitazone lowers islet fat and restores beta cell function of Zucker diabetic fatty rats. J Biol Chem. 1998;273: Weissman PN. Reappraisal of the pharmacologic approach to treatment of type 2 diabetes mellitus. Am J Cardiol. 2002;90(suppl):42G-50G. 10. Ahmann AJ, Riddle MC. Current oral agents for type 2 diabetes: many options, but which one to choose when? Postgrad Med. 2002;111: Sheehan MT. Current therapeutic options in type 2 diabetes mellitus: a practical approach. CM&R. 2003;1: Campbell IW, Menzies DG, Chalmers J, et al. One year comparative trial of metformin and glipizide in type 2 diabetes mellitus. Diabetes Metab. 1994;20: Hoffmann J, Spengler M. Efficacy of 24-week monotherapy with acarbose, glibenclamide, or placebo in NIDDM patients: the Essen Study. Diabetes Care. 1994;17: Segal P, Feig PU, Schernthaner G, et al. The efficacy and safety of miglitol therapy compared with glibenclamide in patients with NIDDM inadequately controlled by diet alone. Diabetes Care. 1997;20: Wolffenbuttel BH, Landgraf R. A 1-year multi-center, randomized double-blind comparison of repaglinide and glyburide for the treatment of type 2 diabetes: Dutch and German Repaglinide Study Group. Diabetes Care. 1999;22: Horton ES, Whitehouse F, Ghazzi MN, et al. Troglitazone in combination with sulfonylureas restores glycemic control in patients with type 2 diabetes: the troglitazone study group. Diabetes Care. 1998;21: Hoffmann J, Spengler M. Efficacy of 24-week monotherapy with acarbose, metformin, or placebo in dietary-treated NIDDM patients: the Essen-II Study. Am J Med. 1997;103: Inzucchi SE, Maggs DG, Spollett GR, et al. Efficacy and metabolic effects of metformin and troglitazone in type II diabetes mellitus. N Engl J Med. 1998;338: Moses R, Slobodniuk R, Boyages S, et al. Effect of repaglinide addition to metformin monotherapy on glycemic control in patients with type 2 diabetes. Diabetes Care. 1999;22: Horton ES, Clingingbeard C, Gatlin M, et al. Nateglinide alone and in combination with metformin improves glycemic control by reducing mealtime glucose levels in type 2 diabetes. Diabetes Care. 2000;23: Raskin P, Jovanovic L, Berger S, et al. Repaglinide/troglitazone combination therapy: improved glycemic control in patients with type 2 diabetes. Diabetes Care. 2000;23: Wickersham RM, Novak KK, managing eds. Drug Facts and Comparisons. St. Louis, MO: Kluwer; Kirpichnikov D, McFarlane SI, Sowers JR. Metformin: an update. AnnInternMed. 2002;137: Glucophage. Physicians Desk Reference. 57th ed. Montvale, NJ: 25. Precose. Physicians Desk Reference. 57th ed. Montvale, NJ: 26. Glyset. Physicians Desk Reference. 57th ed. Montvale, NJ: 27. Scheen AJ. Hepatotoxicity with thiazolidinediones: is it a class effect? Drug Saf. 2001;24: Avandia. Physicians Desk Reference. 57th ed. Montvale, NJ: 29. Actos. Physicians Desk Reference. 57th ed. Montvale, NJ: 30. Prandin. Physicians Desk Reference. 57th ed. Montvale, NJ: 31. Starlix. Physicians Desk Reference. 57th ed. Montvale, NJ: 32. Nathan DM. Initial management of glycemia in type 2 diabetes mellitus. N Engl J Med. 2002;347: Turner RC, Cull CA, Frighi V, et al. Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: progressive requirement for multiple therapies (UKPDS 40). JAMA. 1999;281: JOURNAL OF PHARMACY PRACTICE 2004(17.1)