Articles
Dulaglutide versus insulin glargine in patients with type 2 diabetes and moderate-to-severe chronic kidney disease (AWARD-7): a multicentre, open-label, randomised trial

https://doi.org/10.1016/S2213-8587(18)30104-9Get rights and content

Summary

Background

Many antihyperglycaemic drugs, including insulin, are primarily cleared by the kidneys, restricting treatment options for patients with kidney disease. Dulaglutide is a long-acting glucagon-like peptide-1 receptor agonist that is not cleared by the kidneys, and confers a lower risk of hypoglycaemia than does insulin. We assessed the efficacy and safety of dulaglutide in patients with type 2 diabetes and moderate-to-severe chronic kidney disease.

Methods

AWARD-7 was a multicentre, open-label trial done at 99 sites in nine countries. Eligible patients were adults with type 2 diabetes and moderate-to-severe chronic kidney disease (stages 3–4), with an HbA1c of 7·5–10·5%, and who were being treated with insulin or insulin plus an oral antihyperglycaemic drug and were taking a maximum tolerated dose of an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker. Participants were randomly assigned (1:1:1) by use of a computer-generated random sequence with an interactive response system to once-weekly injectable dulaglutide 1·5 mg, once-weekly dulaglutide 0·75 mg, or daily insulin glargine as basal therapy, all in combination with insulin lispro, for 52 weeks. Insulin glargine and lispro doses were titrated as per an adjustment algorithm; dulaglutide doses were masked to participants and investigators. The primary outcome was HbA1c at 26 weeks, with a 0·4% non-inferiority margin. Secondary outcomes included estimated glomerular filtration rate (eGFR) and urine albumin-to-creatinine ratio (UACR). The primary analysis population was all randomly assigned patients who received at least one dose of study treatment and had at least one post-randomisation HbA1c measurement. The safety population was all patients who received at least one dose of study treatment and had any post-dose data. This study is registered with ClinicalTrials.gov, number NCT01621178.

Findings

Between Aug 15, 2012, and Nov 30, 2015, 577 patients were randomly assigned, 193 to dulaglutide 1·5 mg, 190 to dulaglutide 0·75 mg, and 194 to insulin glargine. The effects on HbA1c change at 26 weeks of dulaglutide 1·5 mg and 0·75 mg were non-inferior to those of insulin glargine (least squares mean [LSM] −1·2% [SE 0·1] with dulaglutide 1·5 mg [183 patients]; −1·1% [0·1] with dulaglutide 0·75 mg [180 patients]; −1·1% [0·1] with insulin glargine [186 patients]; one-sided p≤0·0001 for both dulaglutide doses vs insulin glargine). The differences in HbA1c concentration at 26 weeks between dulaglutide and insulin glargine treatments were LSM difference −0·05% (95% CI −0·26 to 0·15, p<0·0001) with dulaglutide 1·5 mg and 0·02% (−0·18 to −0·22, p=0·0001) with dulaglutide 0·75 mg. HbA1c-lowering effects persisted to 52 weeks (LSM −1·1% [SE 0·1] with dulaglutide 1·5 mg; −1·1% [0·1] with dulaglutide 0·75 mg; −1·0% [0·1] with insulin glargine). At 52 weeks, eGFR was higher with dulaglutide 1·5 mg (Chronic Kidney Disease Epidemiology Collaboration equation by cystatin C geometric LSM 34·0 mL/min per 1·73 m2 [SE 0·7]; p=0·005 vs insulin glargine) and dulaglutide 0·75 mg (33·8 mL/min per 1·73 m2 [0·7]; p=0·009 vs insulin glargine) than with insulin glargine (31·3 mL/min per 1·73 m2 [0·7]). At 52 weeks, the effects of dulaglutide 1·5 mg and 0·75 mg on UACR reduction were not significantly different from that of insulin glargine (LSM −22·5% [95% CI −35·1 to −7·5] with dulaglutide 1·5 mg; −20·1% [–33·1 to −4·6] with dulaglutide 0·75 mg; −13·0% [–27·1 to 3·9] with insulin glargine). Proportions of patients with any serious adverse events were similar across groups (20% [38 of 192] with dulaglutide 1·5 mg, 24% [45 of 190] with dulaglutide 0·75 mg, and 27% [52 of 194] with insulin glargine). Dulaglutide was associated with higher rates of nausea (20% [38 of 192] with dulaglutide 1·5 mg and 14% [27 of 190] with 0·75 mg, vs 5% [nine of 194] with insulin glargine) and diarrhoea (17% [33 of 192] with dulaglutide 1·5 mg and 16% [30 of 190] with 0·75 mg, vs 7% [14 of 194] with insulin glargine) and lower rates of symptomatic hypoglycaemia (4·4 events per patient per year with dulaglutide 1·5 mg and 4·3 with dulaglutide 0·75 mg, vs 9·6 with insulin glargine). End-stage renal disease occurred in 38 participants: eight (4%) of 192 with dulaglutide 1·5 mg, 14 (7%) of 190 with dulaglutide 0·75 mg, and 16 (8%) of 194 with insulin glargine.

Interpretation

In patients with type 2 diabetes and moderate-to-severe chronic kidney disease, once-weekly dulaglutide produced glycaemic control similar to that achieved with insulin glargine, with reduced decline in eGFR. Dulaglutide seems to be safe to use to achieve glycaemic control in patients with moderate-to-severe chronic kidney disease.

Funding

Eli Lilly and Company.

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

References (29)

  • MF Moen et al.

    Frequency of hypoglycemia and its significance in chronic kidney disease

    Clin J Am Soc Nephrol

    (2009)
  • J Jendle et al.

    Efficacy and safety of dulaglutide in the treatment of type 2 diabetes: a comprehensive review of the dulaglutide clinical data focusing on the AWARD phase 3 clinical trial program

    Diabetes Metab Res Revs

    (2016)
  • M Pawaskar et al.

    Observational study of kidney function and albuminuria in patients with type 2 diabetes treated with exenatide BID versus insulin glargine

    Ann Pharmacother

    (2014)
  • KR Tuttle et al.

    Effects of once-weekly dulaglutide on kidney function in patients with type 2 diabetes in phase II and III clinical trials

    Diabetes Obes Metab

    (2017)
  • Cited by (391)

    • Novel obesity treatments

      2023, CMAJ. Canadian Medical Association Journal
    View all citing articles on Scopus

    Dr Zimmermann retired in December, 2017

    View full text