Diabetes Care JUNE 21, 2023

Dulaglutide and Kidney Function-Related Outcomes in Type 2 Diabetes: A REWIND Post Hoc Analysis

The REWIND Trial Investigators

Bottom Line

In this post hoc analysis of the REWIND trial, once-weekly dulaglutide demonstrated a significant reduction in the risk of a composite kidney function-related outcome and a slower rate of eGFR decline compared to placebo in patients with type 2 diabetes.

Key Findings

1. Dulaglutide was associated with a 25% reduction in the hazard of a composite kidney function-related outcome (sustained ≥40% eGFR decline, ESRD, or renal death) compared to placebo (HR 0.75; 95% CI 0.62–0.92; P = 0.004).

2. A sustained ≥40% decline in eGFR occurred significantly less frequently with dulaglutide than with placebo (HR 0.72; 95% CI 0.58–0.88; P = 0.002).

3. The mean annual decline in eGFR was significantly slower in the dulaglutide group compared to the placebo group (-1.37 vs. -1.56 mL/min/1.73 m2/year; P < 0.001).

4. Renal benefits were consistent across subgroups defined by baseline urinary albumin-to-creatinine ratio (UACR) and baseline eGFR.

Study Design

Design

Post hoc analysis of an RCT

Double-Blind

Sample

9,901

Patients

Duration

5.4 yr

Median

Setting

Multicenter, Global

Population Adults with type 2 diabetes, HbA1c ≤9.5%, and either established cardiovascular disease or multiple cardiovascular risk factors.

Intervention Once-weekly subcutaneous dulaglutide 1.5 mg

Comparator Once-weekly subcutaneous placebo

Outcome Time to occurrence of a composite kidney function-related outcome defined as sustained ≥40% decline in eGFR, end-stage renal disease, or renal-related death.

Study Limitations

• The study is a post hoc exploratory analysis, which inherently limits the ability to infer definitive causality compared to prespecified primary endpoints.

• The analysis excludes the component of new-onset macroalbuminuria, which was a significant driver of renal benefits observed in the primary REWIND trial results.

• As a post hoc investigation, these findings should be considered hypothesis-generating rather than confirmatory.

Clinical Significance

This analysis provides further evidence supporting the potential of dulaglutide to confer renoprotection in patients with type 2 diabetes across a broad spectrum of cardiovascular risk and kidney function, reinforcing its role as an important therapeutic option for both glycemic management and long-term organ protection.

Historical Context

The original REWIND trial (2019) established that once-weekly dulaglutide reduced major adverse cardiovascular events in a broad population of type 2 diabetes patients. While the primary trial demonstrated benefits in a composite renal outcome (primarily driven by reduced macroalbuminuria), this subsequent post hoc analysis was necessary to isolate the effects of dulaglutide on hard endpoints of kidney function decline (eGFR decline, ESRD, and renal death).

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

What are the primary physiological mechanisms through which GLP-1 receptor agonists like dulaglutide provide nephroprotection, and are these effects solely dependent on their glucose-lowering capacity?

Key Response

Nephroprotection from GLP-1 RAs involves both indirect effects (reduced hyperglycemia, blood pressure, and weight) and direct effects. Direct mechanisms include the inhibition of the sodium-hydrogen exchanger 3 (NHE3) in the proximal tubule leading to natriuresis, and the reduction of pro-inflammatory and pro-fibrotic cytokines (like TGF-beta). Studies, including REWIND, suggest these benefits are partly independent of glycemic control.

Resident

The REWIND trial used a composite kidney outcome. When evaluating the 15% risk reduction reported, which component drove the results, and how does this influence the clinical decision to start dulaglutide in a patient with early-stage CKD?

Key Response

The kidney benefit in REWIND was primarily driven by a reduction in new-onset macroalbuminuria. While 'hard' endpoints like doubling of serum creatinine or ESKD were less frequent due to the relatively low-risk population, the reduction in albuminuria is a key clinical marker for slowing the progression of diabetic kidney disease, making dulaglutide a viable option for early intervention.

Fellow

How does the eGFR slope benefit observed with dulaglutide in the REWIND analysis compare to the hemodynamic 'dip' and subsequent stabilization seen with SGLT2 inhibitors, and what does this imply for dual therapy?

Key Response

Unlike SGLT2 inhibitors, which cause an acute, reversible dip in eGFR due to tubuloglomerular feedback, GLP-1 RAs like dulaglutide do not typically show this initial drop. Instead, they demonstrate a gradual preservation of the eGFR slope over time. This suggests that combining GLP-1 RAs with SGLT2 inhibitors may provide additive nephroprotective benefits through distinct hemodynamic and anti-inflammatory pathways.

Attending

In a patient with Type 2 Diabetes and an eGFR of 75 mL/min/1.73m² who is already on a maximum tolerated dose of an ACE inhibitor and an SGLT2 inhibitor, does the REWIND data provide sufficient evidence to add dulaglutide specifically for long-term renal preservation?

Key Response

REWIND's strength is its population with relatively preserved kidney function and long follow-up (5.4 years). The data suggests that even in those with lower baseline renal risk, dulaglutide slows the loss of eGFR. For an attending, this reinforces the 'holistic' management of the patient, where GLP-1 RAs serve as a powerful third pillar of organ protection alongside RAS blockade and SGLT2 inhibition.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

This study is a post hoc analysis of a cardiovascular outcomes trial. What statistical challenges arise when analyzing eGFR slopes over 5.4 years in a population with low event rates, and how might informative censoring affect the kidney function findings?

Key Response

Post hoc analyses face risks of multiplicity and type I error. In longitudinal eGFR data, 'informative censoring' (patients dropping out due to death or illness) can bias results. Methodologists must use mixed-effects models or joint modeling to account for the correlation between repeated measures and ensure that the slope estimates are not skewed by patients who exited the study early.

Journal Editor

Given that REWIND was not originally designed with a primary kidney endpoint, does the use of a composite outcome including macroalbuminuria provide enough evidence of clinical significance for a top-tier journal, or should the findings be viewed strictly as hypothesis-generating until a primary renal trial is completed?

Key Response

Editors look for 'hard' clinical outcomes. While albuminuria is a validated surrogate, the low number of ESKD events in REWIND is a limitation. A tough reviewer would flag the risk of 'over-interpreting' the composite outcome. However, the large sample size and consistency of the eGFR slope across subgroups provide the rigor needed for high-impact publication, provided the limitations are transparently discussed.

Guideline Committee

Should current KDIGO and ADA guidelines be updated to grant GLP-1 RAs a 'Level 1' recommendation for kidney protection specifically, or should they remain secondary to SGLT2 inhibitors until more dedicated renal trials like FLOW are fully integrated into the evidence base?

Key Response

Currently, ADA and KDIGO guidelines recommend SGLT2 inhibitors as first-line for CKD in T2DM. While REWIND provides robust evidence for dulaglutide, most guidelines require primary outcome trials (like FLOW for semaglutide) to elevate a class to Level 1A for 'renal' indications. REWIND supports GLP-1 RAs as a preferred choice when SGLT2 inhibitors are contraindicated or for further risk reduction, but likely doesn't yet displace them from the primary spot.

Clinical Landscape

Noteworthy Related Trials

2015

EMPA-REG OUTCOME Trial

n = 7,020 · NEJM

Tested

Empagliflozin 10 mg or 25 mg daily

Population

T2DM patients with established cardiovascular disease

Comparator

Placebo

Endpoint

Time to first occurrence of 3-point MACE

Key result: Empagliflozin reduced cardiovascular death and showed a striking preservation of kidney function and a decrease in the incidence of incident or worsening nephropathy.

2016

LEADER Trial

n = 9,340 · NEJM

Tested

Liraglutide 1.8 mg daily

Population

T2DM patients with high cardiovascular risk

Comparator

Placebo

Endpoint

Time to first occurrence of 3-point MACE

Key result: Liraglutide significantly reduced the risk of major adverse cardiovascular events and secondary renal outcomes in high-risk T2DM patients.

2016

SUSTAIN-6 Trial

n = 3,297 · NEJM

Tested

Semaglutide 0.5 mg or 1.0 mg weekly

Population

T2DM patients at high cardiovascular risk

Comparator

Placebo

Endpoint

Time to first occurrence of 3-point MACE

Key result: Semaglutide significantly reduced cardiovascular death, nonfatal MI, and nonfatal stroke, with a significant reduction in the development or progression of nephropathy.

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