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Clinical trials have shown that GLP-1 RAs reduce HbA1c and weight in type 2 diabetes, but are these outcomes confounded by concomitant medications?
The glucagon-like peptide (GLP)-1 receptor agonist dulaglutide has been shown in clinical trials to reduce both HbA1c and weight, however, a new study indicates that these two outcomes seem to have only a weak correlation to each other and likely occur independently.
“Although dulaglutide demonstrated dose-dependent effects on both weight loss and HbA1c reduction, the relationship was weak in this analysis and may have been confounded by concomitant medications associated with weight gain,” wrote researchers led by Guillermo E. Umpierrez, of Emory University School of Medicine.
Umpierrez and colleagues conducted this study to determine if a relationship existed between changes in weight and glycemic control in patients treated with dulaglutide. To do this they looked at data from 5171 patients with type 2 diabetes included in the six AWARD trials studying dulaglutide, all of which were randomized controlled trials. In these trials, 1719 patients were assigned dulaglutide 1.5 mg and 1417 were assigned 0.75 mg. Instead of a pooled analysis, Umpierrez and colleagues analyzed each trial separately using data taken at 26 weeks after therapy initiation.
Data showed that dulaglutide had a significant dose-dependent effect on HbA1c. Patients assigned the 1.5-mg dose had a reduction in HbA1c that ranged from 0.78% in the monotherapy study to 1.64% in the basal-bolus trial. For the 0.75-mg dose, the reduction in HbA1c ranged from 0.71% in the monotherapy trial to 1.59% in the basal-bolus trial.
Similarly, the researchers found that weight change was also dose dependent and varied based on the additional treatments patients were taking. For the 1.5-mg dose of dulaglutide, change in weight ranged from -0.87 kg in the basal-bolus study to -3.18 kg in the trial comparing dulaglutide to sitagliptin added to metformin. For the 0.75-mg dose, the change in weight ranged from an increase of 0.20 kg in the study comparing dulaglutide to exenatide twice daily with metformin and pioglitazone, to –2.63 kg in the trial comparing sitagliptin added to metformin.
“While the majority of patients in each of the studies experienced an HbA1c reduction, body weight changes varied based on background therapy. In studies with concomitant sulphonylurea, thiazolidinedione, and insulin, which are usually associated with weight gain, the percentage of patients with weight reduction was lower,” the researchers wrote. “Weight gain generally associated with these concomitant therapies might have been attenuated by dulaglutide treatment.”
Taken together, the researchers found that between 55% and 83% of patients on dulaglutide 1.5 mg experienced both a reduction in HbA1c and in weight; similarly, between 41% and 79% of patients assigned the 0.75 mg dose experienced reductions in both.
Both doses of the drug resulted in significantly greater proportions of patients having reductions in weight and HbA1c compared with sitagliptin and insulin glargine. In addition, the 1.5-mg dose resulted in greater loses compared with exenatide twice daily and metformin.
“Because correlations may be impacted by patient-to-patient variability, to investigate this further we also evaluated the mean HbA1c change by weight change categories at 26 weeks,” the researchers explained. “While there were relatively few patients with weight loss >10%, we observed greater HbA1c reductions with increasing weight loss in the monotherapy study and in the trials added on to metformin.”
This study was sponsored by Eli Lilly and Company.
Umpierrez GE, et al. Relationship between weight change and glycaemic control with once weekly dulaglutide treatment in patients with type 2 diabetes. Diabetes Obes Metab. Epub 2016 Mar 11.