The Lancet Diabetes & Endocrinology August 01, 2018

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

Katherine R Tuttle, Mark C Lakshmanan, Brian Rayner, Robert S Busch, Alan G Zimmermann, D Bradley Woodward, Fady T Botros

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Bottom Line

In patients with type 2 diabetes and moderate-to-severe chronic kidney disease, once-weekly dulaglutide demonstrated non-inferior glycemic control compared to insulin glargine, while reducing eGFR decline and lowering the rate of symptomatic hypoglycemia.

Key Findings

1. At 26 weeks, HbA1c changes with dulaglutide 1.5 mg (LSM -1.2%) and 0.75 mg (-1.1%) were non-inferior to insulin glargine (-1.1%) (one-sided p<=0.0001 for both vs glargine).

2. HbA1c-lowering effects were sustained at 52 weeks (-1.1% for both dulaglutide 1.5 mg and 0.75 mg, and -1.0% for insulin glargine).

3. At 52 weeks, eGFR was significantly higher with dulaglutide 1.5 mg (34.0 mL/min/1.73m2, p=0.005) and 0.75 mg (33.8 mL/min/1.73m2, p=0.009) compared to insulin glargine (31.3 mL/min/1.73m2).

4. UACR reductions at 52 weeks were not significantly different across groups (LSM -22.5% with dulaglutide 1.5 mg, -20.1% with dulaglutide 0.75 mg, and -13.0% with insulin glargine).

5. Symptomatic hypoglycemia occurred less frequently with dulaglutide (4.4 and 4.3 events/patient/year for 1.5 mg and 0.75 mg, respectively) versus insulin glargine (9.6 events/patient/year).

6. Rates of nausea (20% and 14% vs 5%) and diarrhea (17% and 16% vs 7%) were higher with dulaglutide 1.5 mg and 0.75 mg compared to insulin glargine.

7. End-stage renal disease occurred in 4% of the dulaglutide 1.5 mg group, 7% of the 0.75 mg group, and 8% of the insulin glargine group.

Study Design

Design

Randomised Trial

Open-Label

Sample

577

Patients

Duration

52 wk

Median

Setting

Multicenter, 9 countries

Population Adults with type 2 diabetes and moderate-to-severe chronic kidney disease (stages 3-4) on max tolerated ACEi/ARB

Intervention Once-weekly dulaglutide 1.5 mg or 0.75 mg, in combination with insulin lispro

Comparator Daily insulin glargine as basal therapy, in combination with insulin lispro

Outcome HbA1c at 26 weeks (0.4% non-inferiority margin)

Study Limitations

• The open-label design for the main treatment arms (dulaglutide vs insulin glargine) may introduce reporting bias for subjective outcomes like hypoglycemia, nausea, and diarrhea.

• The 52-week follow-up period is relatively short for definitively evaluating hard long-term renal endpoints like end-stage renal disease (ESRD).

• The trial relied heavily on surrogate markers (eGFR and UACR) as its primary assessment of renal function changes.

Clinical Significance

AWARD-7 demonstrated that dulaglutide safely provides effective glycemic control comparable to basal insulin in patients with advanced chronic kidney disease, while simultaneously minimizing hypoglycemia risk and attenuating eGFR decline, thus offering a crucial alternative to insulin-only regimens in this high-risk population.

Historical Context

Historically, treatment options for patients with T2DM and moderate-to-severe CKD were highly restricted due to the renal clearance of many oral hypoglycemic agents, leading to an over-reliance on insulin therapy which inherently carried a high risk of severe hypoglycemia. The AWARD-7 trial broke new ground by providing rigorous evidence that a non-renally cleared GLP-1 receptor agonist (dulaglutide) could be safely used in stage 3-4 CKD, showing not only metabolic efficacy and safety but also highlighting potential kidney-protective benefits that sparked subsequent dedicated renal outcome trials for the incretin drug class.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

Why are patients with type 2 diabetes and advanced chronic kidney disease at a particularly high risk for hypoglycemia when treated with insulin glargine, and how does the mechanism of dulaglutide mitigate this risk?

Key Response

Insulin is renally cleared; as GFR drops in advanced CKD, insulin half-life increases, leading to prolonged and unpredictable hypoglycemia. Dulaglutide, a GLP-1 receptor agonist, stimulates insulin secretion in a strictly glucose-dependent manner, significantly reducing the risk of hypoglycemia even when renal clearance is impaired.

Resident

When managing a patient with type 2 diabetes and stage 4 CKD who is currently struggling with hypoglycemic events on basal insulin, how does the AWARD-7 trial support transitioning them to a GLP-1 receptor agonist like dulaglutide?

Key Response

The AWARD-7 trial demonstrated that dulaglutide provides non-inferior HbA1c reduction compared to insulin glargine but with significantly lower rates of symptomatic hypoglycemia and the added benefit of weight loss, making it a safer and often more effective choice for patients with advanced CKD.

Fellow

The AWARD-7 trial noted a reduced decline in eGFR with dulaglutide compared to insulin glargine, particularly in patients with macroalbuminuria. What are the proposed hemodynamic and structural mechanisms by which GLP-1 receptor agonists confer this renoprotection independent of glycemic control?

Key Response

GLP-1 RAs are thought to reduce oxidative stress, decrease renal inflammation, and potentially inhibit the sodium-hydrogen exchanger 3 (NHE3) in the proximal tubule. This leads to reduced intraglomerular pressure, which slows eGFR decline and reduces albuminuria independent of glucose lowering.

Attending

Given the historical reliance on insulin for glycemic control in advanced CKD due to the contraindication of many oral agents, how should the findings of AWARD-7 reshape our clinical inertia and threshold for initiating injectable GLP-1 receptor agonists prior to resorting to basal insulin?

Key Response

Historically, advanced CKD meant limited options and an almost automatic default to insulin despite its risks. AWARD-7 proves that GLP-1 RAs like dulaglutide are not only safe in Stage 3-4 CKD but offer superior safety profiles regarding hypoglycemia and potential renal benefits, suggesting they should be prioritized over basal insulin.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

The AWARD-7 trial utilized an open-label design for the comparison between dulaglutide and insulin glargine. How might this lack of blinding introduce bias in the reporting of subjective endpoints like symptomatic hypoglycemia, and what methodological adjustments could strengthen these findings?

Key Response

In an open-label trial, patients aware they are on a novel therapy might underreport symptoms, or those on insulin might hyper-vigilantly check and report hypoglycemia. Utilizing strictly defined biochemical hypoglycemia thresholds via blinded continuous glucose monitoring (CGM) would provide a more objective measure to validate subjective reporting.

Journal Editor

As a peer reviewer assessing the AWARD-7 trial, how would you scrutinize the insulin glargine titration protocol used in the control arm, and could a suboptimal treat-to-target algorithm have artificially inflated the relative hypoglycemia safety and eGFR benefits seen with dulaglutide?

Key Response

If the insulin titration was too aggressive or did not adequately account for the reduced renal clearance in CKD patients, it could lead to excessive hypoglycemia. A rigorous editorial review would demand a detailed breakdown of the insulin dosing algorithm to ensure the comparator arm accurately reflected cautious, standard-of-care clinical practice for advanced CKD.

Guideline Committee

In light of the AWARD-7 trial and subsequent cardiovascular outcome trials, how should KDIGO and ADA guidelines position GLP-1 receptor agonists in the treatment algorithm for patients with type 2 diabetes and stage 3-4 CKD, particularly regarding their hierarchy relative to SGLT2 inhibitors and basal insulin?

Key Response

Current KDIGO and ADA guidelines strongly recommend SGLT2 inhibitors as first-line therapy for T2D and CKD due to robust renal and cardiovascular benefits. Based on AWARD-7 and similar data, GLP-1 RAs are recommended as the preferred class for patients who cannot tolerate SGLT2 inhibitors or require additional glycemic control, firmly placing them ahead of basal insulin due to combined glycemic efficacy, weight management, and reduced hypoglycemia risk.

Clinical Landscape

Noteworthy Related Trials

2016

LEADER Trial

n = 9,340 · NEJM

Tested

Liraglutide up to 1.8 mg daily

Population

T2DM patients with high cardiovascular risk

Comparator

Placebo

Endpoint

3-point MACE

Key result: Liraglutide significantly reduced the rate of the primary composite cardiovascular outcome and all-cause death, while also showing lower rates of new or worsening nephropathy.

2019

REWIND Trial

n = 9,901 · Lancet

Tested

Dulaglutide 1.5 mg weekly

Population

T2DM patients with or at risk for cardiovascular events

Comparator

Placebo

Endpoint

3-point MACE

Key result: Dulaglutide significantly reduced the risk of the composite cardiovascular outcome compared to placebo, and a secondary analysis showed reduced composite renal outcomes.

2019

CREDENCE Trial

n = 4,401 · NEJM

Tested

Canagliflozin 100 mg daily

Population

T2DM patients with albuminuric chronic kidney disease

Comparator

Placebo

Endpoint

Composite of ESKD, doubling of serum creatinine, or renal/CV death

Key result: Canagliflozin significantly lowered the risk of kidney failure and cardiovascular events in patients with type 2 diabetes and kidney disease.

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