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TAILoR (TelmisArtan and InsuLin Resistance in Human Immunodeficiency Virus [HIV]): An Adaptive-design, Dose-ranging Phase IIb Randomized Trial of Telmisartan for the Reduction of Insulin Resistance in HIV-positive Individuals on Combination Antiretroviral Therapy.

Abstract

BACKGROUND

Combination antiretroviral therapy results in metabolic abnormalities which increase cardiovascular disease risk. We evaluated whether telmisartan reduces insulin resistance in human immunodeficiency virus (HIV)-positive individuals on antiretrovirals.

METHODS

We conducted a multicenter, randomized, open-label, dose-ranging controlled trial of telmisartan. Participants with HIV infection receiving combination antiretroviral therapy were randomized equally to either no intervention (control) or 20, 40, or 80 mg telmisartan once daily. The adaptive design allowed testing of all dose(s) of telmisartan in stage I, with the promising dose(s) being taken into stage II. The primary outcome measure was reduction in homeostasis model assessment of insulin resistance (HOMA-IR) at 24 weeks.

RESULTS

A total of 377 patients were recruited. In stage I, 48, 49, 47, and 45 patients were randomized to control and 20, 40, and 80 mg telmisartan, respectively (total n = 189). At the interim analysis, 80 mg telmisartan was taken forward into stage II. At the end of stage II (n = 105, control; 106, 80-mg arm), there were no differences in HOMA-IR (estimated effect, 0.007; SE, 0.106) at 24 weeks between the telmisartan (80 mg) and nonintervention arms. Longitudinal analysis over 48 weeks showed no change in HOMA-IR, lipid or adipokine levels. There were significant (P ≤ .05), but marginal, improvements in revised Quantitative Insulin Sensitivity Check Index (QUICKI) (0.004) and plasma hs-CRP (-0.222 mg/L) and reduction in liver fat content (1.714 mean reduction; P = .005).

CONCLUSIONS

No significant effect of telmisartan was demonstrated on the primary outcome (HOMA-IR), but there were marginal improvements with some secondary outcome measures. Further studies in this population are warranted to identify novel strategies for preventing cardiovascular morbidity and mortality.

CLINICAL TRIAL REGISTRATION

ISRCTN registry (51069819).

Authors+Show Affiliations

Department of Molecular and Clinical Pharmacology, University of Liverpool, United Kingdom.Department of Biostatistics, University of Liverpool, United Kingdom.Clinical Trials Research Centre, University of Liverpool, United Kingdom.Department of Molecular and Clinical Pharmacology, University of Liverpool, United Kingdom.Clinical Trials Research Centre, University of Liverpool, United Kingdom.Department of Biostatistics, University of Liverpool, United Kingdom.Liverpool Magnetic Resonance Imaging Centre, University of Liverpool, United Kingdom.Department of Mathematics and Statistics, Lancaster University, United Kingdom.Department of Molecular and Clinical Pharmacology, University of Liverpool, United Kingdom.Department of Biostatistics, University of Liverpool, United Kingdom.Department of Molecular and Clinical Pharmacology, University of Liverpool, United Kingdom.No affiliation info available

Pub Type(s)

Journal Article

Language

eng

PubMed ID

31425580

Citation

Pushpakom, Sudeep, et al. "TAILoR (TelmisArtan and InsuLin Resistance in Human Immunodeficiency Virus [HIV]): an Adaptive-design, Dose-ranging Phase IIb Randomized Trial of Telmisartan for the Reduction of Insulin Resistance in HIV-positive Individuals On Combination Antiretroviral Therapy." Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America, 2019.
Pushpakom S, Kolamunnage-Dona R, Taylor C, et al. TAILoR (TelmisArtan and InsuLin Resistance in Human Immunodeficiency Virus [HIV]): An Adaptive-design, Dose-ranging Phase IIb Randomized Trial of Telmisartan for the Reduction of Insulin Resistance in HIV-positive Individuals on Combination Antiretroviral Therapy. Clin Infect Dis. 2019.
Pushpakom, S., Kolamunnage-Dona, R., Taylor, C., Foster, T., Spowart, C., García-Fiñana, M., ... Pirmohamed, M. (2019). TAILoR (TelmisArtan and InsuLin Resistance in Human Immunodeficiency Virus [HIV]): An Adaptive-design, Dose-ranging Phase IIb Randomized Trial of Telmisartan for the Reduction of Insulin Resistance in HIV-positive Individuals on Combination Antiretroviral Therapy. Clinical Infectious Diseases : an Official Publication of the Infectious Diseases Society of America, doi:10.1093/cid/ciz589.
Pushpakom S, et al. TAILoR (TelmisArtan and InsuLin Resistance in Human Immunodeficiency Virus [HIV]): an Adaptive-design, Dose-ranging Phase IIb Randomized Trial of Telmisartan for the Reduction of Insulin Resistance in HIV-positive Individuals On Combination Antiretroviral Therapy. Clin Infect Dis. 2019 Jul 3; PubMed PMID: 31425580.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - TAILoR (TelmisArtan and InsuLin Resistance in Human Immunodeficiency Virus [HIV]): An Adaptive-design, Dose-ranging Phase IIb Randomized Trial of Telmisartan for the Reduction of Insulin Resistance in HIV-positive Individuals on Combination Antiretroviral Therapy. AU - Pushpakom,Sudeep, AU - Kolamunnage-Dona,Ruwanthi, AU - Taylor,Claire, AU - Foster,Terry, AU - Spowart,Cath, AU - García-Fiñana,Marta, AU - Kemp,Graham J, AU - Jaki,Thomas, AU - Khoo,Saye, AU - Williamson,Paula, AU - Pirmohamed,Munir, AU - ,, Y1 - 2019/07/03/ PY - 2019/03/27/received PY - 2019/07/02/accepted PY - 2019/8/20/entrez PY - 2019/8/20/pubmed PY - 2019/8/20/medline KW - HIV KW - antiretroviral drugs KW - insulin resistance KW - metabolic disease KW - telmisartan JF - Clinical infectious diseases : an official publication of the Infectious Diseases Society of America JO - Clin. Infect. Dis. N2 - BACKGROUND: Combination antiretroviral therapy results in metabolic abnormalities which increase cardiovascular disease risk. We evaluated whether telmisartan reduces insulin resistance in human immunodeficiency virus (HIV)-positive individuals on antiretrovirals. METHODS: We conducted a multicenter, randomized, open-label, dose-ranging controlled trial of telmisartan. Participants with HIV infection receiving combination antiretroviral therapy were randomized equally to either no intervention (control) or 20, 40, or 80 mg telmisartan once daily. The adaptive design allowed testing of all dose(s) of telmisartan in stage I, with the promising dose(s) being taken into stage II. The primary outcome measure was reduction in homeostasis model assessment of insulin resistance (HOMA-IR) at 24 weeks. RESULTS: A total of 377 patients were recruited. In stage I, 48, 49, 47, and 45 patients were randomized to control and 20, 40, and 80 mg telmisartan, respectively (total n = 189). At the interim analysis, 80 mg telmisartan was taken forward into stage II. At the end of stage II (n = 105, control; 106, 80-mg arm), there were no differences in HOMA-IR (estimated effect, 0.007; SE, 0.106) at 24 weeks between the telmisartan (80 mg) and nonintervention arms. Longitudinal analysis over 48 weeks showed no change in HOMA-IR, lipid or adipokine levels. There were significant (P ≤ .05), but marginal, improvements in revised Quantitative Insulin Sensitivity Check Index (QUICKI) (0.004) and plasma hs-CRP (-0.222 mg/L) and reduction in liver fat content (1.714 mean reduction; P = .005). CONCLUSIONS: No significant effect of telmisartan was demonstrated on the primary outcome (HOMA-IR), but there were marginal improvements with some secondary outcome measures. Further studies in this population are warranted to identify novel strategies for preventing cardiovascular morbidity and mortality. CLINICAL TRIAL REGISTRATION: ISRCTN registry (51069819). SN - 1537-6591 UR - https://www.unboundmedicine.com/medline/citation/31425580/TAILoR__TelmisArtan_and_InsuLin_Resistance_in_Human_Immunodeficiency_Virus_[HIV]_:_An_Adaptive_design_Dose_ranging_Phase_IIb_Randomized_Trial_of_Telmisartan_for_the_Reduction_of_Insulin_Resistance_in_HIV_positive_Individuals_on_Combination_Antiretroviral_Therapy_ L2 - https://academic.oup.com/cid/article-lookup/doi/10.1093/cid/ciz589 DB - PRIME DP - Unbound Medicine ER -