Glyburide alone or in fixed combination with metformin hydrochloride is used as initial therapy as an adjunct to diet and exercise for the management of type 2 diabetes mellitus in patients whose hyperglycemia cannot be controlled by diet alone. Glyburide also may be used in combination with metformin as second-line therapy as an adjunct to diet and exercise for the management of type 2 diabetes mellitus in patients whose hyperglycemia cannot be controlled with glyburide or metformin monotherapy, diet, and exercise. Sulfonylureas, including glyburide, also may be used in combination with one or more other oral antidiabetic agents or insulin as an adjunct to diet and exercise for the management of type 2 diabetes mellitus in patients who do not achieve adequate glycemic control with diet, exercise, and oral antidiabetic agent monotherapy. A thiazolidinedione antidiabetic agent (e.g., rosiglitazone) has been added to therapy with the fixed combination of glyburide and metformin hydrochloride to improve glycemic control in patients not responding adequately to the fixed combination.
The American Diabetes Association (ADA) currently classifies diabetes mellitus into several subclasses including type 1 (immune mediated or idiopathic), type 2 (predominantly insulin resistance with relative insulin deficiency to predominantly an insulin secretory defect with insulin resistance), gestational diabetes mellitus, or that associated with certain conditions or syndromes (e.g., drug induced, hormonal, that associated with pancreatic disease, infections, specific genetic defects or syndromes). Type 1 diabetes mellitus was previously described as juvenile-onset (JOD) diabetes mellitus, since it usually occurs during youth. Type 2 diabetes mellitus was previously described as adult-onset (AODM) diabetes mellitus. However, type 1 or type 2 diabetes mellitus can occur at any age, and the current classification is based on pathogenesis (e.g., autoimmune destruction of pancreatic β cells, insulin resistance) and clinical presentation rather than on the age of onset. Many patients' diabetes mellitus does not easily fit into a single classification. Epidemiologic data indicate that the incidence of type 2 diabetes mellitus is increasing in children and adolescents such that 8-45% of children with newly diagnosed diabetes have nonimmune-mediated diabetes mellitus; most of these individuals have type 2 diabetes mellitus, although other types, including idiopathic or nonimmune-mediated type 1 diabetes mellitus, also have been reported.
Patients with type 2 diabetes mellitus have insulin resistance and usually have relative (rather than absolute) insulin deficiency. Most patients with type 2 diabetes mellitus (about 80-90%) are overweight or obese; obesity itself also contributes to the insulin resistance and glucose intolerance observed in these patients. Patients with type 2 diabetes mellitus who are not obese may have an increased percentage of abdominal fat, which is an indicator of increased cardiometabolic risk. While children with immune-mediated type 1 diabetes generally are not overweight, the incidence of obesity in children with this form of diabetes is increasing with the increasing incidence of obesity in the US population. Distinguishing between type 1 and type 2 diabetes in children may be difficult since obesity may occur with either type of diabetes mellitus, and autoantigens and ketosis may be present in a substantial number of children with features of type 2 diabetes mellitus (e.g., obesity, acanthosis nigricans).
Oral antidiabetic agents are not effective as sole therapy for patients with type 1 diabetes mellitus; insulin is necessary in these patients. Sulfonylurea antidiabetic agents are not routinely recommended in hospitalized patients with diabetes mellitus. Because of their long duration of action (24 hours with glyburide), sulfonylureas do not allow rapid dosage adjustments to meet changing needs of hospitalized patients. In addition, the risk of hypoglycemia during sulfonylurea therapy is increased in such patients with irregular eating patterns.
Patients with type 2 diabetes mellitus are not dependent initially on insulin (although many patients eventually require insulin for glycemic control) nor are they prone to ketosis; however, insulin may occasionally be required for correction of symptomatic or persistent hyperglycemia that is not controlled by dietary regulation or oral antidiabetic agents (e.g., sulfonylureas), and ketosis may occasionally develop during periods of severe stress (e.g., acute infections, trauma, surgery). Type 2 diabetes mellitus is a heterogeneous subclass of the disease, and subclassification criteria (e.g., basal and stimulated plasma insulin concentrations, insulin resistance) remain to be clearly established. Endogenous insulin is present in type 2 diabetic patients, although plasma insulin concentrations may be decreased, increased, or normal. In type 2 diabetic patients, glucose-stimulated secretion of endogenous insulin is frequently, but not always, reduced and decreased peripheral sensitivity to insulin is almost always associated with glucose intolerance.
Glycemic Control and Microvascular Complications
Current evidence from epidemiologic and clinical studies supports an association between chronic hyperglycemia and the pathogenesis of microvascular complications in patients with diabetes mellitus, and results of randomized, controlled studies in patients with type 1 or type 2 diabetes mellitus indicate that intensive management of hyperglycemia with near-normalization of blood glucose and glycosylated hemoglobin (hemoglobin A1c [HbA1c]) concentrations provides substantial benefits in terms of reducing chronic microvascular (e.g., retinopathy, nephropathy, neuropathy) complications associated with the disease. HbA1c concentration reflects the glycosylation of other proteins throughout the body as a result of recent hyperglycemia and is used as a predictor of risk for development of diabetic microvascular complications. Microvascular complications of diabetes are the principal causes of blindness and renal failure in developed countries and are more closely associated with hyperglycemia than are macrovascular complications.
In the Diabetes Control and Complications Trial (DCCT), the reduction in risk of microvascular complications in patients with type 1 diabetes mellitus correlated continuously with the reduction in HbA1c concentration produced by intensive insulin treatment (e.g., a 40% reduction in risk of microvascular disease for each 10% reduction in HbA1c. These data imply that any decrease in HbA1c levels is beneficial and that complete normalization of blood glucose concentrations may prevent diabetic complications. Data from the largest United Kingdom Prospective Diabetes Study (UKPDS) and other smaller studies in patients with type 2 diabetes mellitus are generally consistent with the same benefits on microvascular complications as those observed with type 1 diabetes mellitus in the DCCT study.
Data from long-term follow-up (over 10 years) of UKPDS patients with type 2 diabetes mellitus who received initial therapy with conventional (diet and oral antidiabetic agents or insulin to achieve fasting plasma glucose concentrations below 270 mg/dL without symptoms of hyperglycemia) antidiabetic treatment or intensive (stepwise introduction of a sulfonylurea [i.e., chlorpropamide, glyburide], then insulin, or an oral sulfonylurea and insulin, or insulin alone to achieve fasting plasma glucose concentrations of 108 mg/dL) antidiabetic regimens indicate that intensive treatment with monotherapy generally is not capable of maintaining strict glycemic control (i.e., maintenance of blood glucose concentrations of 108 mg/dL or normal values) over time and that combination therapy eventually becomes necessary in most patients to attain target glucose concentrations in the long term; in UKPDS, intensive treatment that eventually required combination therapy in most patients resulted in median HbA1c concentrations of 7%. Because of the benefits of strict glycemic control, the goal of therapy for type 2 diabetes mellitus is to lower blood glucose to as close to normal as possible, which generally requires aggressive management efforts (e.g., mixing therapy with various antidiabetic agents including sulfonylureas, metformin, insulin, and/or possibly others) over time. For additional information on clinical studies demonstrating the benefits of strict glycemic control on microvascular complications in patients with type 1 or 2 diabetes mellitus, .
Glycemic Control and Macrovascular Complications
Current evidence indicates that appropriate management of dyslipidemia, blood pressure, and vascular thrombosis provides substantial benefits in terms of reducing macrovascular complications associated with diabetes mellitus; intensive glycemic control generally has not been associated with appreciable reductions in macrovascular outcomes in controlled trials. Reduction in blood pressure to a mean of 144/82 mm Hg (''tight blood pressure control'') in patients with diabetes mellitus and uncomplicated mild to moderate hypertension in UKPDS substantially reduced the incidence of virtually all macrovascular (e.g., stroke, heart failure) and microvascular (e.g., retinopathy, vitreous hemorrhage, renal failure) outcomes and diabetes-related mortality; blood pressure and glycemic control were additive in their beneficial effects on these end points. While intensive antidiabetic therapy titrated with the goal of reducing HbA1c to near-normal concentrations (6-6.5% or less) has not been associated with appreciable reductions in cardiovascular events during the randomized portion of controlled trials examining such outcomes, results of long-term follow-up (10-11 years) from DCCT and UKPDS indicate a delayed cardiovascular benefit in patients treated with intensive antidiabetic therapy early in the course of type 1 or type 2 diabetes mellitus. For additional details regarding the effects of intensive antidiabetic therapy on macrovascular outcomes,
The ADA currently states that it is reasonable to attempt to achieve in patients with type 2 diabetes mellitus the same blood glucose and HbA1c goals recommended for patients with type 1 diabetes mellitus. Based on target values for blood glucose and HbA1c used in clinical trials (e.g., DCCT) for type 1 diabetic patients, modified somewhat to reduce the risk of severe hypoglycemia, ADA currently recommends target preprandial (fasting) and peak postprandial (1-2 hours after the beginning of a meal) plasma glucose concentrations of 70-130 and less than 180 mg/dL, respectively, and HbA1c concentrations of less than 7% (based on a nondiabetic range of 4-6%) in general in patients with type 1 or type 2 diabetes mellitus who are not pregnant. HbA1c concentrations of 7% or greater should prompt clinicians to initiate or adjust antidiabetic therapy in nonpregnant patients with the goal of achieving HbA1c concentrations of less than 7%. Patients with diabetes mellitus who have elevated HbA1c concentrations despite having adequate preprandial glucose concentrations should monitor glucose concentrations 1-2 hours after the start of a meal. Treatment with agents (e.g., α-glucosidase inhibitors, exenatide, pramlintide) that principally lower postprandial glucose concentrations to within target ranges also should reduce HbA1c.
More stringent treatment goals (i.e., an HbA1c concentration less than 6%) may be considered in selected patients. An individualized HbA1c goal that is closer to normal without risking substantial hypoglycemia is reasonable in patients with short duration of diabetes mellitus, no appreciable cardiovascular disease, and a long life expectancy. Achievement of HbA1c values of less than 7% is not appropriate or practical for some patients, and clinical judgment should be used in designing a treatment regimen based on the potential benefits and risks (e.g., hypoglycemia) of more intensified therapy. For additional details on individualizing treatment in patients with diabetes mellitus,
Considerations in Initiating and Maintaining Antidiabetic Therapy
When initiating therapy for type 2 diabetes mellitus who do not have severe symptoms, most clinicians recommend that diet be emphasized as the primary form of treatment; caloric restriction and weight reduction are essential in obese patients. Although appropriate dietary management and weight reduction alone may be effective in controlling blood glucose concentration and symptoms of hyperglycemia, many patients receiving dietary advice fail to achieve and maintain adequate glycemic control with dietary modification alone.
Recognizing that lifestyle interventions often fail to achieve or maintain the target glycemic goal within the first year of initiation of such interventions, ADA currently suggests initiation of metformin concurrently with lifestyle interventions at the time of diagnosis of type 2 diabetes mellitus. Other experts suggest concurrent initiation of lifestyle interventions and antidiabetic agents only when HbA1c values of 9% or greater are present at the time of diagnosis of type 2 diabetes mellitus. ADA and other clinicians state that lifestyle interventions should remain a principal consideration in the management of diabetes even after pharmacologic therapy is initiated. The manufacturer states that patients and clinicians should recognize that dietary management is the principal consideration in the management of diabetes mellitus and that antidiabetic therapy is used only as an adjunct to, and not as a substitute for or a convenient means to avoid, proper dietary management. In addition, loss of blood glucose control on diet alone may be temporary in some patients, requiring only short-term management with drug therapy. The importance of regular physical activity should also be emphasized, and cardiovascular risk factors should be identified and corrective measures employed when feasible. If lifestyle interventions alone are initiated and these interventions fail to reduce symptoms and/or blood glucose concentration, initiation of monotherapy with an oral antidiabetic agent (e.g., metformin, sulfonylurea, acarbose) or insulin should be considered.
Several large, long-term studies have evaluated the cardiovascular risks associated with the use of oral sulfonylurea antidiabetic agents.
(See Cautions: Precautions and Contraindications.)The ADA currently considers the beneficial effects of intensive glycemic control with insulin or sulfonylureas and blood pressure control (e.g., concomitant antihypertensive therapy) in diabetic patients to outweigh the risks overall.
Clinical studies indicate that glyburide is as effective as chlorpropamide, glipizide, tolazamide, or tolbutamide for the management of type 2 diabetes mellitus. A relative advantage compared with other sulfonylurea antidiabetic agents has not been clearly established. Some clinicians have suggested that, because of its diuretic action, glyburide may be particularly useful in patients with conditions associated with abnormal fluid retention. In some type 2 diabetic patients who are being treated with insulin, glyburide alone may be effective alternative therapy.
Clinical trial data indicate that sulfonylureas are as effective as metformin in lowering HbA1c (approximately 1.5% decrease) values, but such use is associated with hypoglycemia and weight gain. ADA generally recommends metformin as initial antidiabetic therapy because of the absence of weight gain or hypoglycemia, relatively low expense, and generally low adverse effect profile.
Glyburide may be useful in some patients with type 2 diabetes mellitus who have primary or secondary failure to other sulfonylurea antidiabetic agents; however, primary or secondary failure to glyburide may also occur.
Secondary failure to sulfonylurea drugs is characterized by progressively decreasing diabetic control following 1 month to several years of good control. Interim data from a substudy (UKPDS 26) of UKPDS in newly diagnosed type 2 diabetic patients receiving intensive therapy (maintenance of fasting plasma glucose below 108 mg/dL by increasing doses of either a sulfonylurea [i.e., glyburide or chlorpropamide] to maximum recommended dosage) showed that secondary failure (defined as fasting plasma glucose exceeding 270 mg/dL or symptoms of hyperglycemia despite maximum recommended daily dosage of 20 mg of glyburide or 500 mg of chlorpropamide) occurred overall at about 7% per year. The failure rate at 6 years was 48% among patients receiving glyburide and about 40% among patients receiving chlorpropamide. In the UKPD studies, stepwise addition of insulin or metformin to therapy with maximal dosage of a sulfonylurea was required periodically over time to improve glycemic control. In another substudy (UKPDS 49), progressive deterioration in diabetes control was such that monotherapy was effective in only about 50% of patients after 3 years and in only about 25% of patients after 9 years; thus, most patients require multiple-drug antidiabetic therapy over time to maintain such target levels of disease control. At diagnosis, risk factors predisposing toward sulfonylurea failure included higher fasting plasma glucose concentrations, younger age, and lower pancreatic β-cell reserve.
Glyburide is not effective as sole therapy in patients with diabetes mellitus complicated by acidosis, ketosis, or coma; management of these conditions requires the use of insulin.
Combination Therapy with Metformin or Other Oral Antidiabetic Agents
Sulfonylureas, including glyburide, may be used in combination with one or more other oral antidiabetic agents (e.g., metformin, thiazolidinedione derivatives, α-glucosidase inhibitors) as an adjunct to diet and exercise for the management of type 2 diabetes mellitus in patients who do not achieve adequate glycemic control with diet, exercise, and oral antidiabetic agent monotherapy. Combined therapy with metformin or other oral antidiabetic agents generally is used in patients with longstanding type 2 diabetes mellitus who have poor glycemic control with monotherapy.
ADA and other clinicians recommend initiating therapy with metformin and adding another antidiabetic agent, such as a sulfonylurea, insulin, or a thiazolidinedione if patients fail to achieve or sustain target HbA1c goals. Optimal benefit generally is obtained by addition of a second antidiabetic agent as soon as monotherapy with metformin at the maximum tolerated dosage no longer provides adequate glycemic control (i.e., when the target glycemic goal is not achieved within 2-3 months of initiation of therapy with metformin or at any other time when the target HbA1c goal is not achieved).
A major factor in choosing additional therapy is the degree of glycemic control obtained during metformin monotherapy. In patients with an HbA1c concentration exceeding 8.5% or symptoms secondary to hyperglycemia despite metformin monotherapy, ADA states that consideration should be given to adding insulin. When glycemic control is closer to the target HbA1c goal with metformin monotherapy (e.g., HbA1c less than 7.5%), agents with a lesser potential to lower hyperglycemia and/or slower onset of action may be considered (e.g., sulfonylurea, thiazolidinedione) as additional therapy to metformin. Other antidiabetic agents such as α-glucosidase inhibitors, meglitinides, exenatide, and pramlintide generally are less effective, less well studied, and/or more expensive than recommended therapies (i.e., metformin, sulfonylurea, thiazolidinedione, insulin). However, these agents may be appropriate for treatment of type 2 diabetes mellitus in selected patients.
Glyburide may be used concomitantly with metformin as initial therapy in the management of patients with type 2 diabetes mellitus whose hyperglycemia cannot be controlled by diet and exercise alone. In a 20-week, double-blind, randomized trial in drug-naive patients with type 2 diabetes mellitus whose hyperglycemia was inadequately controlled (baseline HbA1c values between 7 and 11%) by diet and exercise, treatment was initiated with either placebo, glyburide 2.5 mg, metformin hydrochloride 500 mg, or the fixed combination of glyburide 1.25 mg/metformin hydrochloride 250 mg or glyburide 2.5 mg/metformin hydrochloride 500 mg daily. The dosage of each therapy was progressively increased during weeks 4-8 to achieve a target fasting plasma glucose concentration of 126 mg/dL or to a maximum of 4 tablets daily. Patients receiving the fixed combination of glyburide and metformin had greater reductions in HbA1c and fasting plasma glucose concentrations than those receiving glyburide, metformin, or placebo; at the end of the study, strict glycemic control (e.g., HbA1c values less than 7%) was achieved in 59.9, 50.4, 66.4, or 71.7% of patients receiving mean dosages of glyburide 5.3 mg, metformin hydrochloride 1.32 g, glyburide 2.78 mg/metformin hydrochloride 557 mg, or glyburide 4.1 mg/metformin hydrochloride 824 mg, respectively.
In a comparative clinical trial in pediatric patients (9-16 years of age) with type 2 diabetes mellitus, therapy with glyburide in fixed combination with metformin hydrochloride (titrated to a final mean daily dosage of 3.1 mg of glyburide and 623 mg of metformin hydrochloride) was no more effective in improving glycemic control (as determined by reductions in HbA1c) than monotherapy with either component (titrated to a final mean daily dosage of 6.5 mg of glyburide or 1.5 g of metformin hydrochloride).
Glyburide also may be used concomitantly with metformin as second-line therapy in patients who do not achieve adequate control of hyperglycemia despite diet, exercise, and monotherapy with either glyburide (or another sulfonylurea antidiabetic agent) or metformin. In a double-blind, randomized study, patients with type 2 diabetes mellitus whose hyperglycemia was inadequately controlled (mean baseline HbA1c values: 9.5%, mean baseline fasting plasma glucose: 213 mg/dL) with oral sulfonylurea therapy at a dosage at least 50% of the maximum recommended daily dosage (e.g., glyburide 10 mg daily, glipizide 20 mg daily) received therapy with glyburide 20 mg (fixed dosage), metformin hydrochloride 500 mg, or the fixed combination of glyburide 2.5 mg/metformin hydrochloride 500 mg or glyburide 5 mg/metformin hydrochloride 500 mg daily. The dosages of metformin and the fixed-combination preparations were titrated to achieve a target fasting plasma glucose concentration of less than 140 mg/dL or to a maximum of 4 tablets daily. At 16 weeks, patients receiving the fixed combination of glyburide and metformin hydrochloride in daily dosages of up to 20 mg of glyburide and 2 g of metformin hydrochloride had lower HbA1c, fasting plasma glucose, and postprandial plasma glucose concentrations than patients receiving monotherapy with glyburide or metformin, who had no appreciable change in HbA1c values.
In a 24-week double-blind, randomized study, addition of rosiglitazone to therapy in patients not adequately controlled with the fixed combination of glyburide and metformin produced additional improvement in fasting plasma glucose concentrations and HbA1c values compared with the fixed-combination regimen. Strict glycemic control (e.g., HbA1c values less than 7%) was achieved in 42.4% of patients receiving the 3-drug combination regimen compared with 13.5% of those receiving the fixed combination of glyburide and metformin.
For additional information on combination therapy with sulfonylureas and other oral antidiabetic agents, see the sections on combination therapy in Uses in the individual monographs in 68:20.
When lifestyle interventions, metformin, and a second oral antidiabetic agent are not effective in maintaining the target glycemic goal in patients with type 2 diabetes mellitus, ADA and other clinicians generally recommend the addition of insulin therapy. In patients whose HbA1c is close to the target value (less than 8%) on metformin and a second oral antidiabetic agent, addition of a third oral antidiabetic agent instead of insulin may be considered. However, triple combination oral antidiabetic therapy is more costly and potentially not as effective as adding insulin therapy to dual combination oral antidiabetic therapy.
Combination Therapy with Insulin
Combined therapy with insulin and oral antidiabetic agents may be useful in some patients with type 2 diabetes mellitus whose blood glucose concentrations are not adequately controlled with maximal dosages of the oral agent and/or as a means of providing increased flexibility with respect to timing of meals and amount of food ingested. Concomitant therapy with insulin (e.g., given as intermediate- or long-acting insulin at bedtime or rapid-acting insulin at meal times) and one or more oral antidiabetic agents appears to improve glycemic control with lower dosages of insulin than would be required with insulin alone and may decrease the potential for body weight gain associated with insulin therapy. Oral antidiabetic therapy combined with insulin therapy may delay progression to either intensive insulin monotherapy or to a second daytime injection of insulin combined with oral antidiabetic therapy. However, combined therapy may increase the risk of hypoglycemic reactions.
ADA and other clinicians state that combined therapy with insulin and metformin with or without other oral antidiabetic agents is one of several options for the management of hyperglycemia in patients not responding adequately to oral monotherapy with metformin, the preferred initial oral antidiabetic agent. In patients with an HbA1c concentration exceeding 8.5% or symptoms secondary to hyperglycemia despite metformin monotherapy, ADA states that consideration should be given to adding insulin. When patients are not controlled with metformin with or without other oral antidiabetic agents (i.e., sulfonylurea, thiazolidinedione) and basal insulin (e.g., given as intermediate- or long-acting insulin at bedtime or in the morning), therapy with insulin should be intensified by adding additional short-acting or rapid-acting insulin injections at mealtimes. Therapy with insulin secretagogues (i.e., sulfonylureas, meglitinides) should be tapered and discontinued when intensive insulin therapy is initiated, as insulin secretagogues do not appear to be synergistic with such insulin therapy.
Misuse and Abuse
Some herbal dietary supplements promoted for the treatment of diabetes mellitus and purported to contain only natural Chinese herbal ingredients have been found to contain glyburide and phenformin (a biguanide similar to metformin but no longer commercially available in the US). Adulteration of these dietary supplements was discovered after use of one of the glyburide- and phenformin-containing dietary supplements by a patient with diabetes mellitus resulted in several episodes of hypoglycemia, from which the patient fully recovered. Restrictions on the importation and sale of these dietary supplements have been initiated by FDA.