Type 2 diabetic patients are often treated with a combination of antidiabetic agents. The need to use drugs with different and complementary mechanisms of action frequently arises in daily clinical practice. There are several reasons to do this; namely, the disease itself is progressive, with deterioration of glycemic control over time, and monotherapeutic attempts to achieve and maintain glycemic control often fail in the long run (1,2).

Some patients do not accept insulin treatment because of the fear of needles and injections, the fear that the complications of diabetes are caused by insulin, and other false beliefs, and are willing to take as many antidiabetic pills the doctor is prepared to prescribe.

The combination of a sulfonylurea with metformin is commonly used in clinical practice. But when this potent combination is no longer able to provide acceptable glycemic control, the addition of an antidiabetic drug with a different mode of action may lead to improved metabolic control.

The peroxisome proliferator-activated receptor-γ (PPAR-γ) agonist rosiglitazone has been shown to produce significant improvement in glycemic control when administered to patients who were inadequately controlled on the combination of glibenclamide and metformin (3). Similar findings were obtained in a trial with troglitazone, the first member of the thiazolidinedione class of antidiabetic agents. In a double-blind placebo-controlled trial, the addition of troglitazone in a therapeutic regimen of sulfonylurea and metformin in inadequately controlled type 2 diabetic patients led to significant improvement in glycemic control (4). The trial was completed before troglitazone was taken off the market because of hepatotoxicity.

We examined the efficacy of rosiglitazone when added to a therapeutic regimen of glimepiride and metformin in type 2 diabetic patients.

A total of 38 Greek diabetic patients inadequately controlled on maximum doses of glimepiride (6 mg/day) and metformin (2,550 mg/day) were given rosiglitazone. There were 20 men and 18 women, the mean age was 58.6 ± 8.1 (mean ± SD), diabetes duration was 10.5 ± 6 years, and BMI was 31 ± 4.8 kg/m2. The patients were divided into two groups. In the first group (19 patients), the dose of rosiglitazone was 4 mg/day, whereas in the second group (19 patients), the dose was 8 mg/day.

HbA1c levels were measured by high-performance liquid chromatography. Paired t testing was used for statistical analysis, and P < 0.05 was considered significant. Twenty weeks after the addition of rosiglitazone there was a statistically significant decrease in HbA1c levels in both groups.

In the first group of patients, the average HbA1c before the treatment modification was 8.9 ± 1.1% and baseline fasting plasma glucose (FPG) was 10.7 ± 2.2 mmol/l. After the treatment modification HbA1c was 7.8 ± 0.9% (P < 0.001) and FPG 8.9 ± 1.2 mmol/l (P < 0.0001). In the second group, the average baseline HbA1c was 9 ± 1.1% and the baseline FPG was 10.8 ± 2.3 mmol/l. After the treatment modification, HbA1c was 7.6 ± 0.8 (P < 0.0001 and FPG was 7.9 ± 1 mmol/l (P < 0.0001).

The treatment with rosiglitazone was well tolerated. Hypoglycemia was the most frequent side effect in both patient groups (18.6% at 4 mg/day and 28% at 8 mg/day). The dose of glimepiride and/or metformin was reduced in patients with hypoglycemic episodes, and the reduction proved to be effective in avoiding hypoglycemic reactions. Mean body weight increased in both rosiglitazone groups (4.2 kg at 4 mg/day and 4.6 kg at 8 mg/day).

Rosiglitazone treatment has rarely been associated with severe liver reactions (57). No symptoms or signs of liver disease were observed, and no change in liver function tests was noted in the patients in our treatment groups for the 20-week period of follow-up.

Our findings are in accordance with those of other investigators who found that in inadequately controlled type 2 diabetic patients, on treatment with a sulfonylurea and metformin, the addition of rosiglitazone produces significant improvement in glycemic control and is safe and well tolerated (3).

Given the analogous results obtained with troglitazone, it is very possible that this is a class effect of thiazolidinediones and not a specific action of rosiglitazone. However, a major issue is whether hepatotoxicity is a class characteristic of all thiazolidinediones related at least partly to the activation of PPAR-γ receptors, or whether it is unique to troglitazone and thus spares newer glitazones, such as rosiglitazone and pioglitazone.

Turner RC, Cull CA, Frighi V, Holman RR: Glycemic control with diet, sulfonylurea, metformin, or insulin in patients with type 2 diabetes mellitus: progressive requirement for multiple therapies (UKPDS 49): UK Prospective Diabetes Study (UKPDS) Group.
Matthews DR, Cull CA, Stratton IM, Holman RR, Turner RC: Sulphonylurea failure in non-insulin-dependent diabetic patients over six years: UK Prospective Diabetes Study (UKPDS) Group.
Diabet Med
Jones N, Jones T, Menci L, Xu Jane, Freed M, Kreider M: Rosiglitazone in combination with glibenclamide plus metformin is effective and well tolerated in type 2 diabetes patients (Abstract).
44(Suppl. 1)
Yale JF, Valiquett TR, Owens-Grillo JK, Whitcomb RW, Foyt HL: The effect of a thiazolidinedione drug, troglitazone, on glycemia in patients with type 2 diabetes mellitus poorly controlled with sulphonylurea and metformin: a multicenter randomized, double-blind, placebo-controlledtrial.
Ann Intern Med
Al-Salman J, Arjomand H, Kemp DG, Mittal M: Hepatocellular injury in a patient receiving rosiglitazone: a case report.
Ann Intern Med Jan
Forman LM, Simmons DA, Diamond RH: Hepatic failure in a patient taking rosiglitazone.
Ann Intern Med
Gouda HE, Khan A, Schwartz I, Cohen R: Liver failure in a patient treated with long-term rosiglitazone therapy.
Am J Med

Address correspondence to John A. Kiayias, MD, Agisilaou 72 St., Sparti 23100, Greece. E-mail: jkiayias@hotmail.com.