Leucine and perindopril to improve physical performance in people over 70 years with sarcopenia: the LACE factorial RCT
Background: Angiotensin-converting enzyme inhibitors and leucine are promising potential treatments for sarcopenia. Neither has yet been tested in adequately powered randomised trials in patients with sarcopenia. Objectives: To determine the efficacy of leucine and perindopril in improving physical...
| Main Authors: | , , , , , , , , , , , , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
NIHR Journals Library
2022-08-01
|
| Series: | Efficacy and Mechanism Evaluation |
| Subjects: | |
| Online Access: | https://doi.org/10.3310/LLBX6901 |
| _version_ | 1817995200160595968 |
|---|---|
| author | Miles D Witham Simon Adamson Alison Avenell Margaret M Band Tufail Bashir Peter T Donnan Jacob George Adrian Hapca Cheryl Hume Paul Kemp Emma McKenzie Kristina Pilvinyte Christos Rossios Karen Smith Allan D Struthers Deepa Sumukadas |
| author_facet | Miles D Witham Simon Adamson Alison Avenell Margaret M Band Tufail Bashir Peter T Donnan Jacob George Adrian Hapca Cheryl Hume Paul Kemp Emma McKenzie Kristina Pilvinyte Christos Rossios Karen Smith Allan D Struthers Deepa Sumukadas |
| author_sort | Miles D Witham |
| collection | DOAJ |
| description | Background: Angiotensin-converting enzyme inhibitors and leucine are promising potential treatments for sarcopenia. Neither has yet been tested in adequately powered randomised trials in patients with sarcopenia. Objectives: To determine the efficacy of leucine and perindopril in improving physical function in older people with sarcopenia, to evaluate the effect of leucine and perindopril on muscle mass and to evaluate the predictive biomarkers of sarcopenia. Design: A placebo-controlled, parallel group, double-blind, randomised 2 × 2 factorial trial. Setting: Primary care and geriatric medicine secondary care departments in 14 UK centres. Participants: Adults aged ≥ 70 years with low muscle strength and mass, without contraindications to angiotensin-converting enzyme inhibitors and without known diagnosis-specific skeletal myopathy. Interventions: Eligible participants were randomised 1 : 1 to receive 4 mg of oral perindopril or a matching placebo and, separately, were randomised 1 : 1 to receive 2.5 g of oral leucine powder or a matching placebo powder taken thrice daily with meals. Randomisation was performed using an interactive web-based randomisation system run independently of the research team to preserve allocation concealment. Main outcome measures: The primary outcome was the between-group difference in the Short Physical Performance Battery (SPPB) score over the 12-month follow-up period. Other outcome measures included appendicular muscle mass, EQ-5D (EuroQol-5 Dimensions) quality-of-life score, grip strength, quadriceps strength, 6-minute walk distance, activities of daily living, hip bone mineral density and insulin resistance. All adverse events and falls were recorded. Protein-, DNA (deoxyribonucleic acid)- and RNA (ribonucleic acid)-based biomarkers were collected at baseline and at 3 and 12 months. Results: We screened 320 people and randomised 145 participants. Participants had a mean age of 79 (standard deviation 6) years, 78 (54%) were women and the mean SPPB was 7.0 (standard deviation 2.4). The median adherence was lower for perindopril than for placebo (76% vs. 96%; p < 0.001). Perindopril did not improve the primary outcome (adjusted treatment effect –0.1 points, 95% confidence interval –1.2 to 1.0 points). Quality of life was worse in the perindopril group (treatment effect –12 points, 95% confidence interval –21 to –3 points) and more adverse events occurred in the perindopril group (n = 218 vs. n = 165). Falls rates between the groups were similar and other secondary outcomes showed no significant treatment effect. For leucine compared with placebo, 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% confidence interval –1.0 to 1.1 points). No significant treatment effect was found for any secondary outcome. There were similar numbers of adverse events and falls in both groups. Limitations: The trial did not reach its original recruitment target; this trial alone cannot confidently exclude clinically important effects of either perindopril or leucine. Future work: Further exploration of biomarkers predicting response to sarcopenia interventions is warranted. Conclusions: Neither perindopril nor leucine improved physical performance or muscle mass in this trial; meta-analysis confirmed the lack of efficacy of both treatments in improving physical performance. Study registration: This trial is registered as ISRCTN90094835 and EudraCT 2014-003455-61. The systematic review is registered as PROSPERO CRD42014013398. Funding: This project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a MRC and National Institute for Health and Care Research (NIHR) partnership. This will be published in full in Efficacy and Mechanism Evaluation; Vol. 9, No. 8. See the NIHR Journals Library website for further project information. |
| first_indexed | 2024-04-14T02:03:35Z |
| format | Article |
| id | doaj.art-6cbf95e5be004745bf2b2a08f3047014 |
| institution | Directory Open Access Journal |
| issn | 2050-4365 2050-4373 |
| language | English |
| last_indexed | 2024-04-14T02:03:35Z |
| publishDate | 2022-08-01 |
| publisher | NIHR Journals Library |
| record_format | Article |
| series | Efficacy and Mechanism Evaluation |
| spelling | doaj.art-6cbf95e5be004745bf2b2a08f30470142022-12-22T02:18:46ZengNIHR Journals LibraryEfficacy and Mechanism Evaluation2050-43652050-43732022-08-019810.3310/LLBX690113/53/03Leucine and perindopril to improve physical performance in people over 70 years with sarcopenia: the LACE factorial RCTMiles D Witham0Simon Adamson1Alison Avenell2Margaret M Band3Tufail Bashir4Peter T Donnan5Jacob George6Adrian Hapca7Cheryl Hume8Paul Kemp9Emma McKenzie10Kristina Pilvinyte11Christos Rossios12Karen Smith13Allan D Struthers14Deepa Sumukadas15AGE Research Group, NIHR Newcastle Biomedical Research Centre, Newcastle University and Newcastle upon Tyne Hospitals Trust, Newcastle upon Tyne, UKTayside Clinical Trials Unit, University of Dundee, Dundee, UKHealth Services Research Unit, University of Aberdeen, Aberdeen, UKTayside Clinical Trials Unit, University of Dundee, Dundee, UKCardiovascular and Respiratory Interface Section, National Heart and Lung Institute, Imperial College London, London, UKTayside Clinical Trials Unit, University of Dundee, Dundee, UKMolecular and Clinical Medicine, University of Dundee, Dundee, UKTayside Clinical Trials Unit, University of Dundee, Dundee, UKTayside Clinical Trials Unit, University of Dundee, Dundee, UKCardiovascular and Respiratory Interface Section, National Heart and Lung Institute, Imperial College London, London, UKTayside Clinical Trials Unit, University of Dundee, Dundee, UKTayside Clinical Trials Unit, University of Dundee, Dundee, UKCardiovascular and Respiratory Interface Section, National Heart and Lung Institute, Imperial College London, London, UKTayside Clinical Trials Unit, University of Dundee, Dundee, UKMolecular and Clinical Medicine, University of Dundee, Dundee, UKDepartment of Medicine for the Elderly, NHS Tayside, Dundee, UKBackground: Angiotensin-converting enzyme inhibitors and leucine are promising potential treatments for sarcopenia. Neither has yet been tested in adequately powered randomised trials in patients with sarcopenia. Objectives: To determine the efficacy of leucine and perindopril in improving physical function in older people with sarcopenia, to evaluate the effect of leucine and perindopril on muscle mass and to evaluate the predictive biomarkers of sarcopenia. Design: A placebo-controlled, parallel group, double-blind, randomised 2 × 2 factorial trial. Setting: Primary care and geriatric medicine secondary care departments in 14 UK centres. Participants: Adults aged ≥ 70 years with low muscle strength and mass, without contraindications to angiotensin-converting enzyme inhibitors and without known diagnosis-specific skeletal myopathy. Interventions: Eligible participants were randomised 1 : 1 to receive 4 mg of oral perindopril or a matching placebo and, separately, were randomised 1 : 1 to receive 2.5 g of oral leucine powder or a matching placebo powder taken thrice daily with meals. Randomisation was performed using an interactive web-based randomisation system run independently of the research team to preserve allocation concealment. Main outcome measures: The primary outcome was the between-group difference in the Short Physical Performance Battery (SPPB) score over the 12-month follow-up period. Other outcome measures included appendicular muscle mass, EQ-5D (EuroQol-5 Dimensions) quality-of-life score, grip strength, quadriceps strength, 6-minute walk distance, activities of daily living, hip bone mineral density and insulin resistance. All adverse events and falls were recorded. Protein-, DNA (deoxyribonucleic acid)- and RNA (ribonucleic acid)-based biomarkers were collected at baseline and at 3 and 12 months. Results: We screened 320 people and randomised 145 participants. Participants had a mean age of 79 (standard deviation 6) years, 78 (54%) were women and the mean SPPB was 7.0 (standard deviation 2.4). The median adherence was lower for perindopril than for placebo (76% vs. 96%; p < 0.001). Perindopril did not improve the primary outcome (adjusted treatment effect –0.1 points, 95% confidence interval –1.2 to 1.0 points). Quality of life was worse in the perindopril group (treatment effect –12 points, 95% confidence interval –21 to –3 points) and more adverse events occurred in the perindopril group (n = 218 vs. n = 165). Falls rates between the groups were similar and other secondary outcomes showed no significant treatment effect. For leucine compared with placebo, 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% confidence interval –1.0 to 1.1 points). No significant treatment effect was found for any secondary outcome. There were similar numbers of adverse events and falls in both groups. Limitations: The trial did not reach its original recruitment target; this trial alone cannot confidently exclude clinically important effects of either perindopril or leucine. Future work: Further exploration of biomarkers predicting response to sarcopenia interventions is warranted. Conclusions: Neither perindopril nor leucine improved physical performance or muscle mass in this trial; meta-analysis confirmed the lack of efficacy of both treatments in improving physical performance. Study registration: This trial is registered as ISRCTN90094835 and EudraCT 2014-003455-61. The systematic review is registered as PROSPERO CRD42014013398. Funding: This project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a MRC and National Institute for Health and Care Research (NIHR) partnership. This will be published in full in Efficacy and Mechanism Evaluation; Vol. 9, No. 8. See the NIHR Journals Library website for further project information.https://doi.org/10.3310/LLBX6901angiotensin-converting enzyme inhibitorleucinesarcopeniarandomised controlled trial |
| spellingShingle | Miles D Witham Simon Adamson Alison Avenell Margaret M Band Tufail Bashir Peter T Donnan Jacob George Adrian Hapca Cheryl Hume Paul Kemp Emma McKenzie Kristina Pilvinyte Christos Rossios Karen Smith Allan D Struthers Deepa Sumukadas Leucine and perindopril to improve physical performance in people over 70 years with sarcopenia: the LACE factorial RCT Efficacy and Mechanism Evaluation angiotensin-converting enzyme inhibitor leucine sarcopenia randomised controlled trial |
| title | Leucine and perindopril to improve physical performance in people over 70 years with sarcopenia: the LACE factorial RCT |
| title_full | Leucine and perindopril to improve physical performance in people over 70 years with sarcopenia: the LACE factorial RCT |
| title_fullStr | Leucine and perindopril to improve physical performance in people over 70 years with sarcopenia: the LACE factorial RCT |
| title_full_unstemmed | Leucine and perindopril to improve physical performance in people over 70 years with sarcopenia: the LACE factorial RCT |
| title_short | Leucine and perindopril to improve physical performance in people over 70 years with sarcopenia: the LACE factorial RCT |
| title_sort | leucine and perindopril to improve physical performance in people over 70 years with sarcopenia the lace factorial rct |
| topic | angiotensin-converting enzyme inhibitor leucine sarcopenia randomised controlled trial |
| url | https://doi.org/10.3310/LLBX6901 |
| work_keys_str_mv | AT milesdwitham leucineandperindopriltoimprovephysicalperformanceinpeopleover70yearswithsarcopeniathelacefactorialrct AT simonadamson leucineandperindopriltoimprovephysicalperformanceinpeopleover70yearswithsarcopeniathelacefactorialrct AT alisonavenell leucineandperindopriltoimprovephysicalperformanceinpeopleover70yearswithsarcopeniathelacefactorialrct AT margaretmband leucineandperindopriltoimprovephysicalperformanceinpeopleover70yearswithsarcopeniathelacefactorialrct AT tufailbashir leucineandperindopriltoimprovephysicalperformanceinpeopleover70yearswithsarcopeniathelacefactorialrct AT petertdonnan leucineandperindopriltoimprovephysicalperformanceinpeopleover70yearswithsarcopeniathelacefactorialrct AT jacobgeorge leucineandperindopriltoimprovephysicalperformanceinpeopleover70yearswithsarcopeniathelacefactorialrct AT adrianhapca leucineandperindopriltoimprovephysicalperformanceinpeopleover70yearswithsarcopeniathelacefactorialrct AT cherylhume leucineandperindopriltoimprovephysicalperformanceinpeopleover70yearswithsarcopeniathelacefactorialrct AT paulkemp leucineandperindopriltoimprovephysicalperformanceinpeopleover70yearswithsarcopeniathelacefactorialrct AT emmamckenzie leucineandperindopriltoimprovephysicalperformanceinpeopleover70yearswithsarcopeniathelacefactorialrct AT kristinapilvinyte leucineandperindopriltoimprovephysicalperformanceinpeopleover70yearswithsarcopeniathelacefactorialrct AT christosrossios leucineandperindopriltoimprovephysicalperformanceinpeopleover70yearswithsarcopeniathelacefactorialrct AT karensmith leucineandperindopriltoimprovephysicalperformanceinpeopleover70yearswithsarcopeniathelacefactorialrct AT allandstruthers leucineandperindopriltoimprovephysicalperformanceinpeopleover70yearswithsarcopeniathelacefactorialrct AT deepasumukadas leucineandperindopriltoimprovephysicalperformanceinpeopleover70yearswithsarcopeniathelacefactorialrct |