Dulaglutide and renal outcomes in type 2 diabetes: an exploratory analysis of the REWIND randomised, placebo-controlled trial
Hertzel C Gersteinet al
ABSTRACT
Summary
Background
Two glucagon-like peptide-1 (GLP-1) receptor agonists reduced renal outcomes in people with type 2 diabetes at risk for cardiovascular disease. We assessed the long-term e ect of the GLP-1 receptor agonist dulaglutide on renal outcomes in an exploratory analysis of the REWIND trial of the e ect of dulaglutide on cardiovascular disease.
Methods
REWIND was a multicentre, randomised, double-blind, placebo-controlled trial at 371 sites in 24 countries. Men and women aged at least 50 years with type 2 diabetes who had either a previous cardiovascular event or cardiovascular risk factors were randomly assigned (1:1) to either weekly subcutaneous injection of dulaglutide (1·5 mg) or placebo and followed up at least every 6 months for outcomes.
Urinary albumin-to-creatinine ratios (UACRs) and estimated glomerular filltration rates (eGFRs) were estimated from urine and serum values measured in local laboratories every 12 months.
The primary outcome (first occurrence of the composite endpoint of non-fatal myocardial infarction, non-fatal stroke, or death from cardiovascular causes), secondary outcomes (including a composite microvascular outcome), and safety outcomes of this trial have been reported elsewhere.
In this exploratory analysis, we investigate the renal component of the composite microvascular outcome, de ned as the rst occurrence of new macroalbuminuria (UACR >33·9 mg/mmol), a sustained decline in eGFR of 30% or more from baseline, or chronic renal replacement therapy. Analyses were by intention to treat. This trial is registered with ClinicalTrials.gov, number NCT01394952.
Findings
Between Aug 18, 2011, and Aug 14, 2013, 9901 participants were enrolled and randomly assigned to receive dulaglutide (n=4949) or placebo (n=4952). At baseline, 791 (7·9%) had macroalbuminuria and mean eGFR was 76·9 mL/min per 1·73 m2 (SD 22·7).
During a median follow-up of 5·4 years (IQR 5·1–5·9) comprising 51 820 person- years, the renal outcome developed in 848 (17·1%) participants at an incidence rate of 3·5 per 100 person-years in the dulaglutide group and in 970 (19·6%) participants at an incidence rate of 4·1 per 100 person-years in the placebo group (hazard ratio [HR] 0·85, 95% CI 0·77–0·93; p=0·0004).
The clearest effect was for new macroalbuminuria (HR 0·77, 95% CI 0·68–0·87; p<0·0001), with HRs of 0·89 (0·78–1·01; p=0·066) for sustained decline in eGFR of 30% or more and 0·75 (0·39–1·44; p=0·39) for chronic renal replacement therapy.
Interpretation
Long-term use of dulaglutide was associated with reduced composite renal outcomes in people with type 2 diabetes.
Evidence before this study
We searched PubMed for reports published in English between Jan 1, 2010, and March 31, 2019, of double-blind, randomised, placebo-controlled trials that were designed and powered to test the effect of glucagon-like peptide-1 (GLP-1) receptor agonists on incident cardiovascular outcomes in people with type 2 diabetes and additional cardiac risk factors and that reported the e ect of the intervention on renal outcomes. Search terms were “type 2 diabetes”, “GLP1-RA”, “glucagon-like peptide receptor 1 agonist”, “glucagon-like peptide receptor 1 analogue”, “lixisenatide”, “liraglutide”, “semaglutide”, “taspoglutide”, “albiglutide”, “dulaglutide”, “renal disease”, “renal function”, “renal”, “cardiovascular disease”, and “randomized controlled trial”. This search identi ed
three cardiovascular outcomes trials that reported the effects of lixisenatide (ELIXA; n=6068), liraglutide (LEADER; n=9340), and semaglutide (SUSTAIN-6; n=3297) versus placebo on incident renal outcomes in middle-aged people (age ≥50 years) with type 2 diabetes. Mean glycated haemoglobin A1c (HbA1c) ranged from 7·7% to 8·7%, the proportion with an eGFR of
60 mL/min per 1·73 m2 or more ranged from 70% to 77%, and median follow-up durations ranged from 2·1 years to 3·8 years. The composite renal outcome for both the LEADER and SUSTAIN-6 trials (new macroalbuminuria, doubling of serum creatinine concentration and estimated glomerular ltration rate [eGFR] less than 45 mL/min per 1·73 m2, renal replacement therapy, or renal death) was reduced by the GLP-1 receptor agonist compared with placebo, with hazard ratios (HRs) of 0·78 (95% CI 0·67–0·92) and 0·64 (0·46–0·88), respectively.
No composite renal outcome was prespeci ed for ELIXA. Reported renal outcomes in ELIXA were time to new macroalbuminuria (HR 0·81, 95% CI 0·66–0·99) and doubling of serum creatinine (HR 1·16, 0·74–1·83). All three trials suggested that the main renal e ects of the GLP-1 receptor agonists were on progression of albuminuria, with modest e ects on eGFR. These ndings supported exploratory analyses of the e ect on dulaglutide on renal outcomes in the REWIND trial.
Added value of this study
Participants in the REWIND trial had a mean baseline HbA1c of 7·3%, a mean baseline eGFR of 76·9 mL/min per 1·73 m2, and a 35·0% baseline prevalence of albuminuria, and were followed up for a median of 5·4 years. Dulaglutide reduced the prespecified composite renal outcome of new-onset macroalbuminuria, eGFR decline of 30% or more, or chronic renal replacement therapy, with the clearest effect on the macroalbuminuria component. Additional analyses suggested that the renal e ects of dulaglutide could not be completely explained by its e ect on glucose concentration or blood pressure.
Implications of all the available evidence
GLP-1 receptor agonists that have been shown to reduce cardiovascular outcomes also seem to have a salutary e ect on renal outcomes and particularly albuminuria. Future large prospective trials of the effect of these drugs on prespecifed renal outcomes should be done to more clearly characterise their effects on renal function in people with preserved and reduced baseline renal function.
FROM THE ARTICLE
Introduction
Diabetic kidney disease is diagnosed by an estimated glomerular ltration rate (eGFR) of less than 90 mL/min per 1·73 m2 or a urinary albumin-to-creatinine ratio (UACR) of 30 mg/g (3·39 mg/mmol) or more. It a ects up to 40% of people with diabetes,1 in whom it is an independent risk factor for cardiovascular disease, hypertension, retinal disease, and premature death. Moreover, diabetes accounts for up to 45% of people with incident end-stage kidney disease.2 Findings from large randomised controlled trials have shown that chronic renal outcomes can be reduced by intensive glucose control3 and blood pressure lowering,4 blockade of the renin–angiotensin system with either angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers, and sodium-glucose co-transporter-2 (SGLT2) inhibitors.1,2,5,6 The e ect of glucagon-like peptide-1 (GLP-1) receptor agonists on renal outcomes has also been assessed in large cardiovascular outcomes trials of people with type 2 diabetes. In addition to improved glucose control, and lowered blood pressure and bodyweight, trials of liraglutide, semaglutide
During a median follow-up of 5·4 years (IQR 5·1–5·9) comprising 51 820 person- years, the renal outcome developed in 848 (17·1%) participants at an incidence rate of 3·5 per 100 person-years in the dulaglutide group and in 970 (19·6%) participants at an incidence rate of 4·1 per 100 person-years in the placebo group (hazard ratio [HR] 0·85, 95% CI 0·77–0·93; p=0·0004).
The clearest effect was for new macroalbuminuria (HR 0·77, 95% CI 0·68–0·87; p<0·0001), with HRs of 0·89 (0·78–1·01; p=0·066) for sustained decline in eGFR of 30% or more and 0·75 (0·39–1·44; p=0·39) for chronic renal replacement therapy.
Albiglutide reported a significantly reduced hazard of the primary cardiovascular outcome.6–10 Two of the trials also reported that daily liraglutide injections9,11 and weekly semaglutide injections10 reduced the prede ned composite renal outcome overall and in people with a reduced eGFR.11 Moreover, lixisenatide reduced new- onset macroalbuminuria in one trial.12
Dulaglutide is a GLP-1 receptor agonist derived from human GLP-1 that is administered weekly by sub- cutaneous injection. In the REWIND randomised placebo-controlled trial, dulaglutide reduced the risk of cardiovascular events when added to the existing antihyperglycaemic regimens of people with type 2 diabetes.13 A previous trial reported that dulaglutide reduced the 1-year decline in eGFR in patients with stage 3 or 4 chronic kidney disease;14 however, the long- term effect of dulaglutide on renal outcomes in people with type 2 diabetes and a much broader range of eGFR and cardiovascular disease risk is unclear.
Renal outcomes were prospectively defined and collected in the REWIND trial as part of a secondary composite microvascular outcome; however, the protocol did not prespecify separate analyses of the components of this outcome. We did exploratory analyses of the prospectively de ned renal effects of dulaglutide and their relation to glucose and blood pressure lowering within the REWIND trial.
DISCUSSION
Discussion
These exploratory analyses suggest that weekly injections of dulaglutide 1·5 mg for a median period of 5·4 years reduced the hazard of the composite renal outcome compared with placebo in middle-aged people with type 2 diabetes who had mean eGFR of 77 mL/min per 1·73 m2 and baseline prevalence of albuminuria of 35·0%. On the basis of the observed absolute risk di erence, our ndings also suggest that one composite renal outcome event would be prevented for every 31 similar people with type 2 diabetes treated with dulaglutide for a median of 5·4 years. Although dulaglutide numerically reduced all three components of the composite renal outcome (the development of new macroalbuminuria, a sustained ≥30% decline in eGFR, or chronic renal replacement therapy), the largest e ect was noted for the development of macroalbuminuria.
These findings are consistent with those from other cardiovascular outcomes trials of GLP-1 receptor agonists, in which statistically signicant reductions in composite renal outcomes were mainly due to a robust e ect on the development of macroalbuminuria.9,10,12,21 Our findings did not confirm the results of a previous trial that reported a beneficial effect of dulaglutide on the decline in eGFR in people with advanced renal insufficiency (who had a mean eGFR of 38 mL/min per 1·73 m2).14 However, our sensitivity analyses suggested a reduced incidence of a 40% and 50% decline in eGFR with dulaglutide, supporting the possibility that dulaglutide might preserve renal function; this association merits further scrutiny.
These findings for dulaglutide add to what is already known regarding the effect of GLP-1 receptor agonists on renal disease. They suggest that treatment with dulaglutide modestly reduces progression of kidney disease and that the renal e ect might persist for at least 5 years. Our findings also suggest that the effect of dulaglutide on HbA1c and systolic blood pressure might account for a portion of its e ect on the composite renal outcome and particularly its albuminuria component. This possibility is consistent with a meta-analysis of large outcomes trials of people with type 2 diabetes, which reported that glucose lowering reduced the hazard of renal outcomes by 20%, with the largest e ect on macroalbuminuria.3
It is also consistent with a large meta-analysis of trials in people with and without diabetes, which reported that blood pressure lowering mainly reduced albuminuria.
The effect of dulaglutide on HbA pressure clearly cannot account for all of its effect on the renal outcome. Accumulating evidence suggests that GLP-1 receptor agonists directly affectt the kidney by reducing in ammation, reducing oxidative stress, and preserving endothelial function.24 Indeed, the observed reduction in albuminuria might re ect a direct e ect on renal endothelial cells, and by extension endothelial tissue throughout the body.25 A theoretical possibility is based on experimental data and suggests that GLP-1 receptor agonist-mediated inhibition of sodium– hydrogen exchange in the proximal tubule might promote a erent arteriolar constriction and a short- term fall in eGFR due to tubuloglomerular feedback.24 However, the absence of any effect of dulaglutide on the eGFR during the first year of therapy suggests that this is an unlikely mechanism.26
Strengths of this study include a study population that is representative of a large proportion of people with type 2 diabetes, including a high proportion of women, a wide range of baseline renal function, and an HbA typical of the average person with type 2 diabetes.27 Other strengths include the multicentre design; large sample size; long, extensive, and near-complete follow- up; and exploration of the possible explanatory e ect of glycaemia and blood pressure. The major limitation is the exploratory nature of these analyses and the use of local measurement of albuminuria and serum creatinine for estimation of eGFR.
In addition to the reduced incidence of cardiovascular outcomes with dulaglutide that was reported in the REWIND trial,13 these exploratory analyses suggest that about 5 years’ exposure to dulaglutide might reduce progression of renal disease across a wide range of cardiovascular risk, renal function, and glycaemic control. Our findings also suggest that this reduction occurs for reasons that extend beyond the effect of dulaglutide on glucose and blood pressure and is independent of the use of angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers. Irrespective of the reason, these analyses suggest that use of dulaglutide to lower glucose concentrations in people with type 2 diabetes is likely to confer additional renal benefits.
From the Lancet
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