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TZD Effective Third-Line Rx after Failure of Long-term Metformin/GLP-1 RA

This novel study examines the effect of adding another oral agent, rather than insulin, to patients with type 2 diabetes not controlled on metformin plus exenatide.

Assigning patients to a third-line thiazolidinedione (TZD) was an effective and well-tolerated option in patients with inadequately controlled type 2 diabetes (T2DM) after long-term treatment with metformin plus exenatide twice daily injection according to the results of a randomized, open-label trial. However, the use of glimepiride as third-line treatment did not result in significant improvement of glycemic control.

“Our study represents the first active-comparator clinical trial examining patients failing on combined metformin and a GLP-1RA and adding another oral therapy rather than insulin,” wrote Guntram Schernthaner, from the Rudolfstiftung Hospital, Vienna, Austria, and colleagues. “TZD add-on was associated with fewer hypoglycemic episodes and an improved lipid profile; however, these benefits must be balanced against an increase in body weight associated with TZDs.”

In the primary EUREXA trial, patients with T2DM not controlled on metformin were randomly assigned to exenatide twice daily or glimepride as an add-on treatment. In this substudy, 154 patients with inadequate control originally on metformin and exenatide were re-randomly assigned to an add-on glimepiride or a TZD. Patients with inadequate control on metformin and glimepiride(n=166) in the original study received add-on exenatide twice daily.

The patients were on third-line therapy for a median of 2 years. In the group of patients with inadequate control on metformin/exenatide the addition of a TZD resulted in a significantly greater decrease in HbA1c compared with glimepiride (130-week difference=0.48%; P=.001). However, this decrease in HbA1c came with significantly increased BMI and systolic blood pressure.  

Patients assigned a TZD had a mean weight increase of 1.88 kg at 130 weeks compared with a 0.62 kg decrease in patients assigned glimepiride. Patients assigned to glimepiride had significantly greater incidence of any hypoglycemia, and nocturnal, non-nocturnal and documented symptomatic hypoglycemia with blood glucose less than 70 mg/dL.

Patients who received third-line exenatide twice daily had a mean -0.35 reduction in HbA1c from baseline and a -0.82 mean reduction in BMI at 130 weeks. About 17% of patients achieved an HbA1c of less than or equal to 6.5% and 34.2% of patients achieve an HbA1c of 7%. In addition, patients had a mean -2.26 kg change in body weight from baseline to 130 weeks. The researchers noted that with third-line exenatide there was a slight increase in the rate of documented symptomatic hypoglycemia compared with treatment on metformin/glimepiride.

The researchers concluded that both studied add-on therapies had modest efficacy in this patient population, and that the order of the therapies given was also important.

“Metformin followed by exenatide followed by sulfonylurea was not efficacious and was associated with weight gain and hypoglycemia,” the researchers wrote. “In contrast, metformin followed by sulfonylurea followed by exenatide showed some glycemic efficacy, and was associated with weight loss.”


Schernthaner G, Rosas-Guzman J, Dotta F, et al. Treatment escalation options for patients with type 2 diabetes after failure of exenatide BID or glimepiride added to metformin: results from the prospective European Exenatide (EUREXA) study. Diabetes Obes Metab. Epub 2015 Apr 1.