Boxed Warning: Congestive Heart Failure

Contraindication
Diabetic ketoacidosis (DKA), with or without coma. DKA should be treated with insulin.[1]

Cardiac considerations
Like other TZDs, duetact can cause fluid retention when used alone or in combination with other antidiabetic agents, including insulin. Fluid retention may lead to or exacerbate CHF. Duetact should be used with caution in patients at risk for heart failure. Patients should be monitored for symptoms of heart failure or other adverse events related to fluid retention. In clinical trials, a small number of patients with a history of previously existing cardiac disease were reported to develop CHF when treated with pioglitazone in combination with insulin. Reports of CHF have been received in postmarketing experience in patients with and without previously known heart disease.[1] • The UGDP trial found that tolbutamide, a sulfonylurea, was associated with an increased risk of cardiovascular mortality. Glimepiride was not studied in this trial; however, it is prudent to consider that this warning may apply to all sulfonylureas.[1]

Hepatic safety
Reports of hepatitis and of hepatic enzyme elevations to three or more times the upper limit of normal (ULN) have been received in postmarketing experience with pioglitazone. Very rarely, these reports have involved hepatic failure with or without fatal outcome, although causality has not been established. Liver enzymes, including serum ALT, should be evaluated in all patients at initiation of therapy with duetact, and periodically thereafter per the clinical judgment of the healthcare professional. If ALT >2.5X ULN at baseline or if the patient exhibits clinical evidence of active liver disease, do not initiate therapy with duetact.[1]

Other considerations
Duetact may also be associated with edema, anemia, weight gain, and/or ovulation in premenopausal, anovulatory women. Adequate contraception should be recommended for premenopausal women. Macular edema has been reported in some diabetic patients receiving TZD therapy, although a causal relationship is unknown. Persons with diabetes should have routine eye exams and be instructed to immediately report any visual changes to their healthcare provider. As with all sulfonylureas, severe hypoglycemia may occur. Elderly, debilitated, or malnourished patients, or patients with adrenal, pituitary, renal, or hepatic insufficiency, may be more sensitive to the glucose-lowering effect of sulfonylureas and should be started on the lowest dose of duetact. An increased incidence of bone fracture was noted in female patients taking pioglitazone. The risk of fracture should be considered in the care of patients treated with duetact, particularly females, and attention should be given to assessing and maintaining bone health according to current standards of care.[1]

Well-tolerated therapy
In clinical trials using pioglitazone in combination with a sulfonylurea, the most common adverse events (≥5%) were hypoglycemia, upper respiratory tract infection, weight increase, headache, diarrhea, edema, urinary tract infection, pain in limb, and nausea.[1]

Indications and usage
Duetact is indicated with diet and exercise as a once-daily combination therapy to improve glycemic control in patients with type 2 diabetes who are already treated with a combination of pioglitazone and a sulfonylurea or whose diabetes is not adequately controlled with a sulfonylurea alone, or for those patients who have initially responded to pioglitazone alone and require additional glycemic control.[1] • Duetact should not be used in patients with type 1 diabetes. Management of type 2 diabetes should also include nutritional counseling, weight reduction as needed, and exercise.[1]

The major metabolic defects in type 2 diabetes are peripheral insulin resistance in muscle and fat, decreased pancreatic insulin secretion, and increased hepatic glucose output.[2] Dyslipidemia in insulin resistance is represented by hypertriglyceridemia, decreased HDL levels, and increased small dense LDL particles.[3] Renal and gastrointestinal function are also clinical considerations when prescribing an oral agent for type 2 diabetes.[4]