Pioglitazone is used alone (monotherapy) or in combination with a sulfonylurea antidiabetic agent, metformin (either as a fixed-combination preparation or as individual drugs given concurrently), or insulin as an adjunct to diet and exercise to improve glycemic control in patients with type 2 diabetes mellitus. Pioglitazone also is used in fixed combination with glimepiride in patients with type 2 diabetes mellitus who are already receiving a thiazolidinedione and a sulfonylurea separately or who are inadequately controlled on a sulfonylurea or a thiazolidinedione alone. In patients whose hyperglycemia cannot be controlled with these other antidiabetic agents, pioglitazone should be added to, not substituted for, such antidiabetic therapy.
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 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 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 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). For additional details on the clinical classification, complications, and management of diabetes mellitus,
A thiazolidinedione (i.e., pioglitazone or rosiglitazone) generally is considered one of several second-line agents (e.g., including insulin and sulfonylureas) used for the management of hyperglycemia in patients with type 2 diabetes mellitus not responding adequately to oral monotherapy with metformin, the preferred initial oral antidiabetic therapy.
Some data suggest a possible protective effect of pioglitazone with regard to certain cardiovascular outcomes (e.g., death, myocardial infarction, stroke) in patients with type 2 diabetes mellitus. In a randomized, controlled study in over 5000 patients with type 2 diabetes mellitus who were at high risk for macrovascular complications, addition of pioglitazone to existing antidiabetic therapy was associated with a reduction in the secondary composite end point of all-cause mortality, nonfatal myocardial infarction, and stroke compared with placebo; no difference between the study groups was observed with respect to the primary composite study end point (all-cause mortality, nonfatal myocardial infarction, stroke, acute coronary syndrome, endovascular or surgical intervention on the coronary or leg arteries, or above-the-ankle amputation). Results of a meta-analysis of data from randomized, placebo- or active-controlled trials in over 16,000 patients indicated an 18% lower risk of the primary composite end point of death, myocardial infarction, or stroke with pioglitazone therapy. The incidence of serious heart failure was increased with pioglitazone therapy but without an associated increase in mortality. While an increased risk of myocardial ischemic events has not been documented to date with pioglitazone therapy in patients with type 2 diabetes mellitus, both pioglitazone and rosiglitazone, alone or in combination with other antidiabetic agents, can cause fluid retention and other cardiovascular effects that may lead to or exacerbate heart failure. Therefore, the potential risks and benefits of thiazolidinediones versus other second-line antidiabetic agents (sulfonylureas, insulin) should be carefully considered.
(See Heart Failure under Warnings/Precautions: Warnings, in Cautions.)For information on the effects of intensive glycemic control on microvascular and macrovascular complications in patients with diabetes mellitus,
Efficacy as monotherapy for the management of type 2 diabetes mellitus was established in 3 controlled studies of 16-26 weeks' duration. Pioglitazone improved glycemic control as measured by fasting glucose and glycosylated hemoglobin (HbA1c) concentrations.
Efficacy of pioglitazone in combination with a sulfonylurea antidiabetic agent, metformin, or insulin in patients whose type 2 diabetes mellitus was inadequately controlled by therapy with one or more of these agents was established in several controlled studies in which combined therapy improved glycemic control regardless of the dosage of the other antidiabetic agent(s). A thiazolidinedione such as pioglitazone also may be added to therapy with the fixed combination of glyburide and metformin in patients whose hyperglycemia is not adequately controlled with the fixed combination. A thiazolidinedione antidiabetic agent also may be used concomitantly with repaglinide in patients whose hyperglycemia is inadequately controlled with diet, exercise, and monotherapy with metformin, a sulfonylurea, repaglinide, or a thiazolidinedione antidiabetic agent. In a clinical trial in patients with type 2 diabetes mellitus poorly controlled (as determined by HbA1c concentrations exceeding 7%) by metformin or sulfonylurea monotherapy, the combination of repaglinide and pioglitazone reduced fasting plasma glucose and HbA1c concentrations compared with pioglitazone or repaglinide monotherapy. Greater glycemic control was achieved with the combination of pioglitazone (fixed dosage: 30 mg daily) and repaglinide at a lower daily dosage of repaglinide (final median dosage: 6 mg daily) than with repaglinide monotherapy (final median dosage: 10 mg daily).
Pioglitazone also is used in fixed combination with metformin 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. Efficacy and safety of pioglitazone in fixed combination with metformin were established in a 24-week, randomized clinical study in 600 patients with type 2 diabetes mellitus (mean baseline HbA1c 8.7%) inadequately controlled with diet and exercise. Substantial improvements in fasting plasma glucose and HbA1c were observed in patients receiving the fixed combination of pioglitazone and metformin compared with each individual component alone. Efficacy and safety of the fixed combination also have been established based on concurrent administration of the 2 agents given separately and extrapolations from clinical trials evaluating pioglitazone as add-on therapy to metformin. Bioequivalence has been demonstrated between the fixed combination of pioglitazone and metformin and each agent given concurrently.
Pioglitazone also is used in fixed combination with glimepiride in patients with type 2 diabetes mellitus who are already receiving a thiazolidinedione and a sulfonylurea separately or who are inadequately controlled on a sulfonylurea or a thiazolidinedione alone. No clinical trials have been conducted evaluating the fixed combination of pioglitazone and glimepiride as second-line therapy in patients who are inadequately controlled on monotherapy with a sulfonylurea. Safety and efficacy of the fixed combination of pioglitazone and glimepiride in patients with type 2 diabetes mellitus who are inadequately controlled on a sulfonylurea alone have been extrapolated from clinical trials evaluating pioglitazone as add-on therapy to a sulfonylurea.
Because pioglitazone requires insulin for activity, it would not be effective and should not be used in patients with type 1 diabetes mellitus or ketoacidosis.