A 2-year open-label study of exenatide once weekly showed that this medication was safe when combined with a thiazolidinedione (TZD) plus metformin, and that it significantly lowered hemoglobin (Hb) A1c in patients with type 2 diabetes. A second study of patients with type 2 diabetes, the open-label extension study of DURATION-1 (Diabetes Therapy Utilization: Researching Changes in A1c, Weight and Other Factors Through Intervention with Exenatide Once Weekly) trial, showed that the reductions in HbA1c in the trial were sustained at 4 years, along with improvements in cardiometabolic measures.
Michael E. Trautmann, MD, Consultant, Diabetes Drug Development at Eli Lilly, presented the results of these studies at the 2012 ADA annual meeting.
Exenatide plus a TZD: 2-Year Results
In the 2-year, single-arm, open-label study of the safety of exenatide in combination with a TZD, “there were no new safety findings and no negative interaction between the drugs,” said Dr Trautmann.
The known side effects for each drug were seen at the same level as was already known, he stated. For exenatide, these were the gastrointestinal (GI)-related side effect of nausea (17.2%) and injection-site nodule (11.9%). For the TZDs, side effects included mild peripheral edema in 3 patients and edema in 1 patient, but no reports of heart failure. No major hypoglycemic events were reported, and minor hypoglycemic events were rare.
Of the 134 patients, 44 were exenatide-naive and 90 were switched from exenatide twice daily to the once-weekly 2-mg dose. The TZD pioglitazone (≥30 mg daily) was taken by 90% of patients and the TZD rosiglitazone (24 mg daily) was taken by 10% (physicians were free to select the TZD), and metformin by 90% of the patients. No impact was seen from the use of rosiglitazone, and its use was low, with many patients switching to pioglitazone during the trial, because of cardiovascular concerns, Dr Trautmann stated.
To be included in the study, patients had to have an HbA1c level between 7% and 10%. All patients had diabetes for 6 years, most of them were white males, and the average age was 55 years.
The HbA1c was significantly lowered in the overall intention-to-treat (ITT) analysis, from 7.2% at baseline to 6.7%; a similar reduction, from 7.0% to 6.6%, was seen in patients who switched from the twice-daily exenatide dose to the once-weekly dose. The exenatide-naive patients had a slightly larger reduction in HbA1c—from 7.7% to 6.6% at study end.
“Body weight was reduced despite the continuous use of TZDs, which are known to increase body weight quite significantly. Body weight was well maintained over the course of the 2 years,” said Dr Trautmann.
Overall baseline body weight was 98.1 kg; body weight was reduced the most in the exenatide-naive patients, by 2.7 kg, compared with reductions of 0.6 kg and 0.5 kg in the ITT and the switched groups, respectively.
DURATION-1: 4-Year Sustained Benefits with Exenatide
The 4-year open-label extension study of DURATION-1 that included 295 patients showed the durability of exenatide once weekly, resulting in a sustained reduction of 1.7% in HbA1c and a 4-year maintenance of the 2.5-kg weight loss from baseline.
In the randomized DURATION-1 trial, a significantly greater reduction was seen in HbA1c level with exenatide once weekly than with the twice-weekly administration of the drug—a 1.9% reduction compared with 1.5% (P = .002), respectively, at 30 weeks. Weight-loss level was similar in the 295 patients in both groups.
The patients had to have an HbA1c level between 7.1% and 11% to be included in this study. At baseline, patients (average age, 56 years) had an HbA1c of 8.2%, body weight of 100 kg, and diabetes duration of 7 years. The management regimen included exenatide once weekly, diet and exercise, and a TZD, metformin, or a sulfonylurea.
In the 176 patients who completed the 4-year extension, 55% achieved an HbA1c of <7% and 36% achieved an HbA1c <6.5% (mean, 6.9%). Fasting plasma glucose was reduced by 37 mg/dL.
Blood pressure (BP) and lipid levels were improved at 4 years. Reductions were seen in:
- Systolic BP, by 1.6 mm Hg
- Total cholesterol, by 10.9 mg/dL
- Low-density lipoprotein cholesterol, by 8.0 mg/dL.
In addition, the mean change in triglycerides was 13%. Improvement in beta-cell function was observed at the end of the study, as shown by a 26% increase in the homeostasis model assessment-B score and a 13% increase in the homeostasis model assessment-S score (which are measures of beta-cell function).
Of note, mild nausea decreased over time with exenatide once weekly, from 85 events per 100-year patient exposure during weeks 1 to 30, to 15 events for the study duration. Mild nausea is the most common adverse event associated with this regimen. Among patients receiving exenatide once weekly, 6 discontinued the drug because of GI adverse events, and 21 patients withdrew overall.
Few minor hypoglycemia events were observed, most with a sulfonylurea, and no major hypoglycemia event was observed.