A Review of Oral Antidiabetic Agents

Volume IV, Number 3 | May/June 2001
Jeff Ketz, Pharm.D., BCPS

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The benefits of meeting optimal blood glucose goals in diabetic patients are now well understood due to data from many clinical trials (See Table 1). Currently, a variety of oral medications such as sulfonylureas, biguanides, thiazolidinediones, meglitinides, and alpha-glucosidase inhibitors are available to treat type 2 diabetes. Medication regimens should be based on patient-specific factors to optimize blood glucose control and minimize morbidity and mortality. Several factors should be considered when choosing a medication regimen including desired glycemic control, patients' weight and lipid profile, contraindications, and cost..

Table 1:  Glycemic Goals for Patients* with Diabetes
  Goal Action Recommended
Pre-prandial glucose
80-120 mg/dl < 80 mg/dl or > 140 mg/dl
Bedtime glucose 100-140 mg/dl < 100 mg/dl or > 160 mg/dl
Hemoglobin A1c <7% >8%

*Non-pregnant patients
Adapted from Diabetes Care 1998;21(Suppl 1):S23-31.


Sulfonylureas have long been the cornerstone in managing type 2 diabetes. Some examples of sulfonylureas include glyburide (Diabeta®), glipizide (Glucotrol®), and glimepiride (Amaryl®). Sulfonylureas primarily work by increasing endogenous insulin secretion; therefore, they must be used in patients with viable ß-cells. Sulfonylurea monotherapy can lower fasting plasma glucose (FPG) by 60 to 70 mg/dl and lower hemoglobin A1c by 1.5 to 2%. The most significant adverse effects of sulfonylureas are: 1) hypoglycemia which occurs in 2 to 4% of patients per year and 2) weight gain (approximately 4 to 6 kg). Additionally, less common side effects include dermatological and hematological reactions and gastrointestinal disturbances. Sulfonylureas have no effect on triglycerides or cholesterol. The majority of sulfonylureas undergo renal elimination. For example, chlorpropamide should not be used in patients with renal dysfunction (20% is excreted unchanged in the urine) and the active metabolites of glyburide can accumulate in patients with a creatinine clearance less than 30 ml/min. Glipizide is preferred in patients with moderate to severe renal dysfunction. Finally, compared to other oral antidiabetic medications, the sulfonylureas are the least expensive.


Metformin (Glucophage®; Glucophage® XR) is the only biguanide FDA-approved for use in the United States. Metformin acts by decreasing hepatic glucose production, decreasing glucose absorption, and increasing glucose uptake into skeletal muscle. Metformin monotherapy can lower FPG by 60 to 70 mg/dl and lower hemoglobin A1c by 1.5 to 2%. Metformin also decreases triglyceride concentrations, LDL cholesterol, total cholesterol, and body weight, and increases HDL cholesterol. When used as monotherapy, metformin has not been associated with hypoglycemia. Gastrointestinal disturbances (20%) are common including: nausea, abdominal pain, bloating, anorexia, metallic taste and diarrhea. These side effects can be minimized by starting with a low dose, titrating slowly, and by taking metformin with food. Additionally, asymptomatic subnormal B12 levels may occur. Metformin undergoes renal excretion. Lactic acidosis can occur with the administration of metformin, but is extremely rare (occurrence of 3 cases per 100,000 patient years). Patients presenting with vague, flu-like illness should be assessed for presence of lactic acidosis. Metformin is contraindicated in 1) patients with serum creatinine >1.5 (males) and >1.4 (females), 2) patients with hepatic dysfunction, 3) patients with congestive heart failure requiring pharmacologic treatment, 4) patients with a history of binge drinking, and 5) patients with acute or chronic lactic acidosis. Metformin should be used with caution in the elderly, in patients with congestive heart failure, and in patients with acute conditions predisposing them to acute renal failure or acidosis. Additionally, patients undergoing procedures requiring radiographic contrast media should have metformin discontinued prior to the procedure, withheld 48 hours post-procedure, and should not be restarted until the patient's renal function has been evaluated as normal. Renal and hepatic function, as well as routine hematology, should be tested at least annually for patients taking metformin.


Rosiglitazone (Avandia®) and pioglitazone (Actos®) are the two thiazolidinediones FDA-approved for use in the United States. Troglitazone (Rezulin®) was removed from the market due to hepatotoxicity. Thiazolidinediones act 1) by stimulating the PPAR (peroxisome proliferative-insulin-activated receptors) gamma receptor which cause insulin sensitizing effects on skeletal muscle and adipose tissue and 2) by inhibiting hepatic gluconeogenesis. Thiazolidine-diones decrease the insulin requirements of type 2 diabetics. Thiazolidinediones decrease FPG by 35 to 40 mg/dl and lower hemoglobin A1c by 0.5 to 1.5%. When used as monotherapy, both rosiglitazone and pioglitazone have not been associated with hypoglycemia. Thiazolidinediones are associated with a 1 to 4 kg weight gain. Rosiglitazone raises HDL; however, it may also slightly raise LDL cholesterol with minimal effect on triglyceride concentrations. In comparison, pioglitazone raises HDL, has minimal effect on LDL cholesterol, and decreases triglyceride concentrations. Thiazolidinediones may cause increases in plasma volume that result in edema and small decreases in hemoglobin and hematocrit. Rosiglitazone and pioglitazone should be used with caution in patients with advanced congestive heart failure (NYHA Class III/IV). It is also important to note that pioglitazone may decrease the concentration of conjugated oral contraceptives (COCs). Therefore, patients taking pioglitazone and COCs should be informed of this potential interaction. Additionally, thiazolidinediones may cause resumption of ovulation in premenopausal anovulatory women. The clearance of rosiglitazone and pioglitazone is decreased in patients with moderate to severe liver disease. Rosiglitazone and pioglitazone should not be used if ALT values are greater than 2.5 times the upper limit of normal. Additionally, for both agents, liver function tests should be monitored every 2 months for 1 year, then periodically thereafter.


Repaglinide (Prandin®) and nateglinide (Starlix®) are the two meglitinides FDA-approved for use in the United States. Even though meglitinides act at the same receptor as sulfonylureas to stimulate pancreatic insulin secretion, they differ from sulfonylureas by possessing a rapid onset and short duration of action to lower post-prandial glucose. As monotherapy (in six-month trials), repaglinide and nateglinide decrease FPG by 31 mg/dl and 13 mg/dl, respectively, and hemoglobin A1c by 0.6% and 0.4%, respectively. Longer studies with repaglinide demonstrate a decrease in hemoglobin A1c of 1.4 to 1.8%. The incidence of hypoglycemia associated with meglitinides is less than or equal to the incidence of sulfonylurea-induced hypoglycemia. The meglitinides have no effect on cholesterol but may increase body weight. These agents work best at high glucose concentrations, therefore, should be administered prior to or with meals.

Alpha-Glucosidase Inhibitors

There are two alpha-glucosidase inhibitors FDA-approved for use in the United States, acarbose (Precose®) and miglitol (Glyset®). Alpha-glucosidase inhibitors block the action of alpha-glucosidase enzymes at the brush border of the intestine. The inhibition slows the breakdown of dietary oligosaccharides and disaccharides. The delayed digestion of carbohydrates decreases post-prandial glucose concentrations. As monotherapy, alpha-glucosidase inhibitors lower FPG by 20 to 30 mg/dl and hemoglobin A1c by 0.7 to 1%. Additionally, acarbose and miglitol decrease post-prandial glucose by 30 to 70 mg/dl. Acarbose and miglitol have minimal effect on cholesterol and body weight. Gastrointestinal adverse events are common including: abdominal pain (21%), diarrhea (33%), and flatulence (77%). Acarbose may cause elevations in liver function tests; therefore, it is recommended to monitor hepatic enzymes every 3 months for 1 year, then periodically thereafter. In contrast, miglitol is excreted primarily by the kidneys, and should be used with caution in moderate to severe renal failure. It is important to note that pancreatic enzyme tablets will reduce effectiveness of acarbose and miglitol. Patients taking alpha-glucosidase inhibitors should not use table sugar or soft drinks (sucrose) to raise blood glucose during hypoglycemic events. Milk, apple/orange juice, or glucose tablets should be used to reverse hypoglycemia instead because the absorption rates of sucrose and other complex carbohydrates are drastically reduced with the administration of alpha-glucosidase inhibitors.

Combination Product

Glucovance® is a fixed combination of glyburide and metformin. This combination decreases FPG by 50 to 60 mg/dl and hemoglobin A1c by 1.7 to 1.9%. These reductions are greater than that of glyburide or metformin monotherapy. The primary advantage of Glucovance® may be increased patient compliance. The use of combination therapy provides additional glucose lowering effects. Some examples of combination therapy are listed in Table 2.

Table 2:  Combination Therapy with Oral Antidiabetic Agents
Combination Additional Reduction in FPG (mg/dl) Additional Reduction in Hemoglobin A1c (%)
-34 compared to glyburide alone -0.6 compared to glyburide alone
Sulfonylurea*/Pioglitazone** -58 compared to sulfonylurea alone -1.3 compared to sulfonylurea alone
Sulfonylurea*/Rosiglitazoneˆ -48 compared to sulfonylurea alone -0.8 compared to sulfonylurea alone
Glyburide/Metformin -63 compared to glyburide alone -1.7 compared to glyburide alone
Metformin/Acarbose -34 compared to metformin alone -0.6 compared to metformin alone
Metformin/Pioglitazone** -38 compared to metformin alone -0.8 compared to metformin alone
Metformin/Rosiglitazoneˆ -56 compared to metformin alone -0.8 compared to metformin alone

*Sulfonylurea not specified;
**The dose used was 30 mg;
ˆ The dose used was 8 mg


All newly diagnosed patients with type 2 diabetes should have an initial trial of dietary and exercise modifications. However, many patients require pharmacologic treatment without an optimal trial of nutrition and physical activity. Monotherapy with a sulfonylurea or metformin can be used as first-line pharmacotherapy. However, if FPG is >250 mg/dl or random blood glucose is >400 mg/dl, insulin should be considered as initial therapy. Other agents may be added if monotherapy provides inadequate control. If elevations in post-prandial glucose are problematic, meglitinides and alpha-glucosidase inhibitors may be beneficial. Insulin may be added to oral agents to provide additional blood glucose control.

Oral antidiabetic agents (Table 3) can be used alone or in combination to provide effective therapy for type 2 diabetes. When selecting an oral antidiabetic agent, the effects on glucose, lipids, adverse reaction profile, and route of elimination should be considered. Pharmacologic therapy should be tailored to the goals and needs of each individual patient.

Table 3:  Oral Antidiabetic Agents
Drug Dose Range Notes:
Glyburide (DiaBeta®, Micronase®)
1.25 to 20 mg QD or divided BID Glipizide is best absorbed when taken 30 minutes prior to meals. Elderly patients and those with decreased renal function should be started on lowest doses.
Glyburide SR (Glynase®) 1.5 to 12 mg QD  
Glipizide (Glucotrol) 5 to 40 mg QD or divided BID  
Glipizide SR (Glucotrol® XL) 5 to 20 mg QD  
Glimepiride (Amaryl®) 1 to 8 mg QD  
Metformin (Glucophage®) Initial dose: 500 BID
Maximum dose: 2550 mg/day divided BID or TID WM
Note cautions in renal impairment. Note cautions for patients undergoing procedures requiring contrast media. Higher doses of Glucophage® may be the best tolerated given TID.
Glucophage® XR Initial dose: 500 QD
Maximum Dose: 2000 mg/day
Conversion from Glucophage® to Glucophage® XR: Same total daily dose, but once a day up to maximum daily dose of 2000 mg/day
Pioglitazone (Actos®) 15 to 45 mg QD Onset of action 2 weeks, maximum effects in 2 to 3 months. Thiazolidinediones may cause resumption of ovulation.
Rosiglitazone (Avandia®) 4 to 8 mg QD or divided BID  
Nateglinide (Starlix®) 60 to 120 mg TID WM Do not take dose if meal skipped.
Repaglinide (Prandin®) 0.5 to 4 mg TID to QID WM Maximum dose: 16 mg/day  
Acarbose (Precose®) 25 to 100 mg TID WM Take with first bite of meal. Initial dose 25 mg QD and titrate upward to minimize gastrointestinal effects.
Miglitol (Glyset®) 25 to 100 mg TID WM  
Glyburide/Metformin (Glucovance®) Initial dose: 1.25 mg glyburide/250 mg metformin QD,
Maximum dose: 10 mg glyburide/2000 mg metformin divided BID WM
See above notes for glyburide and metformin.

QD = once a day; BID = twice a day; TID = three times a day; WM = with meals
Adapted from the package of inserts of the above mentioned agents.

References Available Upon Request

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Center for Continuing Education | 1950 Richmond Road, TR204, Lyndhurst, OH 44124