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Telmisartan to reduce insulin resistance in HIV-positive individuals on combination antiretroviral therapy: the TAILoR dose-ranging Phase II RCT

Abstract
Combination antiretroviral therapy (cART) is the standard for human immunodeficiency virus (HIV) infection treatment but can result in metabolic abnormalities, such as insulin resistance, dyslipidaemia and lipodystrophy, which can increase the risk of cardiovascular disease.The objective of the trial was to evaluate whether or not telmisartan, an angiotensin II receptor antagonist and a peroxisome proliferator-activated receptor-γ partial agonist, could reduce insulin resistance in HIV-positive individuals on cART, and affect blood and imaging biomarkers of cardiometabolic disease.A Phase II, multicentre, randomised, open-labelled, dose-ranging trial of telmisartan over a period of 48 weeks with an adaptive design comprising two stages was used to identify the optimal dose of telmisartan. Participants were randomised to receive one of the three doses of telmisartan (20, 40 and 80 mg) or no intervention (control).Recruitment was from 19 HIV specialist centres in the UK.A total of 377 patients infected with HIV who met the prespecified inclusion/exclusion criteria.20-, 40- and 80-mg tablets of telmisartan.The primary outcome measure was reduction in the homeostatic model assessment of insulin resistance (HOMA-IR), a marker of insulin resistance, at 24 weeks. Secondary outcome measures were changes in plasma lipid profile; Quantitative Insulin Sensitivity Check Index (QUICKI) and revised QUICKI, alternative markers of insulin resistance, plasma adipokines (adiponectin, leptin, interleukin 8, tumour necrosis factor alpha, resistin); high-sensitivity C-reactive protein (hs-CRP); body fat redistribution, as measured by magnetic resonance imaging/proton magnetic resonance spectroscopy; changes in renal markers (albumin-to-creatinine ratio, neutrophil gelatinase-associated lipocalin); and tolerability to telmisartan.At the interim analysis, 80 mg of telmisartan was taken forward into the second stage of the study. Baseline characteristics were balanced across treatment arms. There were no differences in HOMA-IR [0.007, standard error (SE) 0.106], QUICKI (0.001, SE 0.001) and revised QUICKI (0.002, SE 0.002) at 24 weeks between the telmisartan (80 mg; n = 106) and non-intervention (n = 105) arms. Longitudinal analysis over 48 weeks showed that there was no change in HOMA-IR, lipid or adipokine levels; however, but there were significant, but marginal, improvements in revised QUICKI [0.004, 95% confidence interval (CI) 0.000 to 0.008] and plasma hs-CRP (–0.222, 95% CI –0.433 to –0.011) over 48 weeks. Substudies also showed a significant reduction in the liver fat content at 24 weeks (1.714, 95% CI –2.787 to –0.642; p = 0.005) and urinary albumin excretion at 48 weeks (–0.665, 95% CI –1.31 to –0.019; p = 0.04). There were no differences in serious adverse events between the telmisartan and control arms.The patients had modest elevations of HOMA-IR at baseline, and our trial could have been under-powered to detect smaller improvements in insulin resistance over time.Using a novel adaptive design, we demonstrated that there was no significant effect of telmisartan (80 mg) on the primary outcome measure of HOMA-IR and some secondary outcomes (plasma lipids and adipokines). Telmisartan did lead to favourable, and biologically plausible, changes of the secondary longitudinal outcome measures: revised QUICKI, hs-CRP, hepatic fat accumulation and urinary albumin excretion. Taken collectively, our findings showed that telmisartan did not reduce insulin resistance in patients infected with HIV on antiretrovirals.The mechanistic basis of adipocyte regulation will be studied to allow for development of biomarkers and interventions.Current Controlled Trials ISRCTN51069819.This project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a Medical Research Council and National Institute for Health Research partnership.

Authors

Department of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UKDepartment of Biostatistics, University of Liverpool, Liverpool, UKClinical Trials Research Centre, University of Liverpool, Liverpool, UKDepartment of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UKClinical Trials Research Centre, University of Liverpool, Liverpool, UKDepartment of Biostatistics, University of Liverpool, Liverpool, UKLiverpool Magnetic Resonance Imaging Centre, University of Liverpool, Liverpool, UKDepartment of Mathematics and Statistics, Lancaster University, Lancaster, UKDepartment of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UKDepartment of Biostatistics, University of Liverpool, Liverpool, UKDepartment of Molecular and Clinical Pharmacology, University of Liverpool, Liverpool, UK

Publisher

NIHR Journals Library
Southampton (UK)

Language

eng

PubMed ID

31318501

Citation

Telmisartan to reduce insulin resistance in HIV-positive individuals on combination antiretroviral therapy: the TAILoR dose-ranging Phase II RCT. NIHR Journals Library, 2019, Southampton (UK).
Telmisartan to reduce insulin resistance in HIV-positive individuals on combination antiretroviral therapy: the TAILoR dose-ranging Phase II RCT. Southampton (UK): NIHR Journals Library; 2019.
(2019). In Telmisartan to reduce insulin resistance in HIV-positive individuals on combination antiretroviral therapy: the TAILoR dose-ranging Phase II RCT. Southampton (UK): NIHR Journals Library;
Telmisartan to reduce insulin resistance in HIV-positive individuals on combination antiretroviral therapy: the TAILoR dose-ranging Phase II RCT. Southampton (UK): NIHR Journals Library; 2019.
* Article titles in AMA citation format should be in sentence-case
TY - BOOK T1 - Telmisartan to reduce insulin resistance in HIV-positive individuals on combination antiretroviral therapy: the TAILoR dose-ranging Phase II RCT Y1 - 2019/7// PY - 2019/7/19/pubmed PY - 2019/7/19/medline PY - 2019/7/19/entrez KW - HIV KW - ANTIRETROVIRAL DRUGS KW - INSULIN RESISTANCE KW - METABOLIC DISEASE KW - TELMISARTAN KW - DRUG SAFETY KW - ADIPOSE TISSUE KW - ADIPOKINES KW - LIPODYSTROPHY KW - FAT REDISTRIBUTION KW - CARDIOVASCULAR DISEASE KW - ADAPTIVE TRIALS N2 - BACKGROUND: Combination antiretroviral therapy (cART) is the standard for human immunodeficiency virus (HIV) infection treatment but can result in metabolic abnormalities, such as insulin resistance, dyslipidaemia and lipodystrophy, which can increase the risk of cardiovascular disease. OBJECTIVE: The objective of the trial was to evaluate whether or not telmisartan, an angiotensin II receptor antagonist and a peroxisome proliferator-activated receptor-γ partial agonist, could reduce insulin resistance in HIV-positive individuals on cART, and affect blood and imaging biomarkers of cardiometabolic disease. DESIGN: A Phase II, multicentre, randomised, open-labelled, dose-ranging trial of telmisartan over a period of 48 weeks with an adaptive design comprising two stages was used to identify the optimal dose of telmisartan. Participants were randomised to receive one of the three doses of telmisartan (20, 40 and 80 mg) or no intervention (control). SETTING: Recruitment was from 19 HIV specialist centres in the UK. PARTICIPANTS: A total of 377 patients infected with HIV who met the prespecified inclusion/exclusion criteria. INTERVENTIONS: 20-, 40- and 80-mg tablets of telmisartan. MAIN OUTCOME MEASURES: The primary outcome measure was reduction in the homeostatic model assessment of insulin resistance (HOMA-IR), a marker of insulin resistance, at 24 weeks. Secondary outcome measures were changes in plasma lipid profile; Quantitative Insulin Sensitivity Check Index (QUICKI) and revised QUICKI, alternative markers of insulin resistance, plasma adipokines (adiponectin, leptin, interleukin 8, tumour necrosis factor alpha, resistin); high-sensitivity C-reactive protein (hs-CRP); body fat redistribution, as measured by magnetic resonance imaging/proton magnetic resonance spectroscopy; changes in renal markers (albumin-to-creatinine ratio, neutrophil gelatinase-associated lipocalin); and tolerability to telmisartan. RESULTS: At the interim analysis, 80 mg of telmisartan was taken forward into the second stage of the study. Baseline characteristics were balanced across treatment arms. There were no differences in HOMA-IR [0.007, standard error (SE) 0.106], QUICKI (0.001, SE 0.001) and revised QUICKI (0.002, SE 0.002) at 24 weeks between the telmisartan (80 mg; n = 106) and non-intervention (n = 105) arms. Longitudinal analysis over 48 weeks showed that there was no change in HOMA-IR, lipid or adipokine levels; however, but there were significant, but marginal, improvements in revised QUICKI [0.004, 95% confidence interval (CI) 0.000 to 0.008] and plasma hs-CRP (–0.222, 95% CI –0.433 to –0.011) over 48 weeks. Substudies also showed a significant reduction in the liver fat content at 24 weeks (1.714, 95% CI –2.787 to –0.642; p = 0.005) and urinary albumin excretion at 48 weeks (–0.665, 95% CI –1.31 to –0.019; p = 0.04). There were no differences in serious adverse events between the telmisartan and control arms. LIMITATIONS: The patients had modest elevations of HOMA-IR at baseline, and our trial could have been under-powered to detect smaller improvements in insulin resistance over time. CONCLUSIONS: Using a novel adaptive design, we demonstrated that there was no significant effect of telmisartan (80 mg) on the primary outcome measure of HOMA-IR and some secondary outcomes (plasma lipids and adipokines). Telmisartan did lead to favourable, and biologically plausible, changes of the secondary longitudinal outcome measures: revised QUICKI, hs-CRP, hepatic fat accumulation and urinary albumin excretion. Taken collectively, our findings showed that telmisartan did not reduce insulin resistance in patients infected with HIV on antiretrovirals. FUTURE WORK: The mechanistic basis of adipocyte regulation will be studied to allow for development of biomarkers and interventions. TRIAL REGISTRATION: Current Controlled Trials ISRCTN51069819. FUNDING: This project was funded by the Efficacy and Mechanism Evaluation (EME) programme, a Medical Research Council and National Institute for Health Research partnership. PB - NIHR Journals Library CY - Southampton (UK) UR - https://www.unboundmedicine.com/medline/citation/31318501/Telmisartan_to_reduce_insulin_resistance_in_HIV-positive_individuals_on_combination_antiretroviral_therapy:_the_TAILoR_dose-ranging_Phase_II_RCT L2 - https://www.ncbi.nlm.nih.gov/books/NBK544102 DB - PRIME DP - Unbound Medicine ER -