The Lancet July 13, 2019

Dulaglutide and renal outcomes in type 2 diabetes: an exploratory analysis of the REWIND randomised, placebo-controlled trial

Hertzel C. Gerstein, Helen M. Colhoun, Gilles R. Dagenais, et al.

Bottom Line

In a prespecified exploratory analysis of the REWIND trial, once-weekly dulaglutide significantly reduced the risk of a composite renal outcome in patients with type 2 diabetes, primarily driven by a reduction in new-onset macroalbuminuria.

Key Findings

1. Over a median follow-up of 5.4 years, the primary composite renal outcome occurred in 17.1% of patients in the dulaglutide group compared to 19.6% in the placebo group (HR 0.85, 95% CI 0.77-0.93; P=0.0004) [2.1.2].

2. The reduction in the composite renal outcome was primarily driven by a significantly lower incidence of new macroalbuminuria in the dulaglutide group versus placebo (8.9% vs. 11.3%; HR 0.77, 95% CI 0.68-0.87; P<0.0001).

3. A sustained decline in eGFR of 30% or more occurred less frequently with dulaglutide, though the difference did not reach statistical significance at this threshold (HR 0.89, 95% CI 0.78-1.01; P=0.066); however, a sustained eGFR decline of 50% or more was significantly reduced (1.2% vs. 2.2%; P=0.0002).

4. There was no significant difference between the groups regarding the incidence of chronic renal replacement therapy (HR 0.75, 95% CI 0.39-1.44; P=0.39), reflective of the very low event rate in this predominantly primary prevention cohort.

Study Design

Design

Exploratory Analysis of RCT

Double-Blind

Sample

9,901

Patients

Duration

5.4 yr

Median

Setting

24 countries

Population Men and women aged 50 years or older with type 2 diabetes and either established cardiovascular disease or multiple cardiovascular risk factors.

Intervention Dulaglutide 1.5 mg once-weekly subcutaneous injection.

Comparator Placebo once-weekly subcutaneous injection.

Outcome First occurrence of a composite renal outcome including new macroalbuminuria (UACR > 33.9 mg/mmol), sustained decline in eGFR of 30% or more from baseline, or chronic renal replacement therapy.

Study Limitations

• The renal endpoints were evaluated as part of a prespecified exploratory analysis of a secondary outcome, rather than the primary endpoint of the trial.

• The overall benefit in the composite renal outcome was overwhelmingly driven by the reduction in macroalbuminuria, a surrogate marker, rather than harder clinical endpoints like chronic renal replacement therapy.

• Because the REWIND cohort had relatively preserved baseline renal function and low rates of advanced diabetic kidney disease, the findings cannot be fully extrapolated to patients with severe CKD.

• The reliance on estimated GFR rather than measured GFR may have introduced inherent variability into the renal decline assessments.

Clinical Significance

This exploratory analysis of the landmark REWIND CVOT provides critical evidence that the once-weekly GLP-1 receptor agonist dulaglutide mitigates the progression of early diabetic kidney disease, primarily by preventing the onset of macroalbuminuria. In contrast to dedicated renal outcome trials that enrolled patients with advanced CKD, REWIND demonstrated that microvascular renoprotective benefits can be achieved in a broad type 2 diabetes population, even among those without established cardiovascular disease or severe renal impairment. These findings solidify the role of GLP-1 RAs in comprehensively managing cardiorenal risk in early type 2 diabetes.

Historical Context

At the time of REWIND's publication in 2019, SGLT2 inhibitors had just established themselves as the premier renoprotective agents with dedicated trials like CREDENCE. Meanwhile, cardiovascular outcome trials (CVOTs) for GLP-1 RAs-such as LEADER (liraglutide) and SUSTAIN-6 (semaglutide)-had shown promising signals of secondary microvascular renal protection, largely driven by reduced albuminuria. REWIND was historically unique because it enrolled the highest proportion of primary prevention patients (nearly 70% without prior CVD) of any GLP-1 RA CVOT to date, and its median follow-up of 5.4 years was the longest. This analysis extended the class effect of GLP-1 RA renoprotection to a lower-risk, earlier-stage population.

Guided Discussion

High-yield insights from every perspective

Med Student

Medical Student

How does a GLP-1 receptor agonist like dulaglutide provide renal protection in patients with type 2 diabetes, independent of its glucose-lowering effects?

Key Response

GLP-1 RAs reduce hyperfiltration by modulating the renin-angiotensin-aldosterone system and reducing proximal tubular sodium reabsorption, leading to increased distal sodium delivery, restored tubuloglomerular feedback, and reduced intraglomerular pressure. They also possess direct anti-inflammatory and anti-fibrotic properties in the kidney.

Resident

In a patient with type 2 diabetes and newly diagnosed macroalbuminuria, how should the REWIND data on dulaglutide influence your choice between initiating a GLP-1 receptor agonist versus an SGLT2 inhibitor?

Key Response

While REWIND shows dulaglutide reduces macroalbuminuria, SGLT2 inhibitors have dedicated primary renal outcome trials showing robust reductions in eGFR decline and ESRD risk. Current guidelines prioritize SGLT2 inhibitors for patients with established diabetic kidney disease, using GLP-1 RAs as an add-on for further glycemic or weight control, or as an alternative if SGLT2 inhibitors are contraindicated.

Fellow

The renal composite outcome in REWIND was primarily driven by a reduction in new-onset macroalbuminuria rather than a reduction in sustained eGFR decline. Why might this specific driver limit the clinical weight of the conclusion regarding hard renal endpoints?

Key Response

Macroalbuminuria is an intermediate surrogate marker and does not always reliably predict progression to end-stage renal disease (ESRD). Since hard endpoints like a 50% eGFR decline or ESRD events were low and not significantly reduced independently, the trial suggests early structural or functional benefit but lacks definitive proof of preventing terminal renal failure compared to dedicated CKD trials.

Attending

The REWIND trial included a uniquely high proportion of patients without prior cardiovascular disease and with normal baseline renal function. How does this primary prevention cohort change the way we counsel average-risk patients with early type 2 diabetes about long-term organ protection?

Key Response

Unlike earlier cardiovascular outcome trials that focused almost exclusively on secondary prevention in high-risk patients, REWIND proves that early initiation of GLP-1 RAs in broader, lower-risk primary prevention populations offers meaningful microvascular (renal) and macrovascular protection, shifting the paradigm from strictly glycemic control to early, comprehensive end-organ preservation.

Scholarly Review

Critical appraisal through the lens of expert reviewers and guideline development

PhD

This study was a prespecified exploratory analysis of a cardiovascular outcome trial. Statistically, what are the inherent limitations of evaluating composite renal outcomes without formal alpha-spending adjustments, and how does this affect the interpretation of the results?

Key Response

Exploratory endpoints are typically not included in the hierarchical testing strategy used to control the family-wise error rate. Therefore, nominal p-values for these renal outcomes carry a higher risk of type I error (false positives) due to multiple testing and should be viewed as hypothesis-generating rather than definitive proof, particularly when event rates for hard components are low.

Journal Editor

In assessing the validity of these renal outcomes, how should peer reviewers scrutinize the handling of competing risks, such as cardiovascular death, particularly when evaluating time-to-first-event models for a renal composite endpoint in a diabetes trial?

Key Response

Since patients in cardiovascular outcome trials are at high risk of cardiovascular death, a competing risk framework (like the Fine-Gray model) is essential. If standard Kaplan-Meier or Cox proportional hazards models are used without acknowledging that early death prevents a patient from reaching a renal endpoint, the treatment's true effect on renal outcomes might be misestimated or biased.

Guideline Committee

Given that ADA and KDIGO guidelines strongly recommend SGLT2 inhibitors for diabetic kidney disease, does the REWIND exploratory data provide sufficient evidence to elevate GLP-1 receptor agonists to an equivalent Level A recommendation for primary prevention of CKD in T2D?

Key Response

No. The evidence from REWIND is exploratory, driven largely by albuminuria rather than hard eGFR/ESRD endpoints, and derived from a trial designed for cardiovascular outcomes. Guidelines maintain SGLT2 inhibitors as the primary recommendation for CKD progression based on dedicated renal trials (e.g., DAPA-CKD), whereas GLP-1 RAs remain highly recommended for cardiovascular risk reduction or when SGLT2 inhibitors are not tolerated, serving as complementary rather than primary definitive renal therapy.

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 risk of the primary composite outcome of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke, and showed secondary benefits in reducing the progression of diabetic nephropathy.

2016

SUSTAIN-6 Trial

n = 3,297 · NEJM

Tested

Semaglutide 0.5 mg or 1.0 mg weekly

Population

T2DM patients with high cardiovascular risk

Comparator

Placebo

Endpoint

3-point MACE

Key result: Semaglutide significantly lowered the rate of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke, and a secondary analysis showed a significant reduction in new or worsening nephropathy.

2018

AWARD-7 Trial

n = 577 · Lancet Diabetes Endocrinol

Tested

Dulaglutide 0.75 mg or 1.5 mg weekly plus insulin glargine

Population

T2DM patients with moderate-to-severe CKD (Stages 3-4)

Comparator

Insulin glargine daily

Endpoint

HbA1c at 26 weeks

Key result: Dulaglutide produced similar glycemic control to insulin glargine but was associated with significantly less decline in eGFR, highlighting its safety and potential renal benefits.

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