Metformin is used as monotherapy as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus. Metformin may also be used in combination with a sulfonylurea or a thiazolidinedione antidiabetic agent as an adjunct to diet and exercise in patients with type 2 diabetes mellitus who do not achieve adequate glycemic control with metformin, sulfonylurea, or thiazolidinedione monotherapy.
Metformin may be used with repaglinide in patients with type 2 diabetes mellitus who have inadequate glycemic control with metformin or repaglinide monotherapy. Metformin is commercially available in fixed combination with repaglinide for use in patients with type 2 diabetes mellitus who are already receiving repaglinide and metformin concurrently as separate components or in those who have inadequate glycemic control with repaglinide or metformin monotherapy. Metformin also may be used concomitantly with nateglinide for the management of type 2 diabetes mellitus in treatment-naive patients (those not previously treated with antidiabetic agents) as well as in those who have previously received antidiabetic therapy.
Metformin is commercially available in fixed combination with glyburide or glipizide for use as an adjunct to diet and exercise to improve glycemic control in adults with diabetes mellitus; such fixed-combination preparations may be used as initial therapy in patients whose hyperglycemia cannot be controlled by diet and exercise alone, or as second-line therapy in patients who do not achieve adequate control of hyperglycemia with metformin or sulfonylurea monotherapy. A thiazolidinedione may be added to metformin in fixed combination with glyburide in patients who have inadequate glycemic control with fixed-combination therapy.
Metformin is commercially available in fixed combination with rosiglitazone for use in the management of type 2 diabetes mellitus when treatment with both rosiglitazone and metformin is appropriate. Metformin is commercially available in fixed combination with pioglitazone (as immediate- or extended-release tablets) for use as an adjunct to diet and exercise in patients with type 2 diabetes mellitus who have inadequate glycemic control with pioglitazone or metformin monotherapy or in those who are already receiving pioglitazone and metformin concurrently as separate components.
Metformin is commercially available in fixed combination with sitagliptin for use when treatment with both sitagliptin and metformin is appropriate.
Metformin also may be used as adjunctive therapy in patients with type 2 diabetes mellitus receiving insulin therapy to improve glycemic control and/or decrease the dosage of insulin needed to obtain optimal glycemic control.
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 mellitus 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).
Metformin is 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 occasionally may 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 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. Endogenous insulin is present in type 2 diabetic patients, although plasma insulin concentrations may be decreased, increased, or normal. In patients with type 2 diabetes mellitus, 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 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 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), a reduction of approximately 50-75% in the risk of development or progression of retinopathy, nephropathy, and neuropathy was demonstrated during an average 6.5 years of follow-up in patients with type 1 diabetes mellitus receiving intensive insulin treatment (3 or more insulin injections daily with dosage adjusted according to results of at least 4 daily blood glucose determinations, dietary intake, and anticipated exercise) compared with that in patients receiving conventional insulin treatment (1 or 2 insulin injections daily, self-monitoring of blood or urine glucose values, education about diet and exercise). However, the incidence of severe hypoglycemia, including multiple episodes in some patients, was 3 times higher in the intensive-treatment group than in the conventional-treatment group. The reduction in risk of microvascular complications in the DCCT study correlated continuously with the reduction in HbA1c concentration (hemoglobin A1c) produced by intensive insulin treatment (e.g., a 40% reduction in risk of microvascular disease for each 10% reduction in hemoglobin A1c). These data imply that any decrease in HbA1c levels 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.
In another randomized, controlled study (Stockholm Diabetes Intervention Study) in patients with type 1 diabetes mellitus who were evaluated for up to 7.5 years, blood glucose control (as determined by HbA1c concentrations) was improved, and the incidence of microvascular complications (e.g., decreased visual acuity, retinopathy, nephropathy, decreased nerve conduction velocity) reduced, with intensive insulin treatment (e.g., at least 3 insulin injections daily accompanied by intensive educational efforts) compared with that in patients receiving standard treatment (e.g., generally 2 insulin injections daily without intensive educational efforts).
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 of oral hypoglycemic agents on microvascular complications as those observed in type 1 diabetics receiving insulin therapy in the DCCT.
The UKPDS evaluated middle-aged, newly diagnosed, overweight (exceeding 120% of ideal body weight) or non-overweight patients with type 2 diabetes mellitus who received conventional or intensive treatment regimens with an oral sulfonylurea agent and/or insulin; overweight patients also could be allocated to metformin therapy in the same proportions as those allocated to sulfonylureas and insulin. Initial therapy consisted of an oral antidiabetic agent (sulfonylurea or metformin) or insulin, with stepwise addition of metformin (or glyburide in those initially allocated to metformin) in those poorly controlled on initial therapy or conversion to insulin alone in patients not adequately controlled with 2 oral agents. Intensive treatment consisted of antidiabetic therapy targeted to a fasting plasma glucose concentration of less than 108 mg/dL or, in patients receiving insulin, preprandial glucose concentrations of 72-126 mg/dL. Conventional treatment consisted of antidiabetic therapy targeted to a fasting plasma glucose concentration of less than 270 mg/dL without symptoms of hyperglycemia. Results of UKPDS indicate greater beneficial effects on retinopathy, nephropathy, and possibly neuropathy with intensive glucose-lowering therapy (median achieved HbA1c concentration: 7%) in type 2 diabetics compared with that in the conventional treatment group (median achieved HbA1c concentration: 7.9%). The overall incidence of microvascular complications was reduced by 25% with intensive therapy. Epidemiologic analysis of UKPDS results indicates a continuous relationship between the risks of microvascular complications and glycemia, with a 35% reduction in risk for each 1% reduction in HbA1c, and no evidence of a glycemic threshold.
The ADVANCE study also evaluated the relatively short-term effects (median follow-up: 5 years) of conventional or intensive therapy on the development of major vascular complications. The primary end point was the composite of major macrovascular (death from cardiovascular events, nonfatal myocardial infarction, or nonfatal stroke) and major microvascular (new or worsening nephropathy or retinopathy) events. While the incidence of the primary composite end point was reduced by approximately 10% in the ADVANCE study, the beneficial effect was due principally to a 21% reduction in microvascular events (nephropathy); there was no appreciable reduction in macrovascular outcomes. Intensive antidiabetic therapy (mean achieved HbA1c concentration: 6.5%) was associated with a reduction in new or worsening nephropathy compared with conventional treatment (mean achieved HbA1c concentration of 7.3%), but there was no effect on the development of new or worsening retinopathy. Results of the Veterans Affairs Diabetes Trial (VADT), another study similar in design to the ADVANCE study, also indicated that intensive therapy in patients with poorly controlled type 2 diabetes mellitus (median baseline HbA1c concentration of 9.4%) did not lessen the rate of microvascular complications compared with standard antidiabetic therapy.
In UKPDS, fasting plasma glucose concentrations and HbA1c values steadily increased over 10 years in the patients receiving conventional therapy, and more than 80% of these patients eventually required antidiabetic therapy in addition to diet to maintain fasting plasma glucose concentrations within the desired goal of less than 270 mg/dL. In patients receiving intensive therapy initiated with chlorpropamide, glyburide, or insulin, fasting plasma glucose concentrations and HbA1c values decreased during the first year of the study. Subsequent increases in these indices of glycemic control after the first year paralleled that in the conventional therapy group for the remainder of the study, indicating slow decline of pancreatic β-cell function and loss of glycemic control regardless of intensity of therapy. In contrast to UKPDS, no diminution in the effect on HbA1c or fasting blood glucose concentrations with either intensive or conventional therapy was observed in ADVANCE or VADT over a median follow-up of 5 or 5.6 years, respectively.
Data from long-term follow-up (over 10 years) of middle-aged, newly diagnosed UKPDS patients with type 2 diabetes mellitus indicate that strict glycemic control (i.e., maintenance of fasting blood glucose concentrations below 108 mg/dL) was not achieved with initial intensive oral antidiabetic therapy (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) in most patients; at 3 and 9 years, 50 and 75%, respectively, of patients required combination therapy with sulfonylureas or initiation of insulin to maintain adequate glycemic control. While strict guidelines for insulin dosage adjustments were used in the DCCT study, adjustments of antidiabetic therapy dosage in UKPDS were not as frequent (dosage adjustments allowed every 3 months); in addition, the definition of secondary treatment failure with sulfonylureas and the time of institution of supplementary antidiabetic therapy changed as the study progressed. 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.
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.
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) or insulin should be considered.
Clinical studies indicate that metformin is as effective (approximately 1.5% decrease in HbA1c values) as a sulfonylurea antidiabetic agent (e.g., chlorpropamide, glyburide, glipizide, tolbutamide) for the management of type 2 diabetes mellitus. Although metformin often has been used in patients who did not achieve adequate glycemic control with sulfonylurea monotherapy and who did not have symptoms of severe insulin deficiency (e.g., ketosis, uncontrolled weight loss), many clinicians recommend either metformin or a sulfonylurea as initial monotherapy in patients with type 2 diabetes mellitus whose hyperglycemia is not controlled despite dietary modification and exercise. Potential advantages of metformin compared with sulfonylurea antidiabetic agents or insulin include a minimal risk of hypoglycemia, more favorable effects on serum lipids, reduction of hyperinsulinemia, and weight loss or lack of weight gain. Type 2 diabetic patients who are very obese or who have baseline fasting blood glucose concentrations exceeding 200 mg/dL may be less likely to respond to therapy with sulfonylurea antidiabetic agents. Therefore, since metformin may stabilize or even decrease body weight, the drug may be particularly useful as initial monotherapy in obese individuals who might gain weight while receiving a sulfonylurea. Metformin is equally effective in lean or obese patients with type 2 diabetes mellitus. Metformin may be effective as replacement monotherapy in some patients with primary or secondary failure to sulfonylureas.
(See Diabetes Mellitus: Combination Therapy, in Uses.)
In controlled studies of up to 8 months' duration in adults with type 2 diabetes mellitus, therapy with metformin hydrochloride (0.5-3 g daily) reduced fasting and postprandial glucose concentrations and HbA1c substantially more than did placebo. The antihyperglycemic effect of metformin does not appear to correlate with duration of diabetes, age, obesity, race, fasting insulin concentrations, or baseline plasma lipid concentrations. In a placebo-controlled study in pediatric (10-16 years of age), treatment-naive (i.e., those receiving diet therapy only), obese patients with type 2 diabetes mellitus, the net difference in fasting plasma glucose concentrations in patients receiving metformin hydrochloride (up to 2 g daily) or placebo for up to 16 weeks was 64.3 mg/dL, reflecting an increase in fasting plasma glucose concentrations in the placebo group and an improvement in glycemic control with metformin therapy. The improvement in glycemic control with metformin in these pediatric patients was similar to that observed in clinical studies with the drug in adults. A small, similar weight loss occurred in patients receiving either metformin or placebo in this study. In a multicenter, randomized, controlled study in newly diagnosed, asymptomatic patients with type 2 diabetes mellitus, the efficacy of metformin therapy in reducing fasting plasma glucose (target value: less than 108 mg/dL) and HbA1c concentrations in a subgroup of obese patients was similar to that of therapy with a sulfonylurea (chlorpropamide, glyburide, or glipizide) or insulin in nonobese patients; all drug regimens improved glycemic control compared with conventional (diet only) therapy. However, unlike sulfonylurea or insulin therapy, metformin therapy generally decreased plasma insulin concentrations and was not associated with weight gain or an increased incidence of hypoglycemia. In this long-term study, gradual deterioration in glycemic control occurred with all therapies over the study period despite increases in drug dosage or combined drug therapy; HbA1c concentrations generally had increased to baseline levels after 4-5 years of therapy with any of the drug regimens. Such deterioration in glycemic control has been attributed to a progressive decline in pancreatic β-cell function rather than a reduction in insulin sensitivity.
Oral antidiabetic agents, including metformin, are 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. Metformin is not recommended for use in hospitalized patients with diabetes mellitus, as such patients may be at greater risk for the development of lactic acidosis; management of such patients usually requires the use of insulin.
Metformin may be used concomitantly with one or more oral antidiabetic agents (e.g., a sulfonylurea, a thiazolidinedione, a meglitinide, and/or an α-glucosidase inhibitor) or insulin to improve glycemic control in patients with type 2 diabetes.
Primary or secondary failure may occur with metformin as well as with other antidiabetic therapy (e.g., sulfonylureas). In patients receiving initial monotherapy with metformin, the incidence of primary and secondary failures appears to be less than or similar to that in patients receiving sulfonylurea monotherapy. Secondary failure to metformin is characterized by progressively decreasing diabetic control following 1 month to several years of good control. Combined therapy with metformin and another oral antidiabetic agent generally is used in patients with longstanding type 2 diabetes mellitus who have poor glycemic control with monotherapy; the sequence in which metformin or a sulfonylurea is used at initiation of therapy does not appear to alter the effectiveness of combined therapy with the drugs. However, ADA and other clinicians currently 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. Optimum benefit generally is obtained by addition of a second antidiabetic agent as soon as monotherapy with metformin no longer provides adequate glycemic control (i.e., when the target glycemic goal is not achieved within 2-3 months of initiation of metformin therapy or at any other time when the HbA1c goal is not achieved).
Combination Therapy with Oral Antidiabetic Agents
Combined therapy with metformin and other oral antidiabetic agents in patients not adequately controlled with monotherapy may reduce symptoms or allow reduced insulin dosages; some clinicians consider use of combination oral antidiabetic therapy as a means to delay or avoid institution of insulin. When glycemic control cannot be improved after 1-3 months of combined therapy with oral antidiabetic agents (e.g., a sulfonylurea) at maximal doses or if the effectiveness of such combined therapy declines, the manufacturer recommends switching to insulin therapy with or without continuance of metformin therapy. However, ADA considers the choice of additional second-line therapy to depend on the degree of glycemic control achieved during metformin monotherapy. In patients with HbA1c exceeding 8.5% or symptomatic hyperglycemia despite metformin monotherapy, ADA states that consideration should be given to adding insulin.
(See Combination Therapy with Insulin under Uses: Diabetes Mellitus.)
When glycemic control is closer to the target HbA1c goal with metformin monotherapy (e.g., HbA1c less than 7.5%), an agent with a lesser potential to lower glycemia and/or slower onset of action may be considered (e.g., sulfonylurea, thiazolidinedione) as additional therapy to metformin. ADA states that other antidiabetic agents such as α-glucosidase inhibitors, meglitinides, exenatide, or pramlintide generally are less effective, less well studied, and/or more expensive than recommended therapies (i.e., metformin, a sulfonylurea, a thiazolidinedione, insulin). However, these agents may be appropriate for treatment of type 2 diabetes mellitus in selected patients.
Metformin is commercially available in fixed combination with glyburide or glipizide for use as initial therapy in the management of patients with type 2 diabetes mellitus whose hyperglycemia cannot be controlled by diet and exercise alone. In several comparative trials in such patients, therapy with metformin in fixed combination with glyburide or glipizide was more effective in improving glycemic control (as determined by HbA1c values, fasting plasma glucose concentrations) than monotherapy with either component. A greater percentage of patients receiving metformin in fixed combination with glipizide or glipizide achieved strict glycemic control (e.g., HbA1c values less than 7%) than patients receiving monotherapy with metformin, glyburide, or glipizide.
Metformin in fixed combination with glyburide or glipizide also is used to improve glycemic control in patients with type 2 diabetes mellitus who are inadequately controlled with either sulfonylurea or metformin monotherapy. In several comparative studies in such patients, greater glycemic control (as determined by HbA1c values, fasting plasma glucose concentrations) was achieved with the fixed combination of metformin and glyburide or glipizide than with metformin, glyburide, or glipizide monotherapy. Strict glycemic control (e.g., HbA1c values less than 7%) was achieved in a greater percentage of patients receiving fixed combinations of metformin with a sulfonylurea (glyburide or glipizide) than with sulfonylurea or metformin monotherapy. In a comparative clinical trial in pediatric patients (9-16 years of age) with type 2 diabetes mellitus, therapy with metformin in fixed combination with glyburide (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 values) than monotherapy with either component (titrated to final mean daily dosages of 6.5 mg of glyburide or 1.5 g of metformin hydrochloride).
Metformin (immediate- or extended-release) is used in fixed combination with pioglitazone in patients with type 2 diabetes mellitus who have inadequate glycemic control with pioglitazone or metformin monotherapy or in those who are already receiving pioglitazone and metformin concurrently as separate components. No clinical trials have evaluated the fixed combination of metformin and pioglitazone; efficacy and safety of the fixed combination has been established based on concurrent administration of the 2 agents given separately. Safety and efficacy of the fixed combination of metformin and pioglitazone in patients with type 2 diabetes mellitus are extrapolated from clinical trials evaluating pioglitazone as add-on therapy to metformin.
Metformin also is used in combination with rosiglitazone (either as a fixed-combination preparation or as individual drugs given concurrently) in patients with type 2 diabetes mellitus when treatment with both metformin and rosiglitazone is appropriate.
The fixed-combination preparation containing metformin and rosiglitazone has not been specifically studied in patients previously receiving metformin monotherapy; however, clinical trials have evaluated rosiglitazone (4 or 8 mg once daily) as add-on therapy in patients who had inadequate glycemic control with metformin (2.5 g once daily). In these studies, substantial improvements in fasting plasma glucose and HbA1c concentrations were observed with the combination of rosiglitazone and metformin compared with metformin alone. In a dose-ranging trial evaluating rosiglitazone 4 or 8 mg as add-on therapy to the maximum daily dosage of metformin hydrochloride, 28.1% of patients receiving the higher dosage of rosiglitazone concurrently with metformin achieved HbA1c values of 7% or less.
A thiazolidinedione may be added to metformin in fixed combination with glyburide in patients with type 2 diabetes mellitus who have inadequate glycemic control with the fixed combination. In such patients, the addition of rosiglitazone to combined therapy with metformin and glyburide has reduced fasting glucose concentrations and HbA1c values. Strict glycemic control (e.g., HbA1c values less than 7%) was achieved in 42.4% of patients of receiving the triple combination of metformin, glyburide, and rosiglitazone compared with 13.5% of those receiving metformin and glyburide.
Metformin in fixed combination with repaglinide is used in patients with type 2 diabetes mellitus who have inadequate glycemic control with repaglinide or metformin monotherapy or in those who are already receiving repaglinide and metformin concurrently as separate components. In a double-blind, controlled trial in patients with type 2 diabetes mellitus who had inadequate glycemic control with metformin monotherapy, add-on therapy with repaglinide resulted in greater glycemic control (as determined by HbA1c values, fasting plasma glucose concentrations) than metformin or repaglinide monotherapy. Combined therapy with metformin and repaglinide resulted in a greater reduction in HbA1c and fasting plasma glucose concentrations at a lower repaglinide dosage than with repaglinide monotherapy. However, the incidence of hypoglycemia with combined metformin and repaglinide therapy was higher than with repaglinide monotherapy. In addition, body weight increased in patients receiving repaglinide alone or combined with metformin but remained stable in those receiving metformin monotherapy.
In a clinical trial in patients who had inadequate glycemic control (HbA1c exceeding 7.1%) with metformin monotherapy, addition of repaglinide to metformin therapy produced reductions in fasting plasma glucose concentrations and HbA1c averaging 39.6 mg/dL and 1.4%, respectively, compared with reductions averaging 4.5 mg/dL and 0.33%, respectively, with metformin alone; patients receiving repaglinide therapy alone had an increase in fasting plasma glucose concentrations of 8.8 mg/dL and a reduction of 0.38% in HbA1c. In a clinical trial in treatment-naive patients or patients who had previously received antidiabetic therapy (followed by a washout period of at least 2 months), combined therapy with metformin hydrochloride and nateglinide resulted in greater reductions in HbA1c and fasting plasma glucose concentrations than metformin or nateglinide monotherapy.
In another clinical trial in patients with type 2 diabetes mellitus who had inadequate glycemic control with metformin, a sulfonylurea, or insulin, the combination of pioglitazone (30 mg daily) and metformin (and withdrawal of other antidiabetic therapy) reduced fasting plasma glucose concentrations and HbA1c values compared with metformin therapy alone, regardless of whether patients were receiving lower (less than 2 g daily) or higher (2 g daily or more) dosages of metformin hydrochloride.
In a multicenter, controlled study in patients whose hyperglycemia was inadequately controlled by diet and metformin therapy, the addition of acarbose produced appreciable improvement in postprandial plasma glucose concentrations and modest improvement in HbA1c. Fasting plasma glucose concentrations generally are not reduced by addition of acarbose to therapy with metformin since acarbose acts principally during a meal to delay carbohydrate absorption. Limited data suggest that combined therapy with metformin and a sulfonylurea is as effective or more effective in reducing fasting blood glucose and HbA1c concentrations than combined therapy with acarbose and a sulfonylurea; however, acarbose may provide better control of postprandial blood glucose concentrations.
Conflicting data regarding the long-term benefit of metformin as part of an intensive antidiabetic regimen have been reported in UKPDS, which consisted of middle-aged, newly diagnosed, overweight (exceeding 120% of ideal body weight) or non-overweight patients with type 2 diabetes mellitus who received long-term therapy (over 10 years) with intensive or conventional treatment.
(See Glycemic Control and Microvascular Complications, under Uses: Diabetes Mellitus.)In a UKPDS substudy, overweight patients receiving metformin as initial therapy in a stepwise intensive regimen had a 32% lower risk of developing any diabetes-related endpoint (including macrovascular and microvascular complications) compared with those managed by dietary modification alone; the reduction in any diabetes-related end point was greater in those receiving metformin than in those receiving initial intensive therapy with a sulfonylurea or insulin. The risk for diabetes-related death or myocardial infarction (39% lower) was also lower with intensive therapy with metformin or sulfonylureas or insulin compared with conventional therapy; no differences between the effects of intensive therapies were noted. In contrast, a second UKPDS substudy in which metformin was added to sulfonylurea therapy to improve glycemic control resulted in an increase in the risk of diabetes-related death or death from any cause compared with continuing therapy with a sulfonylurea alone. A pooled analysis of both trials and epidemiologic analysis of other data from UKPDS in patients who received stepwise therapy with metformin and sulfonylurea therapy because of progressive hyperglycemia showed a small reduction in diabetes-related death, all-cause mortality, myocardial infarction, and stroke. Reasons for disparate results of these trials are unclear but may be related to trial design, the relatively smaller number of patients receiving metformin, analytical methods, or differences in response between overweight and non-overweight patients. Pending the results of additional studies, the American Diabetes Association (ADA) and other clinicians do not recommend changing current guidelines regarding the use of metformin as monotherapy or in combination with sulfonylureas.
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 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, ADA states that 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
Metformin is used in combination with insulin in patients in whom adequate glycemic control cannot be achieved by monotherapy with an oral antidiabetic agent, diet, and exercise. 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 agent for initiation of oral antidiabetic therapy. In patients with a HbA1c exceeding 8.5% or symptoms secondary to hyperglycemia) despite metformin monotherapy, consideration should be given to adding insulin. When glycemia is not controlled with metformin with or without other oral antidiabetic agents 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.
Combined therapy with insulin and one or more oral antidiabetic agents appears to increase glycemic control with lower doses of insulin than would be required with insulin alone and with a decreased potential for body weight gain associated with insulin therapy. Data from a small, placebo-controlled, 24-week trial indicate that addition of metformin improved glycemic control (as measured by a reduction in HbA1c) in patients who failed to achieve adequate glycemic control with insulin therapy; insulin dosage in patients receiving adjunctive metformin therapy was decreased by 16%. In another small, placebo-controlled study in patients adequately controlled with insulin therapy, insulin dosage requirements were reduced by 19% after addition of metformin.
Metformin has been used as an adjunct to insulin to reduce insulin requirements in a limited number of patients with type 1 diabetes mellitus, but the potential benefits and risks require further evaluation before such combined therapy can be recommended.
Polycystic Ovary Syndrome
Metformin has been used in the management of metabolic and reproductive abnormalities associated with polycystic ovary syndrome. However, adequate and well-controlled clinical trials evaluating metformin therapy for polycystic ovary syndrome remain limited, particularly regarding long-term efficacy, and available data are conflicting regarding the benefits of the drug in ameliorating various manifestations of the condition.
While metformin has beneficial effects on cardiovascular risk factors such as insulin resistance and obesity, evidence from pooled analyses of data suggest that the drug has limited overall benefits on reproductive outcomes (e.g., live birth rates) in women with polycystic ovary syndrome. As with diabetes mellitus, lifestyle changes (e.g., diet, exercise, weight loss in obese patients) are strongly recommended for the initial management of polycystic ovary syndrome; however, long-term success with such measures alone is difficult to achieve and drug therapy, including metformin, often is used for symptomatic management of this condition.
Polycystic ovary syndrome is characterized by chronic anovulation (generally manifested as oligomenorrhea or amenorrhea) and hyperandrogenism (excessive production of male hormones in women) with clinical manifestations of irregular menstrual cycles, infertility, hirsutism, acne, and dyslipidemia. While the principal etiology is unknown, insulin resistance with compensatory hyperinsulinemia is a prominent manifestation of polycystic ovary syndrome. Hyperinsulinemia stimulates ovarian and adrenal androgen secretion, leading to hyperandrogenism and its associated clinical manifestations. In addition, cardiovascular risk factors such as obesity and impaired glucose tolerance, including metabolic syndrome and type 2 diabetes mellitus, are present in a substantial proportion of women with polycystic ovary syndrome, making the use of insulin-sensitizing drugs such as metformin reasonable in the treatment of this condition.
Metformin and other insulin-sensitizing agents (e.g., thiazolidinedione antidiabetic agents) improve insulin resistance, which leads to a reduction in androgen production in ovarian theca cells and potential beneficial effects on metabolic and hormonal abnormalities associated with polycystic ovary syndrome. Although metformin therapy has not been shown specifically to reduce cardiovascular events in women with polycystic ovary syndrome, the drug's pharmacologic and clinical effects support its use as maintenance therapy to ameliorate insulin resistance and hyperinsulinemia in such women.
Estrogen-progestin oral contraceptives with or without an antiandrogen (e.g., spironolactone) traditionally have been used in the long-term management of polycystic ovary syndrome; however, such therapy may worsen preexisting insulin resistance and glucose tolerance and potentially increase cardiovascular risk. In a meta-analysis based on a small number of randomized, controlled trials in patients with polycystic ovary syndrome, oral contraceptive therapy (ethinyl estradiol with cyproterone acetate [not commercially available in the US] or norgestimate) for up to 12 months was associated with improvement in menstrual pattern and serum androgen concentrations compared with metformin, while metformin was more effective than oral contraceptives in reducing fasting insulin and triglyceride concentrations. However, a preference for either drug as maintenance therapy for polycystic ovary syndrome could not be determined because of a lack of adequate trial data. Another meta-analysis was unable to determine clinically important effects of metformin or thiazolidinedione therapy on metabolic or hyperandrogenism parameters such as fasting insulin or glucose concentrations, hirsutism, or hormone levels. Because of a lack of adequate long-term clinical trials, the effects of therapy with oral contraceptives or metformin on long-term outcomes such as diabetes, cardiovascular disease, or endometrial cancer in women with polycystic ovary syndrome have not been established.
Variable effects have been reported with metformin therapy used alone or in combination with fertility-enhancing drugs (e.g., clomiphene) for the treatment of infertility in women with polycystic ovary syndrome. Currently available evidence suggests that metformin hydrochloride dosages of 1.5-2.5 g daily in women with polycystic ovary syndrome increase the frequency of spontaneous ovulation, menstrual cyclicity, and ovulatory response after ovarian stimulation (e.g., with clomiphene, recombinant follicle-stimulating hormone). However, improvement in the rate of live births with metformin therapy generally has not been comparable to that associated with clomiphene therapy in such women. Results of a meta-analysis also indicated improvement in ovulation and clinical pregnancy rates with combined metformin and clomiphene treatment compared with clomiphene alone in women with polycystic ovary syndrome. However, another meta-analysis found only minimal improvement in ovulation rate and no improvement in pregnancy rate with metformin therapy. Some clinicians suggest that metformin therapy may be useful for inducing ovulation in women with polycystic ovary syndrome who desire pregnancy at a more distant time (e.g., more than 6 months away), and that clomiphene therapy may be preferable in those who desire to become pregnant much sooner. A potential advantage of metformin therapy over clomiphene for infertility is a reduced chance of twin or triplet pregnancy with metformin. Additional large, randomized, well-controlled studies are needed to establish the efficacy of metformin alone or in combination with other therapies for treatment of infertility associated with polycystic ovary syndrome.