Drug interactions between Levemir and metformin/pioglitazone

metformin ↔ insulin detemir

Applies to:metformin/pioglitazone and Levemir (insulin detemir)

MONITOR: Metformin can potentiate the hypoglycemic effects of insulin. The mechanism may involve either increases in cellular mechanisms controlled by insulin or effects on complementary biochemical reactions. While this interaction can be used to clinical advantage, clinicians should be aware that coadministration of metformin increases the risk of hypoglycemia associated with insulin.

MANAGEMENT: Close monitoring for the development of hypoglycemia is recommended if metformin is coadministered with insulin, particularly in patients with advanced age and/or renal impairment. Patients should be apprised of the signs and symptoms of hypoglycemia (e.g., headache, dizziness, drowsiness, nausea, hunger, tremor, weakness, sweating, palpitations), how to treat it, and to contact their physician if it occurs.

pioglitazone ↔ insulin detemir

Applies to:metformin/pioglitazone and Levemir (insulin detemir)

MONITOR: Coadministration of a thiazolidinedione in combination with insulin may increase the risk of edema compared to insulin alone. The mechanism is unknown but may involve enhancement of the antinatriuretic and/or peripheral vasodilatory effects of insulin. In a study of 319 type 2 diabetic patients inadequately controlled on twice-daily insulin monotherapy, edema occurred in 13.1% and 16.2% of the patients coadministered rosiglitazone 4 mg/day and 8 mg/day, respectively, compared to 4.7% of those coadministered a matching placebo. Small but statistically significant decreases in hemoglobin and hematocrit were also observed with rosiglitazone compared to placebo. These events were classified as mild to moderate and not considered serious. In a similar study involving 566 patients on stable insulin monotherapy, mild or moderate edema occurred in 12.6% and 17.6% of patients who received pioglitazone 15 mg/day and 30 mg/day, respectively, compared to 7.0% of those who received placebo. Additionally, mild or moderate hypoglycemia occurred in 8% and 15% of patients who received pioglitazone 15 mg/day and 30 mg/day, respectively, compared to 5.0% of those who received placebo. Also, mean change from baseline body weight was 2.3 kg for the 15 mg pioglitazone group and 3.7 kg for the 30 mg pioglitazone group, whereas no change occurred in the placebo group. In a retrospective study of 79 patients who were initially on a thiazolidinedione or insulin separately but were subsequently given both in combination, 20 patients (25.3%) developed edema during the combination, compared to 7 of 71 patients (9.9%) during insulin alone and 1 of 8 patients (12.5%) during thiazolidinedione alone. The mean time to onset of edema was 135 days once combination therapy was initiated. There was no documentation of new-onset or exacerbation of congestive heart failure during combination therapy. However, one patient developed flash pulmonary edema after 2 months of combination therapy and died.

MANAGEMENT: Caution is advised during coadministration of thiazolidinedione and insulin therapy. Patients at risk for heart failure should be closely monitored. Patients should be advised to notify their physician immediately if they experience signs and symptoms of heart failure such as fluid retention, edema, rapid weight gain, or shortness of breath. Patients should also be apprised of the increased risk of hypoglycemia and be alert to potential signs and symptoms of hypoglycemia such as headache, dizziness, drowsiness, nausea, hunger, tremor, weakness, sweating, palpitations.