Repaglinide is used as monotherapy as an adjunct to diet and exercise for the management of type 2 diabetes mellitus in patients whose hyperglycemia cannot be controlled by diet and exercise alone. Repaglinide also may be used in combination with metformin or a thiazolidinedione antidiabetic agent (e.g., pioglitazone, rosiglitazone) 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 monotherapy with metformin, a sulfonylurea, repaglinide, or a thiazolidinedione antidiabetic agent. Because of its short duration of action, repaglinide may be particularly suited for control of postprandial hyperglycemia in patients with type 2 diabetes mellitus. However, comparative studies are needed to elucidate the relative efficacy of repaglinide versus other short-acting sulfonylureas (e.g., tolbutamide).
The American Diabetes Association (ADA) currently classifies diabetes mellitus as 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- or chemical-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 previously was 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 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 mellitus 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 in patients with type 1 diabetes mellitus; insulin is necessary in these patients.
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 be required for correction of symptomatic or persistent hyperglycemia that is not controlled by dietary regulation or oral antidiabetic agents, and ketosis occasionally may develop during periods of severe stress (e.g., acute infection, trauma, surgery). Type 2 diabetes mellitus is a heterogeneous subclass of the disease; hyperglycemia in these patients often is accompanied by other metabolic abnormalities such as obesity, hypertension, hyperlipidemia, and impaired fibrinolysis. Although endogenous insulin is present in type 2 diabetic patients, 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 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., neuropathy, retinopathy, nephropathy) complications associated with the disease. HbA1c reflects the nonenzymatic glycosylation of other proteins throughout the body as a result of recent (e.g., previous 6-8 weeks) hyperglycemia; this measure is used as indicator of chronically elevated blood glucose concentrations and as a predictor of risk for the development of diabetic microvascular complications (e.g., neuropathy, retinopathy, nephropathy). 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 concentrations is beneficial and that complete normalization of blood glucose concentrations may prevent diabetic microvascular complications.
The DCCT was terminated prematurely because of the pronounced benefits of intensive insulin regimens, and all treatment groups were encouraged to institute or continue such intensive insulin therapy. In the Epidemiology of Diabetes Interventions and Complications (EDIC) study, the long-term, open-label continuation phase of the DCCT, the reduction in the risk of microvascular complications (e.g., retinopathy, nephropathy, neuropathy) associated with intensive insulin therapy has been maintained throughout 7 years of follow-up. In addition, the prevalence of hypertension (an important consequence of diabetic nephropathy) in those receiving conventional therapy has exceeded that of those receiving intensive therapy. Patients receiving conventional insulin therapy in the DCCT were able to achieve a lower HbA1c when switched to intensive therapy in the continuation study, although the average HbA1c values achieved during the continuation study were higher (i.e., worse) than those achieved during the DCCT with intensive insulin therapy. Patients who remained on intensive insulin therapy during the EDIC continuation study were not able to maintain the degree of glycemic control achieved during the DCCT; by 5 years of follow-up in the EDIC study, HbA1c values were similar in both intensive and conventional therapy groups. The EDIC study demonstrated that the greater the duration of chronically elevated plasma glucose concentrations (as determined by HbA1c values), the greater the risk of microvascular complications. Conversely, the longer patients can maintain a target HbA1c of 7% of less, the greater the delay in the onset of these complications.
Data from the United Kingdom Prospective Diabetes Study (UKPDS) and the Action in Diabetes and VAscular disease: preterax and diamicroN modified release Controlled Evaluation (ADVANCE) study in patients with type 2 diabetes mellitus generally are consistent with the same benefits on microvascular complications in type 2 diabetes mellitus as those observed in type 1 diabetes mellitus in the DCCT study.
Data from the long-term UKPDS in middle-aged, newly diagnosed patients with type 2 diabetes mellitus indicate that strict glycemic control (i.e., maintenance of fasting blood glucose concentrations below 108 mg/dL) is not maintained over time and that combination therapy eventually becomes necessary in most patients to attain target glycemic levels 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 type 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 less than 6%) can be considered in selected patients. An individualized HbA1c concentration goal that is closer to normal without risking substantial hypoglycemia is reasonable in patients with a short duration of diabetes mellitus, no appreciable cardiovascular disease, and a long life expectancy. Less stringent treatment goals may be appropriate in patients with long-standing diabetes mellitus in whom the general HbA1c concentration goal of less than 7% is difficult to obtain despite adequate education on self-management of the disease, appropriate glucose monitoring, and effective dosages of multiple antidiabetic agents, including insulin. 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 patients with 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 levels 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. In addition, loss of blood glucose control on diet alone can be temporary in some patients, requiring only short-term management with drug therapy. The importance of regular physical activity also should 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 concentrations within 2-3 months of diagnosis, initiation of monotherapy with an oral antidiabetic agent (e.g., metformin, sulfonylurea, acarbose) or insulin. The patient and clinician should recognize that dietary management is the principal consideration in the management of diabetes mellitus and that oral 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 implementing strict glycemic control in patients with type 2 diabetes, antidiabetic therapy should be individualized considering advanced age, comorbid conditions, preexisting clinically relevant microvascular and macrovascular complications or other vascular risk factors, degree of hyperglycemia, and life expectancy. 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 also should 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 concentrations within 2-3 months of diagnosis, initiation of monotherapy with metformin or another oral antidiabetic agent (e.g., a sulfonylurea, acarbose) or insulin should be considered. For more information on the stepwise approach to the management of type 2 diabetes mellitus,
Repaglinide reduces both fasting and postprandial blood glucose concentrations and HbA1c in patients with type 2 diabetes mellitus; these reductions are superior to those with placebo and are dose-dependent over a range of 0.25-16 mg of repaglinide daily. Because repaglinide therapy produces a more physiologic profile of insulin secretion (i.e., rapid onset and short duration of action) compared with sulfonylureas, repaglinide may be particularly useful for control of postprandial hyperglycemia through use of a ''one meal, one dose; no meal, no dose'' concept, allowing for increased flexibility of meal patterns (e.g., especially in adolescents, who may have an irregular eating schedule) and a reduced risk of hypoglycemia between meals or in the event of a missed meal. Repaglinide is almost as effective as metformin or sulfonylureas in improving glycemic control (approximately 1.5% decrease in HbA1c values), but has a shorter duration of action and is more expensive than metformin. ADA and other clinicians recommend metformin as initial antidiabetic therapy, provided no contraindications exist, because of the absence of weight gain or hypoglycemia, generally low adverse effect profile, and relatively low cost. In a randomized study, patients who ate 2, 3, or 4 meals daily with repaglinide doses prior to each meal achieved similar glycemic control (as assessed by serum glucose profiles and serum fructosamine concentrations) regardless of the number of meals and repaglinide doses daily. In another double-blind, randomized study, mean minimum blood glucose concentrations (obtained between lunch and dinner) were reduced from 77 to 61 mg/dL when lunch was omitted in patients receiving glyburide twice daily (before breakfast and dinner) but were essentially unchanged in those receiving preprandial repaglinide (i.e., dose omitted when lunch omitted); all hypoglycemic events (defined as blood glucose concentrations less than 45 mg/dL) in the study occurred in glyburide-treated patients.
In controlled clinical trials of 4-24 weeks' duration, repaglinide was more effective than placebo in reducing fasting and postprandial blood glucose concentrations and HbA1c in patients with type 2 diabetes mellitus, both in those previously treated with sulfonylureas and treatment-naive patients (i.e., those not previously treated with oral antidiabetic agents). In a 24-week, placebo-controlled trial, repaglinide was most effective in patients not previously treated with oral antidiabetic agents and in those in relatively good glycemic control (HbA1c less than 8%) at study entry; the reduction in HbA1c was 1.7 and 2.1% in the previously treated and treatment-naive groups, respectively. In both short-term and long-term comparative studies, repaglinide (after initial dosage titration) was as effective as glyburide and more effective than glipizide for the management of hyperglycemia in treatment-naive patients with type 2 diabetes mellitus. Similar to sulfonylurea therapy, repaglinide therapy generally increases postprandial plasma insulin concentrations and is associated with weight gain (3.3%) in patients who have not previously received oral sulfonylurea therapy. The hypoglycemic effect of repaglinide does not appear to be influenced by duration of diabetes, race, or age.
While repaglinide has been used effectively as initial monotherapy in appropriately selected patients with type 2 diabetes mellitus, data are limited concerning use of the drug as monotherapy in patients who did not achieve adequate glycemic control with other oral antidiabetic monotherapy (e.g., glyburide, metformin). In several placebo-controlled trials (12 or 24 weeks' duration) that included a subgroup of patients who had previously received oral antidiabetic therapy, the difference in HbA1c between repaglinide therapy and placebo was 1.6-1.7%, reflecting mainly an increase in HbA1c in the placebo groups (1.4-1.5%) rather than an improvement in glycemic control with repaglinide. In another trial of patients with poorly controlled diabetes mellitus during metformin therapy, switching to repaglinide therapy did not appreciably improve glycemic control; however, repaglinide monotherapy maintained glycemic control with fewer adverse GI effects than metformin monotherapy. Body weight does not change when patients are switched from other oral antidiabetic therapy to repaglinide.
While data concerning secondary failure with repaglinide are limited, interim data from a substudy (UKPDS 26) of UKPDS in newly diagnosed type 2 diabetic patients receiving intensive therapy (maintenance of fasting plasma glucose in a range from 108 mg/dL to less than 270 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 despite a maximum recommended daily dosage of 20 mg of glyburide or 500 mg of chlorpropamide or symptoms of hyperglycemia) 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 UKPDS, 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.
Repaglinide 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. ADA does not recommend use of meglitinides in hospitalized patients with diabetes mellitus because data on such use are limited in such patients.
Repaglinide may be used concomitantly with metformin or a thiazolidinedione (e.g., pioglitazone, rosiglitazone) in patients with type 2 diabetes who do not achieve adequate glycemic control with appropriate diet, exercise, and monotherapy with metformin, a sulfonylurea, repaglinide, or a thiazolidinedione antidiabetic agent. However, 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 maintain 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). The American Diabetes Association (ADA) generally recommends metformin as initial antidiabetic therapy in patients with type 2 diabetes mellitus, provided no contraindications exist, because of the absence of weight gain or hypoglycemia, generally low adverse effect profile, and relatively low cost.
ADA states that meglitinides may be appropriate choices in selected patients but are not preferred as second-line therapy after failure with metformin monotherapy because of their overall lower effectiveness, limited clinical data, and relative expense.
Data are limited concerning the incidence of primary failure (lack of glycemic response after 1-3 months of therapy with fasting blood glucose concentrations exceeding 140 mg/dL) or secondary failure (progressively decreasing diabetic control following 1 month to several years of good control) with repaglinide therapy. In several comparative clinical trials in which fixed dosages of repaglinide or glyburide were used after initial dosage titration, glycemic control (as determined by fasting plasma glucose and HbA1c concentrations) was maintained for the first 6-9 months of the studies but gradually declined (i.e., fasting glucose and HbA1c values increased) thereafter. Although not representative of clinical practice because of the fixed dosages used in these studies, the percentage of patients who withdrew because of ineffective therapy was 3.3% among both treatment groups in one study, 8-12% among repaglinide-treated patients in another study, and 18% in each treatment group in the third study; whether these figures represent primary or secondary failure of oral antidiabetic therapy was not reported. In a clinical trial in patients poorly controlled by metformin monotherapy, the combination of repaglinide and metformin reduced fasting plasma glucose concentrations and HbA1c by 39.2 mg/dL and 1.41%, respectively, compared with reductions of 4.5 mg/dL and 0.33%, respectively, with metformin alone; patients receiving repaglinide therapy alone had an increase in fasting glucose concentrations of 8.8 mg/dL and a reduction of 0.38% in HbA1c. In this study, the dosage of metformin hydrochloride was kept constant (final median dosage of 1.5 g either as monotherapy or as a component of combination therapy), and the dosage of repaglinide was titrated for 4-8 weeks followed by a 3-month maintenance period. Greater glycemic control was achieved with combined repaglinide and metformin therapy at half the median daily dosage of repaglinide compared with that used for repaglinide monotherapy. In a clinical trial in patients with inadequate glycemic control (as determined by HbA1c values exceeding 7%) while receiving metformin or sulfonylurea monotherapy, the combination of repaglinide (6 mg daily) and rosiglitazone (4 mg daily) reduced fasting plasma glucose concentrations and HbA1c by 94 mg/dL and 1.43%, respectively, at 24 weeks compared with reductions of 54 mg/dL and 0.17%, respectively, with repaglinide (12 mg daily) alone; patients receiving rosiglitazone monotherapy (8 mg daily) had a decrease in fasting glucose concentrations of 67 mg/dL and a reduction of 0.56% in HbA1c.
Combined therapy with repaglinide and other oral antidiabetic agents (e.g., metformin) in patients not adequately controlled with monotherapy may reduce symptoms and delay or avoid institution of insulin.
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. However, other options in patients not adequately controlled on 2 oral antidiabetic agents include addition of a third oral agent, addition of a bedtime dose of a long-acting (e.g., isophane) insulin, or switching to a multiple-injection insulin regimen. In patients whose HbA1c is close to the target level (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. Repaglinide has been used in combination with isophane (NPH) insulin to improve glycemic control in patients with type 2 diabetes mellitus who no longer respond adequately to therapy with one or more oral antidiabetic agents. In a placebo-controlled trial, therapy with repaglinide alone or combined with NPH insulin at bedtime improved glycemic control (as measured by a reduction in fasting blood glucose concentrations and HbA1c) in patients inadequately controlled with sulfonylurea therapy with or without metformin. Pooled analysis of data from a number of clinical trials, each evaluating the combination of repaglinide and isophane insulin a limited number of patients, revealed myocardial ischemia in a small number of such patients; repaglinide is not indicated for use in such a combination regimen. 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.