Lixisenatide and renal outcomes in patients with type 2 diabetes and acute coronary syndrome: an exploratory analysis of the ELIXA randomised, placebo-controlled trial

Marcel H. A. Muskiet, Lennart Tonneijck, Yao Huang, Minzhi Liu, Aramesh Saremi, Hiddo J. L. Heerspink, Daniël H. van Raalte

Research output: Contribution to journalArticleAcademicpeer-review

Abstract

Background: The results of the ELIXA trial demonstrated the cardiovascular safety of lixisenatide, a short-acting glucagon-like peptide-1 receptor agonist, in patients with type 2 diabetes and acute coronary syndrome. In this exploratory analysis of ELIXA, we investigate the effect of lixisenatide on renal outcomes. Methods: ELIXA was a randomised, double-blind, placebo-controlled trial, done at 828 sites in 49 countries. Patients with type 2 diabetes and a recent coronary artery event were randomly assigned (1:1) to a daily subcutaneous injection of lixisenatide (10–20 μg) or volume-matched placebo, in addition to usual care, until at least 844 patients had an adjudicated major adverse cardiovascular event included in the primary outcome. Patients, study staff, and individuals involved in analysis of trial data were masked to treatment assignment. The primary and secondary endpoints of this trial have been reported previously. Here, in an exploratory analysis of ELIXA, we investigated percentage change in urinary albumin-to-creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR) according to prespecified albuminuria status at baseline (normoalbuminuria [UACR <30 mg/g]; microalbuminuria [≥30 to ≤300 mg/g]; and macroalbuminuria [>300 mg/g]) using a mixed-effect model with repeated measures. Time to new-onset macroalbuminuria and doubling of serum creatinine were also assessed with Cox proportional hazards models. The ELIXA trial is registered with ClinicalTrials.gov, number NCT01147250, and is completed. Findings: Of 6068 patients randomly allocated between July 9, 2010, and Aug 2, 2013, baseline UACR data were available for 5978 (99%). Median follow-up time was 108 weeks. 4441 (74%; 2191 assigned to placebo and 2250 assigned to lixisenatide) had normoalbuminuria, 1148 (19%; 596 assigned to placebo and 552 assigned to lixisenatide) had microalbuminuria, and 389 (7%; 207 assigned to placebo and 182 assigned to lixisenatide) had macroalbuminuria. After 108 weeks, the placebo-adjusted least-squares mean percentage change in UACR from baseline with lixisenatide was −1·69% (95% CI −11·69 to 8·30; p=0·7398) in patients with normoalbuminuria, −21·10% (−42·25 to 0·04; p=0·0502) in patients with microalbuminuria, and −39·18% (−68·53 to −9·84; p=0·0070) in patients with macroalbuminuria. Lixisenatide was associated with a reduced risk of new-onset macroalbuminuria compared with placebo when adjusted for baseline HbA1c (hazard ratio [HR] 0·808 [95% CI 0·660 to 0·991; p=0·0404]) or baseline and on-trial HbA1c (HR 0·815 [0·665 to 0·999; p=0·0491]); point estimates were similar when adjusted for other traditional renal risk factors. At week 108, the largest eGFR decline from baseline was observed in the macroalbuminuric group, but no significant differences were observed between the two treatment groups. No significant differences in eGFR decline were identified between treatment groups in any UACR subgroup. In the trial safety population, doubling of serum creatinine occurred in 35 (1%) of 3032 patients in the placebo group and 41 (1%) of 3031 patients in the lixisenatide group (HR 1·163, 95% CI 0·741–1·825; p=0·5127). As previously reported in the ELIXA trial, the proportion of patients with renal adverse events was low (48 [1·6%] of 3032 patients in the placebo group vs 48 [1·6%] of 3031 patients in the lixisenatide group) and did not significantly differ between treatment groups. Interpretation: Lixisenatide reduces progression of UACR in macroalbuminuric patients, and is associated with a lower risk of new-onset macroalbuminuria after adjustment for baseline and on-trial HbA1c and other traditional renal risk factors. Funding: Sanofi.
Original languageEnglish
Pages (from-to)859-869
JournalThe Lancet Diabetes and Endocrinology
Volume6
Issue number11
DOIs
Publication statusPublished - 2018

Cite this

@article{2718516d197546049c08e764c9152bd9,
title = "Lixisenatide and renal outcomes in patients with type 2 diabetes and acute coronary syndrome: an exploratory analysis of the ELIXA randomised, placebo-controlled trial",
abstract = "Background: The results of the ELIXA trial demonstrated the cardiovascular safety of lixisenatide, a short-acting glucagon-like peptide-1 receptor agonist, in patients with type 2 diabetes and acute coronary syndrome. In this exploratory analysis of ELIXA, we investigate the effect of lixisenatide on renal outcomes. Methods: ELIXA was a randomised, double-blind, placebo-controlled trial, done at 828 sites in 49 countries. Patients with type 2 diabetes and a recent coronary artery event were randomly assigned (1:1) to a daily subcutaneous injection of lixisenatide (10–20 μg) or volume-matched placebo, in addition to usual care, until at least 844 patients had an adjudicated major adverse cardiovascular event included in the primary outcome. Patients, study staff, and individuals involved in analysis of trial data were masked to treatment assignment. The primary and secondary endpoints of this trial have been reported previously. Here, in an exploratory analysis of ELIXA, we investigated percentage change in urinary albumin-to-creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR) according to prespecified albuminuria status at baseline (normoalbuminuria [UACR <30 mg/g]; microalbuminuria [≥30 to ≤300 mg/g]; and macroalbuminuria [>300 mg/g]) using a mixed-effect model with repeated measures. Time to new-onset macroalbuminuria and doubling of serum creatinine were also assessed with Cox proportional hazards models. The ELIXA trial is registered with ClinicalTrials.gov, number NCT01147250, and is completed. Findings: Of 6068 patients randomly allocated between July 9, 2010, and Aug 2, 2013, baseline UACR data were available for 5978 (99{\%}). Median follow-up time was 108 weeks. 4441 (74{\%}; 2191 assigned to placebo and 2250 assigned to lixisenatide) had normoalbuminuria, 1148 (19{\%}; 596 assigned to placebo and 552 assigned to lixisenatide) had microalbuminuria, and 389 (7{\%}; 207 assigned to placebo and 182 assigned to lixisenatide) had macroalbuminuria. After 108 weeks, the placebo-adjusted least-squares mean percentage change in UACR from baseline with lixisenatide was −1·69{\%} (95{\%} CI −11·69 to 8·30; p=0·7398) in patients with normoalbuminuria, −21·10{\%} (−42·25 to 0·04; p=0·0502) in patients with microalbuminuria, and −39·18{\%} (−68·53 to −9·84; p=0·0070) in patients with macroalbuminuria. Lixisenatide was associated with a reduced risk of new-onset macroalbuminuria compared with placebo when adjusted for baseline HbA1c (hazard ratio [HR] 0·808 [95{\%} CI 0·660 to 0·991; p=0·0404]) or baseline and on-trial HbA1c (HR 0·815 [0·665 to 0·999; p=0·0491]); point estimates were similar when adjusted for other traditional renal risk factors. At week 108, the largest eGFR decline from baseline was observed in the macroalbuminuric group, but no significant differences were observed between the two treatment groups. No significant differences in eGFR decline were identified between treatment groups in any UACR subgroup. In the trial safety population, doubling of serum creatinine occurred in 35 (1{\%}) of 3032 patients in the placebo group and 41 (1{\%}) of 3031 patients in the lixisenatide group (HR 1·163, 95{\%} CI 0·741–1·825; p=0·5127). As previously reported in the ELIXA trial, the proportion of patients with renal adverse events was low (48 [1·6{\%}] of 3032 patients in the placebo group vs 48 [1·6{\%}] of 3031 patients in the lixisenatide group) and did not significantly differ between treatment groups. Interpretation: Lixisenatide reduces progression of UACR in macroalbuminuric patients, and is associated with a lower risk of new-onset macroalbuminuria after adjustment for baseline and on-trial HbA1c and other traditional renal risk factors. Funding: Sanofi.",
author = "Muskiet, {Marcel H. A.} and Lennart Tonneijck and Yao Huang and Minzhi Liu and Aramesh Saremi and Heerspink, {Hiddo J. L.} and {van Raalte}, {Dani{\"e}l H.}",
year = "2018",
doi = "10.1016/S2213-8587(18)30268-7",
language = "English",
volume = "6",
pages = "859--869",
journal = "Lancet diabetes & endocrinology",
issn = "2213-8587",
publisher = "Elsevier BV",
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}

Lixisenatide and renal outcomes in patients with type 2 diabetes and acute coronary syndrome: an exploratory analysis of the ELIXA randomised, placebo-controlled trial. / Muskiet, Marcel H. A.; Tonneijck, Lennart; Huang, Yao; Liu, Minzhi; Saremi, Aramesh; Heerspink, Hiddo J. L.; van Raalte, Daniël H.

In: The Lancet Diabetes and Endocrinology, Vol. 6, No. 11, 2018, p. 859-869.

Research output: Contribution to journalArticleAcademicpeer-review

TY - JOUR

T1 - Lixisenatide and renal outcomes in patients with type 2 diabetes and acute coronary syndrome: an exploratory analysis of the ELIXA randomised, placebo-controlled trial

AU - Muskiet, Marcel H. A.

AU - Tonneijck, Lennart

AU - Huang, Yao

AU - Liu, Minzhi

AU - Saremi, Aramesh

AU - Heerspink, Hiddo J. L.

AU - van Raalte, Daniël H.

PY - 2018

Y1 - 2018

N2 - Background: The results of the ELIXA trial demonstrated the cardiovascular safety of lixisenatide, a short-acting glucagon-like peptide-1 receptor agonist, in patients with type 2 diabetes and acute coronary syndrome. In this exploratory analysis of ELIXA, we investigate the effect of lixisenatide on renal outcomes. Methods: ELIXA was a randomised, double-blind, placebo-controlled trial, done at 828 sites in 49 countries. Patients with type 2 diabetes and a recent coronary artery event were randomly assigned (1:1) to a daily subcutaneous injection of lixisenatide (10–20 μg) or volume-matched placebo, in addition to usual care, until at least 844 patients had an adjudicated major adverse cardiovascular event included in the primary outcome. Patients, study staff, and individuals involved in analysis of trial data were masked to treatment assignment. The primary and secondary endpoints of this trial have been reported previously. Here, in an exploratory analysis of ELIXA, we investigated percentage change in urinary albumin-to-creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR) according to prespecified albuminuria status at baseline (normoalbuminuria [UACR <30 mg/g]; microalbuminuria [≥30 to ≤300 mg/g]; and macroalbuminuria [>300 mg/g]) using a mixed-effect model with repeated measures. Time to new-onset macroalbuminuria and doubling of serum creatinine were also assessed with Cox proportional hazards models. The ELIXA trial is registered with ClinicalTrials.gov, number NCT01147250, and is completed. Findings: Of 6068 patients randomly allocated between July 9, 2010, and Aug 2, 2013, baseline UACR data were available for 5978 (99%). Median follow-up time was 108 weeks. 4441 (74%; 2191 assigned to placebo and 2250 assigned to lixisenatide) had normoalbuminuria, 1148 (19%; 596 assigned to placebo and 552 assigned to lixisenatide) had microalbuminuria, and 389 (7%; 207 assigned to placebo and 182 assigned to lixisenatide) had macroalbuminuria. After 108 weeks, the placebo-adjusted least-squares mean percentage change in UACR from baseline with lixisenatide was −1·69% (95% CI −11·69 to 8·30; p=0·7398) in patients with normoalbuminuria, −21·10% (−42·25 to 0·04; p=0·0502) in patients with microalbuminuria, and −39·18% (−68·53 to −9·84; p=0·0070) in patients with macroalbuminuria. Lixisenatide was associated with a reduced risk of new-onset macroalbuminuria compared with placebo when adjusted for baseline HbA1c (hazard ratio [HR] 0·808 [95% CI 0·660 to 0·991; p=0·0404]) or baseline and on-trial HbA1c (HR 0·815 [0·665 to 0·999; p=0·0491]); point estimates were similar when adjusted for other traditional renal risk factors. At week 108, the largest eGFR decline from baseline was observed in the macroalbuminuric group, but no significant differences were observed between the two treatment groups. No significant differences in eGFR decline were identified between treatment groups in any UACR subgroup. In the trial safety population, doubling of serum creatinine occurred in 35 (1%) of 3032 patients in the placebo group and 41 (1%) of 3031 patients in the lixisenatide group (HR 1·163, 95% CI 0·741–1·825; p=0·5127). As previously reported in the ELIXA trial, the proportion of patients with renal adverse events was low (48 [1·6%] of 3032 patients in the placebo group vs 48 [1·6%] of 3031 patients in the lixisenatide group) and did not significantly differ between treatment groups. Interpretation: Lixisenatide reduces progression of UACR in macroalbuminuric patients, and is associated with a lower risk of new-onset macroalbuminuria after adjustment for baseline and on-trial HbA1c and other traditional renal risk factors. Funding: Sanofi.

AB - Background: The results of the ELIXA trial demonstrated the cardiovascular safety of lixisenatide, a short-acting glucagon-like peptide-1 receptor agonist, in patients with type 2 diabetes and acute coronary syndrome. In this exploratory analysis of ELIXA, we investigate the effect of lixisenatide on renal outcomes. Methods: ELIXA was a randomised, double-blind, placebo-controlled trial, done at 828 sites in 49 countries. Patients with type 2 diabetes and a recent coronary artery event were randomly assigned (1:1) to a daily subcutaneous injection of lixisenatide (10–20 μg) or volume-matched placebo, in addition to usual care, until at least 844 patients had an adjudicated major adverse cardiovascular event included in the primary outcome. Patients, study staff, and individuals involved in analysis of trial data were masked to treatment assignment. The primary and secondary endpoints of this trial have been reported previously. Here, in an exploratory analysis of ELIXA, we investigated percentage change in urinary albumin-to-creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR) according to prespecified albuminuria status at baseline (normoalbuminuria [UACR <30 mg/g]; microalbuminuria [≥30 to ≤300 mg/g]; and macroalbuminuria [>300 mg/g]) using a mixed-effect model with repeated measures. Time to new-onset macroalbuminuria and doubling of serum creatinine were also assessed with Cox proportional hazards models. The ELIXA trial is registered with ClinicalTrials.gov, number NCT01147250, and is completed. Findings: Of 6068 patients randomly allocated between July 9, 2010, and Aug 2, 2013, baseline UACR data were available for 5978 (99%). Median follow-up time was 108 weeks. 4441 (74%; 2191 assigned to placebo and 2250 assigned to lixisenatide) had normoalbuminuria, 1148 (19%; 596 assigned to placebo and 552 assigned to lixisenatide) had microalbuminuria, and 389 (7%; 207 assigned to placebo and 182 assigned to lixisenatide) had macroalbuminuria. After 108 weeks, the placebo-adjusted least-squares mean percentage change in UACR from baseline with lixisenatide was −1·69% (95% CI −11·69 to 8·30; p=0·7398) in patients with normoalbuminuria, −21·10% (−42·25 to 0·04; p=0·0502) in patients with microalbuminuria, and −39·18% (−68·53 to −9·84; p=0·0070) in patients with macroalbuminuria. Lixisenatide was associated with a reduced risk of new-onset macroalbuminuria compared with placebo when adjusted for baseline HbA1c (hazard ratio [HR] 0·808 [95% CI 0·660 to 0·991; p=0·0404]) or baseline and on-trial HbA1c (HR 0·815 [0·665 to 0·999; p=0·0491]); point estimates were similar when adjusted for other traditional renal risk factors. At week 108, the largest eGFR decline from baseline was observed in the macroalbuminuric group, but no significant differences were observed between the two treatment groups. No significant differences in eGFR decline were identified between treatment groups in any UACR subgroup. In the trial safety population, doubling of serum creatinine occurred in 35 (1%) of 3032 patients in the placebo group and 41 (1%) of 3031 patients in the lixisenatide group (HR 1·163, 95% CI 0·741–1·825; p=0·5127). As previously reported in the ELIXA trial, the proportion of patients with renal adverse events was low (48 [1·6%] of 3032 patients in the placebo group vs 48 [1·6%] of 3031 patients in the lixisenatide group) and did not significantly differ between treatment groups. Interpretation: Lixisenatide reduces progression of UACR in macroalbuminuric patients, and is associated with a lower risk of new-onset macroalbuminuria after adjustment for baseline and on-trial HbA1c and other traditional renal risk factors. Funding: Sanofi.

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UR - https://www.ncbi.nlm.nih.gov/pubmed/30292589

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