ArticlesDulaglutide versus insulin glargine in patients with type 2 diabetes and moderate-to-severe chronic kidney disease (AWARD-7): a multicentre, open-label, randomised trial
Introduction
Diabetic kidney disease occurs in about 40% of patients with type 2 diabetes.1 Moreover, chronic kidney disease, whether attributable to diabetes or not, considerably increases the complexity and risks of diabetes management.2 In moderate-to-severe chronic kidney disease, treatment options for hyperglycaemia are limited.3 Many antihyperglycaemic drugs, including insulin, are primarily cleared by the kidneys, and therefore require dose adjustments or are contraindicated for patients with chronic kidney disease.4, 5 These patients are at an increased risk of hypoglycaemia because of reduced drug clearance and impaired gluconeogenesis by the kidney.6 Therefore, safe and effective antihyperglycaemic drugs that confer a reduced risk of hypoglycaemia are needed for this population.
Dulaglutide is a long-acting glucagon-like peptide-1 (GLP-1) receptor agonist approved for the treatment of type 2 diabetes.7 It is composed of two identical GLP-1 (7–37) analogues that are protected against dipeptidyl peptidase-4 (DPP-4) action and fused to a modified IgG4 Fc fragment by a small peptide link.7 Dulaglutide is not cleared by the kidney and administration to patients with mild-to-severe impairment of kidney function does not increase drug exposure, according to pharmacokinetic findings.7 Therefore, no dose adjustment for dulaglutide is recommended for patients with chronic kidney disease. The available data suggest that GLP-1 receptor agonists, including dulaglutide, do not have adverse effects on the kidney.8, 9, 10, 11 Furthermore, preclinical evidence suggests that several direct GLP-1 receptor agonist-related mechanisms—including reductions in protein kinase C signalling, oxidative stress, and inflammatory responses—might actually protect the kidney.12, 13 In clinical trials designed to assess cardiovascular safety outcomes for two GLP-1 receptor agonists, liraglutide and semaglutide mitigated macroalbuminuria onset and progression.14, 15, 16 The slope of estimated glomerular filtration rate (eGFR) decline was also attenuated with liraglutide in patients with an eGFR of 30–59 mL/min per 1·73 m2.16 However, there have been few clinical studies done on GLP-1 receptor agonists in patients with moderate-to-severe chronic kidney disease and most were placebo-controlled.
The aim of the AWARD-7 trial was to assess the glycaemic efficacy and overall safety, including kidney-related safety, of once-weekly dulaglutide compared with daily insulin glargine as basal therapy, both in combination with insulin lispro, for patients with type 2 diabetes and moderate-to-severe chronic kidney disease.
Section snippets
Study design and participants
AWARD-7 was a 52-week, randomised, multicentre, open-label (masked dulaglutide dose), parallel-arm trial done at 99 clinical research sites in nine countries (Brazil, Hungary, Mexico, Poland, Romania, South Africa, Spain, Ukraine, and the USA).
Adults aged 18 years or older with type 2 diabetes and moderate-to-severe chronic kidney disease (stages 3–4)1 were eligible for inclusion. Key inclusion criteria included the following: HbA1c in the range 7·5–10·5% (58·46–91·25 mmol/mol); treatment with
Results
Enrolment began on Aug 15, 2012, and ended on Nov 30, 2015; the last patient completed the study on Dec 20, 2016. Overall, 577 participants were randomly assigned to study treatment (figure 1), and 480 participants completed 52 weeks of treatment. Most study discontinuations were due to participant decision or adverse events. Baseline demographics, clinical characteristics, and concomitant medication use were similar between groups (table 1; appendix).
At 26 weeks, all treatment groups had mean
Discussion
In participants with type 2 diabetes and moderate-to-severe chronic kidney disease, once-weekly treatment with dulaglutide produced clinically meaningful improvements in glycaemic control, with efficacy similar to that of daily insulin glargine as basal therapy in terms of change in HbA1c. Analysis of secondary endpoints suggested that dulaglutide treatment was associated with weight loss, a lower rate of hypoglycaemia, a smaller decline in eGFR, and a greater reduction in albuminuria compared
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Dr Zimmermann retired in December, 2017