Physicians' Academy for Cardiovascular Education

GLP-1 receptor agonist dulaglutide is efficacious and safe as add-on therapy in type 2 diabetes

Wysham C et al., Diabetes Care. 2014 - Diabetes Care. 2014 May 30

 

Efficacy and Safety of Dulaglutide Added on to Pioglitazone and Metformin Versus Exenatide in Type 2 Diabetes in a Randomized Controlled Trial (AWARD-1)

 
Wysham C, Blevins T, Arakaki R et al.
Diabetes Care. 2014 May 30. pii: DC_132760. [Epub ahead of print]
 

Background

As intensification of treatment of type 2 diabetes is often required over time, guidelines recommend metformin for initial drug therapy, after which other oral agents such as sulfonylurea, thiazolidinedione, dipeptidyl peptidase-4 (DPP-4) inhibitors may be added if needed [1]. When oral agents alone are not sufficient for a patient to achieve glycaemic control, injectable agents such as a GLP-1 receptor agonist can be used.
Dulaglutide is a long-acting human GLP-1 receptor agonist in development, administered once weekly as treatment for type 2 diabetes [2,3]. In contrast to native GLP-1, dulaglutide is resistant to degradation by DPP-4, and its absorption and renal clearance is slowed down due to its large size. Its half-life is approximately 5 days, which makes it suitable for once weekly subcutaneous administration. Dulaglutide potentiates glucose-dependent insulin secretion, inhibits glucagon secretion and delays gastric emptying, via GLP-1 signalling.
The aim of the AWARD-1 (Assessment of Weekly AdministRation of LY2189265 [dulaglutide] in Diabetes Assessment-1) study was to compare efficacy and safety profiles of once weekly dulaglutide with placebo and with exenatide twice daily in patients with type 2 diabetes treated with maximally tolerated doses of metformin and pioglitazone. Thus, this study compares a short acting GLP-1 receptor antagonist (exenatide) with a long acting one (dulaglutide). 976 Patients were randomised (2:2:2:1) to subcutaneous injections of once weekly dulaglutide 1.5 mg or dulaglutide 0.75 mg, exenatide BID (5 μg BID for the first 4 weeks, then 10 μg for the remainder of the study), or once weekly placebo. After 26 weeks, placebo-treated patients were switched in a blinded fashion (1:1 ratio) to dulaglutide 1.5 mg or dulaglutide 0.75 mg.
 

Main results

  • Least squares (LS) mean + SE HbA1c change from baseline to week 26 was -1.51 ± 0.06% for dulaglutide 1.5 mg, -1.30 ± 0.06% for dulaglutide 0.75 mg, -0.99 ± 0.06% for exenatide, and -0.46 ± 0.08% for placebo. Dulaglutide 1.5 mg and 0.75 mg were superior to placebo as well as exenatide.
  • Change in HbA1c from baseline to week 52 were somewhat lower than at 26 weeks (-1.36 ± 0.08% for dulaglutide 1.5 mg, -1.07 ± 0.08% for dulaglutide 0.75 mg, and -0.80 ± 0.08% for exenatide, but both doses of dulaglutide remained superior to exenatide.
  • After 26 weeks, the proportion of patients that achieved target HbA1c<7% was significantly higher in the dulaglutide groups (78% in 1.5 mg group and 66% in 0.75 mg group) than in exenatide-treated patients (52%, P<0.001 for both comparisons). 63%, 53% and 38% respectively attained HbA1c <6.5%, and 24% of patients in the placebo arm (P<0.001 in all comparisons). At week 52 similar results were obtained.
  • All active treatment arms showed a greater decrease in fasting serum glucose (FSG), with LS mean differences between dulaglutide 1.5 and 0.75 mg vs. exenatide -18 mg/dL and -10 mg/dL respectively (P<0.001 both).
  • LS mean change in body weight from baseline to week 26 was -1.30 kg + 0.29 kg with dulaglutide 1.5 mg, 0.20 + 0.29 kg for dulaglutide 0.75 mg, -1.07 + 0.29 kg for exenatide (all significantly different from placebo) and 1.24 + 0.37 kg for placebo. Weight loss did not differ significantly between dulaglutide 1.5 mg and exenatide. Similar results were seen at week 52.
  • Pancreatic Beta-cell function increased with all active treatment, and more so with dulaglutide 1.5 mg than with exenatide.
  • The incidence of serious adverse events and of adverse events was similar across all treatment arms. Gastrointestinal adverse events were the most commonly reported events in dulaglutide and exenatide-treated patients, most of them mild to moderate in severity.
  • Significantly fewer patients in the dulaglutide 1.5 mg arm experience hypoglycaemia during the first 26 weeks than in the exenatide arm (10.4% vs. 15.9%). This difference was maintained at 52 weeks.
  • Small median increases in serum lipase, total amylase, and pancreatic amylase that remained within the normal range were observed for dulaglutide and exenatide, as compared to placebo.
 

Conclusion

These results show that once weekly dulaglutide on top of maximally tolerated doses of metformin and pioglitazone resulted in significantly larger improvements in HbA1c and the proportion of patients achieving HbA1c targets as compared to placebo, as well as the active comparator exenatide BID at 26 weeks. A clinically relevant mean difference in HbA1c change from baseline between dulaglutide and exenatide of about 0.3-0.5% was seen in the context of a lower risk of hypoglycaemia with dulaglutide. Thus, this once weekly GLP-1 receptor agonist appears to have an acceptable benefit and risk profile in patients with type 2 diabetes.
 
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References

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2. Barrington P, Chien JY, Tibaldi F, Showalter HD, Schneck K, Ellis B: LY2189265, a long-acting glucagon-like peptide-1 analogue, showed a dose-dependent effect on insulin secretion in healthy subjects. Diabetes, obesity & metabolism 2011;13:434-438
3. Glaesner W, Vick AM, Millican R, Ellis B, Tschang SH, Tian Y, Bokvist K, Brenner M, Koester A, Porksen N, Etgen G, Bumol T: Engineering and characterization of the long- acting glucagon-like peptide-1 analogue LY2189265, an Fc fusion protein. Diabetes/metabolism research and reviews 2010;26:287-296