Mild, Reversible Pancytopenia Induced by Rosiglitazone

Rosiglitazone, a member of the thiazolidinediones, is a well-established oral antidiabetic agent. It reduces plasma glucose levels and glucose production, increases glucose clearance, and significantly improves insulin sensitivity, pancreatic β-cell function, and cardiovascular risk factors (1). In addition to the potential risk of liver toxicity, thiazolidinediones can cause fluid retention, which can exacerbate congestive heart failure (2). Hematologic effects reported in clinical trials include only small decreases in Hb and hematocrit. A recent report described rosiglitazone-induced protection against myelotoxicity produced by 5-fluorouracil (3). We report a case of mild, reversible pancytopenia during treatment with rosiglitazone for type 2 diabetes.

A 56-year-old physician with a previous history of ischemic heart disease and hypertension developed symptoms of hyperglycemia and glycosuria and was diagnosed with type 2 diabetes. Treatment with 4 mg rosiglitazone per day was added to previous daily treatment with 100 mg acetylsalicilic acid, 80 mg slow-release propranolol, 5 mg amlodipine besylate, 10 mg phenoxybenzamine, and 10 mg simvastatin. The patient was symptom free. At that time, hematologic indexes were Hb 14.4 g/dl, hematocrit 40.5%, white blood cell count 6,700/μl, and platelets 238,000/μl. HbA_1c was 10.9%.

During treatment, all hematologic indexes decreased following a dose-dependent pattern with rosiglitazone dose. On 8 mg rosiglitazone per day, Hb decreased to 13 g/dl, hematocrit to 37.8%, white blood cell count to 4,300/μl, and platelets to 169,000/μl. On 12 mg rosiglitazone per day (a dose exceeding the recommended maximal dose), Hb decreased to 12.3 g/dl, hematocrit to 34.9%, white blood cell count to 3,600/μl, and platelets to 138,000/μl. When rosiglitazone was decreased to 4 mg daily, Hb increased to 12.7 g/dl, hematocrit to 35.8%, and white blood cell count to 4,200/μl. Two months after rosiglitazone was stopped and replaced with 1.5 mg repaglinide daily, Hb returned to 13.9 g/dl, hematocrit to 42.2%, white blood cell count to 6,100/μl, and platelets to 157,000/μl.

No other medication was added or changed during this time. No edema or other signs of fluid overload developed during treatment. Currently, the patient is treated with 1.5 mg repaglinide per day, and his diabetes is well controlled.

To date, the only known adverse hematologic effect of rosiglitazone is mild anemia presumed to be secondary to increased plasma volume. Furthermore, a recent report describes a hematologic advantage of rosiglitazone through the proliferation of granulocyte-macrophage colony-forming units associated with its treatment, an effect attributable to its insulin-sensitizing actions (3). The case presented here demonstrates the development of mild, reversible, and dose-related pancytopenia associated with rosiglitazone treatment. This adverse event seems to be a dose-related rather than an idiosyncratic one. The Hb/hematocrit changes are consistent with many other reports and are ascribed to an increased plasma volume, but the white blood cell count and platelet decreases indicate an effect on the bone marrow. Clinicians should be made aware of the possibility of hematologic toxicities occurring with rosiglitazone therapy. Patients should have their erythrocytes, leukocytes, and platelets monitored while on this drug.