metformin/pioglitazone (Rx)

>10%

Lower limb edema (2.9-11.3%)

Upper respiratory infection (12-16)

1-10%

Weight gain (2.9-6.7%)

Diarrhea (4.8-5.8%)

Nausea (3.6-5.8%)

Urinary tract infection (5.3-5.8%)

Dizziness (4.8-5.4%)

Headache (4.6-5.3%)

Sinusitis (4.4-5%)

Edema (3%)

Postmarketing Reports

Hepatitis and hepatic enzyme elevations to >3 XUL, including very rare incidences of hepatic failure with and without fatal outcome

Cholestatic, hepatocellular, and mixed hepatocellular liver injury

Contraindications

Hypersensitivity

Severe renal disease: eGFR <30 ml/min/1.73 m²

Acute or chronic metabolic acidosis, including DKA with or without coma

NYHA Class III or IV heart failure

Cautions

Temporarily discontinue in patients undergoing radiologic exams using iodinated contrast agents

Do not initiate in patients aged ≥80 years CrCl demonstrates that renal function is not reduced because these patients are more susceptible to developing lactic acidosis

Withhold metformin in presence of any condition associated with hypoxemia, dehydration, or sepsis

Lactic acidosis should be suspected in any diabetic patient with metabolic acidosis lacking evidence of ketoacidosis (ketonuria and ketonemia); lactic acidosis is a medical emergency that must be treated in a hospital setting

Pioglitazone may cause fluid retention and cause or exacerbate existing heart failure

Edema; thiazolidinediones, which are peroxisome proliferator-activated receptor (PPAR) gamma agonists, can cause dose-related fluid retention, particularly when used in combination with insulin

Pioglitazone exerts its antihyperglycemic effect only in presence of insulin; therefore, do not use in type 1 diabetes mellitus or for treatment of diabetic ketoacidosis

May cause hypoglycemia; patients receiving therapy in combination with insulin or other antidiabetic medications (particularly insulin secretagogues such as sulfonylureas) may be at risk for hypoglycemia; a reduction in dose of the concomitant antidiabetic medication may be necessary to reduce the risk of hypoglycemia; hypoglycemia can also occur when caloric intake is deficient or when strenuous be necessary to reduce the risk of hypoglycemia exercise is not compensated by caloric supplement; hypoglycemia may be difficult to recognize in the elderly, and in people who are taking beta-adrenergic blocking drugs

Rare reports of hepatitis and hepatic enzyme elevations to >3 xULN, including very rare incidences of hepatic failure with and without fatal outcome

In controlled clinical trials of metformin, a decrease to subnormal levels of previously normal serum vitamin B12 levels, without clinical manifestations, reported; certain individuals (those with inadequate vitamin B12 or calcium intake or absorption) appear to be predisposed to developing subnormal vitamin B12 levels; in these patients, routine serum vitamin B12 measurements at two- to three-year intervals may be useful

Metformin is substantially excreted by kidney, and risk of metformin accumulation and lactic acidosis increases with degree of renal impairment

Use of metformin in patients with hepatic impairment has been associated with some cases of lactic acidosis; therapy is not recommended in patients with hepatic impairment

Discuss potential for unintended pregnancy with premenopausal women as therapy with metformin/pioglitazone, may result in ovulation in some anovulatory women

Mechanism of Action

Metformin: Biguanide; acts by decreasing endogenous hepatic glucose production, decreases intestinal absorption of glucose, and improves insulin sensitivity by increasing peripheral glucose uptake and utilization; improves glucose tolerance and lowers both basal and postprandial plasma glucose

Pioglitazone: Thiazolidinedione; insulin-sensitizing agent that acts by enhancing peripheral glucose utilization; decreased insulin resistance in the periphery and in the liver, resulting in increased insulin-dependent glucose disposal and decreased hepatic glucose output

Pharmacokinetics