Effect of perindopril or leucine on physical performance in older people with sarcopenia: the LACE randomized controlled trial

Marcus Achison; Simon Adamson; Asangaedem Akpan; Terry Aspray; Alison Avenell; Margaret M. Band; Tufail Bashir; Louise A. Burton; Vera Cvoro; Peter T. Donnan; Gordon W. Duncan; Jacob George; Adam L. Gordon; Celia L. Gregson; Adrian Hapca; Emily Henderson; Cheryl Hume; Thomas A. Jackson; Paul Kemp; Simon Kerr; Alixe Kilgour; Veronica Lyell; Tahir Masud; Andrew McKenzie; Emma McKenzie; Harnish Patel; Kristina Pilvinyte; Helen C. Roberts; Christos Rossios; Avan A. Sayer; Karen T. Smith; Roy L. Soiza; Claire J. Steves; Allan D. Struthers; Deepa Sumukadas; Divya Tiwari; Julie Whitney; Miles D. Witham; LACE study group

doi:10.1002/jcsm.12934

Effect of perindopril or leucine on physical performance in older people with sarcopenia: the LACE randomized controlled trial

Marcus Achison, Simon Adamson, Asangaedem Akpan, Terry Aspray, Alison Avenell, Margaret M. Band, Tufail Bashir, Louise A. Burton, Vera Cvoro, Peter T. Donnan, Gordon W. Duncan, Jacob George, Adam L. Gordon, Celia L. Gregson, Adrian Hapca, Emily Henderson, Cheryl Hume, Thomas A. Jackson, Paul Kemp, Simon KerrAlixe Kilgour, Veronica Lyell, Tahir Masud, Andrew McKenzie, Emma McKenzie, Harnish Patel, Kristina Pilvinyte, Helen C. Roberts, Christos Rossios, Avan A. Sayer, Karen T. Smith, Roy L. Soiza, Claire J. Steves, Allan D. Struthers, Deepa Sumukadas, Divya Tiwari, Julie Whitney, Miles D. Witham^* (Corresponding Author), LACE study group

^*Corresponding author for this work

Research output: Contribution to journal › Article › peer-review

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Abstract

Background
This trial aimed to determine the efficacy of leucine and/or perindopril in improving physical function in older people with sarcopenia.
Methods
Placebo-controlled, parallel group, double-blind, randomised two-by-two factorial trial. We recruited adults aged ≥70 years with sarcopenia, defined as low gait speed (<0.8 m/s on 4m walk) and/or low handgrip strength (women <20kg, men <30kg) plus low muscle mass (using sex and BMI categoryspecific thresholds derived from normative UK BioBank data) from 14 UK centres. Eligible participants were randomised to perindopril 4mg or placebo, and to oral leucine powder 2.5g or placebo thrice daily. The primary outcome was the between-group difference in the Short Physical Performance Battery (SPPB) score over 12-month follow-up by repeated-measures mixed models. Results were combined with existing systematic reviews using random-effects meta-analysis to derive summary estimates of treatment efficacy.
Results
We screened 320 people and randomised 145 participants compared to an original target of 440 participants. For perindopril (n=73, mean age 79 [SD 6], female sex 39 [53%], mean SPPB 7.1 [SD 2.3]) vs no perindopril (n=72, mean age 79 [SD 6], female sex 39 [54%], mean SPPB 6.9 [SD 2.4]), median adherence to perindopril was lower (76% vs 96%; p<0.001). Perindopril did not improve the primary outcome (adjusted treatment effect -0.1 points [95%CI -1.2 to 1.0], p=0.89). No significant treatment benefit was seen for any secondary outcome including muscle mass (adjusted treatment effect -0.4kg [95%CI -1.1 to 0.3], p=0.27). More adverse events occurred in the perindopril group (218 vs 165) but
falls rates were similar. For leucine (n=72, mean age 78 [SD 6], female sex 38 [53%], mean SPPB 7.0 [SD 2.1]) vs no leucine (n=72, mean age 79 [SD 6], female sex 40 [55%], mean SPPB 7.0 [SD 2.5]), median adherence was the same in both groups (76% vs 76%; p=0.99). Leucine did not improve the primary outcome (adjusted treatment effect 0.1 point [95%CI -1.0 to 1.1], p=0.90). No significant
treatment benefit was seen for any secondary outcome including muscle mass (adjusted treatment effect -0.3kg [95%CI -1.0 to 0.4], p=0.47). Meta-analysis of ACEi / angiotensin receptor blocker trials showed no clinically important treatment effect for the SPPB (between-group difference -0.1 points [95%CI -0.4 to 0.2]).
Conclusions
Neither perindopril nor leucine improved physical performance or muscle mass in this trial; metaanalysis did not find evidence of efficacy of either ACE inhibitors or leucine as treatments to improve physical performance.

Original language	English
Pages (from-to)	858-871
Number of pages	14
Journal	Journal of Cachexia, Sarcopenia and Muscle
Volume	13
Issue number	2
Early online date	16 Feb 2022
DOIs	https://doi.org/10.1002/jcsm.12934
Publication status	Published - 1 Apr 2022

Bibliographical note

Acknowledgements:
AAS, TA and MDW acknowledge support from the NIHR Newcastle Biomedical Research Centre. AA acknowledges support from the Health Services Research Unit which is core funded by the Chief Scientist Office of the Scottish Government Health and Social Care Directorate. The authors acknowledge support from the NIHR Ageing Clinical Research Network and the NHS Scotland Support for Science programme, The authors would also thank the efforts of all the research nurses and other ants to the trial, all the participants, and all the staff of the Tayside Clinical Trials Unit for their support of the trial.
Funding:
The LACE trial (project reference 13/53/03) is funded by the Efficacy and Mechanism Evaluation (EME) Programme, an MRC and NIHR partnership. The views expressed in this publication are those of the authors and not necessarily those of the MRC, NIHR or the Department of Health and Social Care.

Data Availability Statement

Online supplementary material
Additional supporting information may be found online in the Supporting Information section at the end of the article

Keywords

Angiotensin converting enzyme inhibitor
Leucine
Sarcopenia
Randomised Controlled Tria
Meta-Analysis as Topic
Humans
Male
Treatment Outcome
Perindopril/therapeutic use
Sarcopenia/drug therapy
Hand Strength/physiology
Female
Aged
Physical Functional Performance
Leucine/therapeutic use
PREVALENCE
SUPPLEMENTATION
INTERVENTIONS
BIOELECTRICAL-IMPEDANCE ANALYSIS
SKELETAL-MUSCLE MASS
ADULTS
ELDERLY-PEOPLE
LOWER-EXTREMITY FUNCTION
Randomized controlled trial
DOUBLE-BLIND
ASSOCIATION

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Achison, M., Adamson, S., Akpan, A., Aspray, T., Avenell, A., Band, M. M., Bashir, T., Burton, L. A., Cvoro, V., Donnan, P. T., Duncan, G. W., George, J., Gordon, A. L., Gregson, C. L., Hapca, A., Henderson, E., Hume, C., Jackson, T. A., Kemp, P., ... LACE study group (2022). Effect of perindopril or leucine on physical performance in older people with sarcopenia: the LACE randomized controlled trial. Journal of Cachexia, Sarcopenia and Muscle, 13(2), 858-871. https://doi.org/10.1002/jcsm.12934

Achison, M, Adamson, S, Akpan, A, Aspray, T, Avenell, A, Band, MM, Bashir, T, Burton, LA, Cvoro, V, Donnan, PT, Duncan, GW, George, J, Gordon, AL, Gregson, CL, Hapca, A, Henderson, E, Hume, C, Jackson, TA, Kemp, P, Kerr, S, Kilgour, A, Lyell, V, Masud, T, McKenzie, A, McKenzie, E, Patel, H, Pilvinyte, K, Roberts, HC, Rossios, C, Sayer, AA, Smith, KT, Soiza, RL, Steves, CJ, Struthers, AD, Sumukadas, D, Tiwari, D, Whitney, J, Witham, MD & LACE study group 2022, 'Effect of perindopril or leucine on physical performance in older people with sarcopenia: the LACE randomized controlled trial', Journal of Cachexia, Sarcopenia and Muscle, vol. 13, no. 2, pp. 858-871. https://doi.org/10.1002/jcsm.12934

@article{97d743f041224929941cea4829460c5e,

title = "Effect of perindopril or leucine on physical performance in older people with sarcopenia: the LACE randomized controlled trial",

abstract = "BackgroundThis trial aimed to determine the efficacy of leucine and/or perindopril in improving physical function in older people with sarcopenia.MethodsPlacebo-controlled, parallel group, double-blind, randomised two-by-two factorial trial. We recruited adults aged ≥70 years with sarcopenia, defined as low gait speed (<0.8 m/s on 4m walk) and/or low handgrip strength (women <20kg, men <30kg) plus low muscle mass (using sex and BMI categoryspecific thresholds derived from normative UK BioBank data) from 14 UK centres. Eligible participants were randomised to perindopril 4mg or placebo, and to oral leucine powder 2.5g or placebo thrice daily. The primary outcome was the between-group difference in the Short Physical Performance Battery (SPPB) score over 12-month follow-up by repeated-measures mixed models. Results were combined with existing systematic reviews using random-effects meta-analysis to derive summary estimates of treatment efficacy.ResultsWe screened 320 people and randomised 145 participants compared to an original target of 440 participants. For perindopril (n=73, mean age 79 [SD 6], female sex 39 [53%], mean SPPB 7.1 [SD 2.3]) vs no perindopril (n=72, mean age 79 [SD 6], female sex 39 [54%], mean SPPB 6.9 [SD 2.4]), median adherence to perindopril was lower (76% vs 96%; p<0.001). Perindopril did not improve the primary outcome (adjusted treatment effect -0.1 points [95%CI -1.2 to 1.0], p=0.89). No significant treatment benefit was seen for any secondary outcome including muscle mass (adjusted treatment effect -0.4kg [95%CI -1.1 to 0.3], p=0.27). More adverse events occurred in the perindopril group (218 vs 165) butfalls rates were similar. For leucine (n=72, mean age 78 [SD 6], female sex 38 [53%], mean SPPB 7.0 [SD 2.1]) vs no leucine (n=72, mean age 79 [SD 6], female sex 40 [55%], mean SPPB 7.0 [SD 2.5]), median adherence was the same in both groups (76% vs 76%; p=0.99). Leucine did not improve the primary outcome (adjusted treatment effect 0.1 point [95%CI -1.0 to 1.1], p=0.90). No significanttreatment benefit was seen for any secondary outcome including muscle mass (adjusted treatment effect -0.3kg [95%CI -1.0 to 0.4], p=0.47). Meta-analysis of ACEi / angiotensin receptor blocker trials showed no clinically important treatment effect for the SPPB (between-group difference -0.1 points [95%CI -0.4 to 0.2]).ConclusionsNeither perindopril nor leucine improved physical performance or muscle mass in this trial; metaanalysis did not find evidence of efficacy of either ACE inhibitors or leucine as treatments to improve physical performance.",

keywords = "Angiotensin converting enzyme inhibitor, Leucine, Sarcopenia, Randomised Controlled Tria, Meta-Analysis as Topic, Humans, Male, Treatment Outcome, Perindopril/therapeutic use, Sarcopenia/drug therapy, Hand Strength/physiology, Female, Aged, Physical Functional Performance, Leucine/therapeutic use, PREVALENCE, SUPPLEMENTATION, INTERVENTIONS, BIOELECTRICAL-IMPEDANCE ANALYSIS, SKELETAL-MUSCLE MASS, ADULTS, ELDERLY-PEOPLE, LOWER-EXTREMITY FUNCTION, Randomized controlled trial, DOUBLE-BLIND, ASSOCIATION",

author = "Marcus Achison and Simon Adamson and Asangaedem Akpan and Terry Aspray and Alison Avenell and Band, {Margaret M.} and Tufail Bashir and Burton, {Louise A.} and Vera Cvoro and Donnan, {Peter T.} and Duncan, {Gordon W.} and Jacob George and Gordon, {Adam L.} and Gregson, {Celia L.} and Adrian Hapca and Emily Henderson and Cheryl Hume and Jackson, {Thomas A.} and Paul Kemp and Simon Kerr and Alixe Kilgour and Veronica Lyell and Tahir Masud and Andrew McKenzie and Emma McKenzie and Harnish Patel and Kristina Pilvinyte and Roberts, {Helen C.} and Christos Rossios and Sayer, {Avan A.} and Smith, {Karen T.} and Soiza, {Roy L.} and Steves, {Claire J.} and Struthers, {Allan D.} and Deepa Sumukadas and Divya Tiwari and Julie Whitney and Witham, {Miles D.} and {LACE study group}",

note = "Acknowledgements: AAS, TA and MDW acknowledge support from the NIHR Newcastle Biomedical Research Centre. AA acknowledges support from the Health Services Research Unit which is core funded by the Chief Scientist Office of the Scottish Government Health and Social Care Directorate. The authors acknowledge support from the NIHR Ageing Clinical Research Network and the NHS Scotland Support for Science programme, The authors would also thank the efforts of all the research nurses and other ants to the trial, all the participants, and all the staff of the Tayside Clinical Trials Unit for their support of the trial. Funding: The LACE trial (project reference 13/53/03) is funded by the Efficacy and Mechanism Evaluation (EME) Programme, an MRC and NIHR partnership. The views expressed in this publication are those of the authors and not necessarily those of the MRC, NIHR or the Department of Health and Social Care.",

year = "2022",

month = apr,

day = "1",

doi = "10.1002/jcsm.12934",

language = "English",

volume = "13",

pages = "858--871",

journal = "Journal of Cachexia, Sarcopenia and Muscle",

issn = "2190-6009",

publisher = "Wiley",

number = "2",

}

TY - JOUR

T1 - Effect of perindopril or leucine on physical performance in older people with sarcopenia

T2 - the LACE randomized controlled trial

AU - Achison, Marcus

AU - Adamson, Simon

AU - Akpan, Asangaedem

AU - Aspray, Terry

AU - Avenell, Alison

AU - Band, Margaret M.

AU - Bashir, Tufail

AU - Burton, Louise A.

AU - Cvoro, Vera

AU - Donnan, Peter T.

AU - Duncan, Gordon W.

AU - George, Jacob

AU - Gordon, Adam L.

AU - Gregson, Celia L.

AU - Hapca, Adrian

AU - Henderson, Emily

AU - Hume, Cheryl

AU - Jackson, Thomas A.

AU - Kemp, Paul

AU - Kerr, Simon

AU - Kilgour, Alixe

AU - Lyell, Veronica

AU - Masud, Tahir

AU - McKenzie, Andrew

AU - McKenzie, Emma

AU - Patel, Harnish

AU - Pilvinyte, Kristina

AU - Roberts, Helen C.

AU - Rossios, Christos

AU - Sayer, Avan A.

AU - Smith, Karen T.

AU - Soiza, Roy L.

AU - Steves, Claire J.

AU - Struthers, Allan D.

AU - Sumukadas, Deepa

AU - Tiwari, Divya

AU - Whitney, Julie

AU - Witham, Miles D.

AU - LACE study group

N1 - Acknowledgements: AAS, TA and MDW acknowledge support from the NIHR Newcastle Biomedical Research Centre. AA acknowledges support from the Health Services Research Unit which is core funded by the Chief Scientist Office of the Scottish Government Health and Social Care Directorate. The authors acknowledge support from the NIHR Ageing Clinical Research Network and the NHS Scotland Support for Science programme, The authors would also thank the efforts of all the research nurses and other ants to the trial, all the participants, and all the staff of the Tayside Clinical Trials Unit for their support of the trial. Funding: The LACE trial (project reference 13/53/03) is funded by the Efficacy and Mechanism Evaluation (EME) Programme, an MRC and NIHR partnership. The views expressed in this publication are those of the authors and not necessarily those of the MRC, NIHR or the Department of Health and Social Care.

PY - 2022/4/1

Y1 - 2022/4/1

N2 - BackgroundThis trial aimed to determine the efficacy of leucine and/or perindopril in improving physical function in older people with sarcopenia.MethodsPlacebo-controlled, parallel group, double-blind, randomised two-by-two factorial trial. We recruited adults aged ≥70 years with sarcopenia, defined as low gait speed (<0.8 m/s on 4m walk) and/or low handgrip strength (women <20kg, men <30kg) plus low muscle mass (using sex and BMI categoryspecific thresholds derived from normative UK BioBank data) from 14 UK centres. Eligible participants were randomised to perindopril 4mg or placebo, and to oral leucine powder 2.5g or placebo thrice daily. The primary outcome was the between-group difference in the Short Physical Performance Battery (SPPB) score over 12-month follow-up by repeated-measures mixed models. Results were combined with existing systematic reviews using random-effects meta-analysis to derive summary estimates of treatment efficacy.ResultsWe screened 320 people and randomised 145 participants compared to an original target of 440 participants. For perindopril (n=73, mean age 79 [SD 6], female sex 39 [53%], mean SPPB 7.1 [SD 2.3]) vs no perindopril (n=72, mean age 79 [SD 6], female sex 39 [54%], mean SPPB 6.9 [SD 2.4]), median adherence to perindopril was lower (76% vs 96%; p<0.001). Perindopril did not improve the primary outcome (adjusted treatment effect -0.1 points [95%CI -1.2 to 1.0], p=0.89). No significant treatment benefit was seen for any secondary outcome including muscle mass (adjusted treatment effect -0.4kg [95%CI -1.1 to 0.3], p=0.27). More adverse events occurred in the perindopril group (218 vs 165) butfalls rates were similar. For leucine (n=72, mean age 78 [SD 6], female sex 38 [53%], mean SPPB 7.0 [SD 2.1]) vs no leucine (n=72, mean age 79 [SD 6], female sex 40 [55%], mean SPPB 7.0 [SD 2.5]), median adherence was the same in both groups (76% vs 76%; p=0.99). Leucine did not improve the primary outcome (adjusted treatment effect 0.1 point [95%CI -1.0 to 1.1], p=0.90). No significanttreatment benefit was seen for any secondary outcome including muscle mass (adjusted treatment effect -0.3kg [95%CI -1.0 to 0.4], p=0.47). Meta-analysis of ACEi / angiotensin receptor blocker trials showed no clinically important treatment effect for the SPPB (between-group difference -0.1 points [95%CI -0.4 to 0.2]).ConclusionsNeither perindopril nor leucine improved physical performance or muscle mass in this trial; metaanalysis did not find evidence of efficacy of either ACE inhibitors or leucine as treatments to improve physical performance.

AB - BackgroundThis trial aimed to determine the efficacy of leucine and/or perindopril in improving physical function in older people with sarcopenia.MethodsPlacebo-controlled, parallel group, double-blind, randomised two-by-two factorial trial. We recruited adults aged ≥70 years with sarcopenia, defined as low gait speed (<0.8 m/s on 4m walk) and/or low handgrip strength (women <20kg, men <30kg) plus low muscle mass (using sex and BMI categoryspecific thresholds derived from normative UK BioBank data) from 14 UK centres. Eligible participants were randomised to perindopril 4mg or placebo, and to oral leucine powder 2.5g or placebo thrice daily. The primary outcome was the between-group difference in the Short Physical Performance Battery (SPPB) score over 12-month follow-up by repeated-measures mixed models. Results were combined with existing systematic reviews using random-effects meta-analysis to derive summary estimates of treatment efficacy.ResultsWe screened 320 people and randomised 145 participants compared to an original target of 440 participants. For perindopril (n=73, mean age 79 [SD 6], female sex 39 [53%], mean SPPB 7.1 [SD 2.3]) vs no perindopril (n=72, mean age 79 [SD 6], female sex 39 [54%], mean SPPB 6.9 [SD 2.4]), median adherence to perindopril was lower (76% vs 96%; p<0.001). Perindopril did not improve the primary outcome (adjusted treatment effect -0.1 points [95%CI -1.2 to 1.0], p=0.89). No significant treatment benefit was seen for any secondary outcome including muscle mass (adjusted treatment effect -0.4kg [95%CI -1.1 to 0.3], p=0.27). More adverse events occurred in the perindopril group (218 vs 165) butfalls rates were similar. For leucine (n=72, mean age 78 [SD 6], female sex 38 [53%], mean SPPB 7.0 [SD 2.1]) vs no leucine (n=72, mean age 79 [SD 6], female sex 40 [55%], mean SPPB 7.0 [SD 2.5]), median adherence was the same in both groups (76% vs 76%; p=0.99). Leucine did not improve the primary outcome (adjusted treatment effect 0.1 point [95%CI -1.0 to 1.1], p=0.90). No significanttreatment benefit was seen for any secondary outcome including muscle mass (adjusted treatment effect -0.3kg [95%CI -1.0 to 0.4], p=0.47). Meta-analysis of ACEi / angiotensin receptor blocker trials showed no clinically important treatment effect for the SPPB (between-group difference -0.1 points [95%CI -0.4 to 0.2]).ConclusionsNeither perindopril nor leucine improved physical performance or muscle mass in this trial; metaanalysis did not find evidence of efficacy of either ACE inhibitors or leucine as treatments to improve physical performance.

KW - Angiotensin converting enzyme inhibitor

KW - Leucine

KW - Sarcopenia

KW - Randomised Controlled Tria

KW - Meta-Analysis as Topic

KW - Humans

KW - Male

KW - Treatment Outcome

KW - Perindopril/therapeutic use

KW - Sarcopenia/drug therapy

KW - Hand Strength/physiology

KW - Female

KW - Aged

KW - Physical Functional Performance

KW - Leucine/therapeutic use

KW - PREVALENCE

KW - SUPPLEMENTATION

KW - INTERVENTIONS

KW - BIOELECTRICAL-IMPEDANCE ANALYSIS

KW - SKELETAL-MUSCLE MASS

KW - ADULTS

KW - ELDERLY-PEOPLE

KW - LOWER-EXTREMITY FUNCTION

KW - Randomized controlled trial

KW - DOUBLE-BLIND

KW - ASSOCIATION

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U2 - 10.1002/jcsm.12934

DO - 10.1002/jcsm.12934

M3 - Article

C2 - 35174663

AN - SCOPUS:85128160996

SN - 2190-6009

VL - 13

SP - 858

EP - 871

JO - Journal of Cachexia, Sarcopenia and Muscle

JF - Journal of Cachexia, Sarcopenia and Muscle

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ER -

Effect of perindopril or leucine on physical performance in older people with sarcopenia: the LACE randomized controlled trial

Abstract

Bibliographical note

Data Availability Statement

Keywords

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