Cardiovascular drugs and COVID-19 clinical outcomes: a systematic review and meta-analysis of randomized controlled trials.

AIMS: To update our previously reported systematic review and meta-analysis of observational studies on cardiovascular drug exposure and COVID-19 clinical outcomes by focusing on newly published randomized controlled trials (RCTs). METHODS: More than 500 databases were searched between 1 November 2020 and 2 October 2021 to identify RCTs that were published after our baseline review. One reviewer extracted data with other reviewers verifying the extracted data for accuracy and completeness. RESULTS: After screening 22 414 records, we included 24 and 21 RCTs in the qualitative and quantitative syntheses, respectively. The most investigated drug classes were angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor blocker (ARBs) and anticoagulants, investigated by 10 and 11 studies respectively. In meta-analyses, ACEI/ARBs did not affect hospitalization length (mean difference -0.42, 95% confidence interval [CI] -1.83; 0.98 d, n = 1183), COVID-19 severity (risk ratio/RR 0.90, 95% CI 0.71; 1.15, n = 1661) or mortality (risk ratio [RR] 0.92, 95% CI 0.58; 1.47, n = 1646). Therapeutic anticoagulation also had no effect (hospitalization length mean difference -0.29, 95% CI -1.13 to 0.56 d, n = 1449; severity RR 0.86, 95% CI 0.70; 1.04, n = 2696; and, mortality RR 0.93, 95% CI 0.77; 1.13, n = 5689). Other investigated drug classes were antiplatelets (aspirin, 2 trials), antithrombotics (sulodexide, 1 trial), calcium channel blockers (amlodipine, 1 trial) and lipid-modifying drugs (atorvastatin, 1 trial). CONCLUSION: Moderate- to high-certainty RCT evidence suggests that cardiovascular drugs such as ACEIs/ARBs are not associated with poor COVID-19 outcomes, and should therefore not be discontinued. These cardiovascular drugs should also not be initiated to treat or prevent COVID-19 unless they are needed for an underlying currently approved therapeutic indication.

Telmisartan reverses antiretroviral-induced adipocyte toxicity and insulin resistance in vitro.

BACKGROUND: Antiretroviral therapy in HIV-positive patients leads to insulin resistance which is central to the pathogenesis of various metabolic abnormalities and cardiovascular disease seen in this patient group. We have investigated the dose-response relationship of telmisartan, an antihypertensive, on adipocytes in vitro in order to determine whether it may have metabolic beneficial effects. METHODS: Using in vitro chronic toxicity models (3T3-F442A murine and primary human adipocytes), we evaluated the effects of different concentrations of telmisartan on adipocyte differentiation and adipogenic gene expression using lipid accumulation assays and real-time polymerase chain reaction, respectively. Adipokine secretion and expression of insulin signalling mediators were evaluated using enzyme-linked immunosorbent assays. RESULTS: Telmisartan partially reversed the deleterious effects of antiretrovirals on adipocyte lipid accumulation, expression of adipogenic regulators (peroxisome proliferator receptor-gamma and lipin 1), adipokine secretion and expression of the insulin signalling mediator pAktSer473. The metabolic effects of telmisartan followed a non-monotonic response with the maximal effect observed at 5 µM in the primary human adipocyte model. CONCLUSION: Telmisartan has beneficial metabolic effects in adipocytes in vitro, but its potential to reduce antiretroviral-induced cardiometabolic disease in HIV-infected individuals needs to be evaluated in a well-designed adequately powered clinical trial.

Telmisartan and Insulin Resistance in HIV (TAILoR): protocol for a dose-ranging phase II randomised open-labelled trial of telmisartan as a strategy for the reduction of insulin resistance in HIV-positive individuals on combination antiretroviral therapy.

INTRODUCTION: Telmisartan, an angiotensin receptor blocker, has beneficial effects on insulin resistance and cardiovascular health in non-HIV populations. This trial will evaluate whether telmisartan can reduce insulin resistance in HIV-positive individuals on combination antiretroviral therapy. METHODS AND ANALYSIS: This is a phase II, multicentre, randomised, open-labelled, dose-ranging trial of telmisartan in 336 HIV-positive individuals over a period of 48 weeks. The trial will use an adaptive design to inform the optimal dose of telmisartan. Patients will be randomised initially 1:1:1:1 to receive one of the three doses of telmisartan (20, 40 and 80 mg) or no intervention (control). An interim analysis will be performed when half of the planned maximum of 336 patients have been followed up for at least 24 weeks. The second stage of the study will depend on the results of interim analysis. The primary outcome measure is a reduction in insulin resistance (as measured by Homeostatic Model Assessment-Insulin Resistance (HOMA-IR)) in telmisartan treated arm(s) after 24 weeks of treatment in comparison with the non-intervention arm. The secondary outcome measures include changes in lipid profile; body fat redistribution (as measured by MRI); plasma and urinary levels of various biomarkers of cardiometabolic and renal health at 12, 24 and 48 weeks. Serious adverse events will be compared between different telmisartan treated dose arm(s) and the control arm. ETHICS AND DISSEMINATION: The study, this protocol and related documents have been approved by the National Research Ethics Service Committee North West-Liverpool Central (Ref: 12/NW/0214). On successful completion, study data will be shared with academic collaborators. The findings from TAILoR will be disseminated through peer-reviewed publications, at scientific conferences, the media and through patient and public involvement. TRIAL REGISTRATION NUMBERS: 04196/0024/001-0001; EUDRACT: 2012-000935-18; ISRCTN: 51069819.

RXRγ gene variants are associated with HIV lipodystrophy.

HIV lipodystrophy (HIVLD), associated with combination antiretroviral therapy (cART), leads to metabolic and cardiovascular diseases. Nuclear receptors play a central role in lipid homoeostasis and drug disposition; their genetic variants may predispose an individual to the development of HIVLD. DNA samples obtained from cART-treated HIV-positive patients with (HIVLD+; 124) and without (HIVLD-; 56) HIVLD were genotyped for 77 single nucleotide polymorphisms in nine nuclear receptor genes. Statistical analysis was carried out using Haploview software and by logistic regression. Three single nucleotide polymorphisms in RXRγ (rs2134095, rs113471, rs2194899) and its haplotypes (HIVLD+, 54%; HIVLD-, 40.6%; P=0.02) showed significant association with HIVLD. Multivariate analysis identified time since diagnosis (P=0.001) and carriage of the RXRγ haplotype (P=0.02) to be independently associated with HIVLD. Genetic variation in RXRγ, a common binding partner of nuclear receptors that modulate lipid homoeostasis and drug disposition, may contribute to the development of HIVLD in cART-treated HIV patients. These results need replication in other cohorts.

Improved glycaemia correlates with liver fat reduction in obese, type 2 diabetes, patients given glucagon-like peptide-1 (GLP-1) receptor agonists.

Glucagon-like peptide-1 receptor agonists (GLP-1 RA) are effective for obese patients with type 2 diabetes mellitus (T2DM) because they concomitantly target obesity and dysglycaemia. Considering the high prevalence of non-alcoholic fatty liver disease (NAFLD) in patients with T2DM, we determined the impact of 6 months' GLP-1 RA therapy on intrahepatic lipid (IHL) in obese, T2DM patients with hepatic steatosis, and evaluated the inter-relationship between changes in IHL with those in glycosylated haemoglobin (HbA(1)c), body weight, and volume of abdominal visceral and subcutaneous adipose tissue (VAT and SAT). We prospectively studied 25 (12 male) patients, age 50±10 years, BMI 38.4±5.6 kg/m(2) (mean ± SD) with baseline IHL of 28.2% (16.5 to 43.1%) and HbA(1)c of 9.6% (7.9 to 10.7%) (median and interquartile range). Patients treated with metformin and sulphonylureas/DPP-IV inhibitors were given 6 months GLP-1 RA (exenatide, n = 19; liraglutide, n = 6). IHL was quantified by liver proton magnetic resonance spectroscopy ((1)H MRS) and VAT and SAT by whole body magnetic resonance imaging (MRI). Treatment was associated with mean weight loss of 5.0 kg (95% CI 3.5,6.5 kg), mean HbA(1c) reduction of 1·6% (17 mmol/mol) (0·8,2·4%) and a 42% relative reduction in IHL (-59.3, -16.5%). The relative reduction in IHL correlated with that in HbA(1)c (ρ = 0.49; p = 0.01) but was not significantly correlated with that in total body weight, VAT or SAT. The greatest IHL reduction occurred in individuals with highest pre-treatment levels. Mechanistic studies are needed to determine potential direct effects of GLP-1 RA on human liver lipid metabolism.

Genetic variants of ABCC10, a novel tenofovir transporter, are associated with kidney tubular dysfunction.

BACKGROUND: Tenofovir (TFV) causes kidney tubular dysfunction (KTD) in some patients, but the mechanism is poorly understood. Genetic variants in TFV transporters are implicated; we explored whether ABCC10 transports TFV and whether ABCC10 single-nucleotide polymorphisms (SNPs) are associated with KTD. METHODS: TFV accumulation was assessed in parental and ABCC10-transfected HEK293 cells (HEK293-ABCC10), CD4(+) cells and monocyte-derived macrophages (MDMs). Substrate specificity was confirmed by cepharanthine (ABCC10 inhibitor) and small interfering RNA (siRNA) studies. Fourteen SNPs in ABCC10 were genotyped in human immunodeficiency virus-positive patients with KTD (n = 19) or without KTD (controls; n = 96). SNP and haplotype analysis was performed using Haploview. RESULTS: TFV accumulation was significantly lower in HEK293-ABCC10 cell lines than in parental HEK293 cells (35% lower; P = .02); this was reversed by cepharanthine. siRNA knockdown of ABCC10 resulted in increased accumulation of TFV in CD4(+) cells (18%; P = .04) and MDMs (25%; P = .04). Two ABCC10 SNPs (rs9349256: odds ratio [OR], 2.3; P = .02; rs2125739, OR, 2.0; P = .05) and their haplotype (OR, 2.1; P = .05) were significantly associated with KTD. rs9349256 was associated with urine phosphorus wasting (P = .02) and ß2 microglobulinuria (P = .04). CONCLUSIONS: TFV is a substrate for ABCC10, and genetic variability within the ABCC10 gene may influence TFV renal tubular transport and contribute to the development of KTD. These results need to be replicated in other cohorts.

Adipogenic gene variants in patients with HIV-associated lipodystrophy.

OBJECTIVES: Although highly active antiretroviral therapy (HAART) has been hugely beneficial in the treatment of HIV, HIV lipodystrophy (HIVLD) associated with HAART is a serious adverse effect, with long-term consequences including metabolic disturbances and an increased risk of atherosclerotic disease. Although HIVLD is clearly related to the drug regimen, individual susceptibility also plays a role. We hypothesized that variation in genes regulating adipogenesis, and in those implicated in inherited forms of lipodystrophy, may predispose to the development of HIVLD. METHODS: DNA samples were obtained from 180 HAART-treatedHIV+ patients: 124 with HIVLD (HIVLD+) and 56 without HIVLD (HIVLD-). Diagnosis of HIVLD was carried out by clinician's confirmation of patient self-report. High-throughput genotyping using Sequenom was used to screen 62 single nucleotide polymorphisms (SNPs) in eight genes involved in adipogenesis and inherited forms of lipodystrophy. Statistical analysis was performed using Haploview. Multivariate analysis (logistic regression) was used to identify independent predictors of HIVLD development in HAART-treated patients. RESULTS: SNPs in two adipogenesis regulators, LPIN1 and CEBPα, showed a significant association with HIVLD whereas a SNP in ZMPSTE24, a zinc metalloproteinase involved in prelamin A processing, showed a trend toward significance. Multivariate analysis identified time since HIV diagnosis (P=0.001) and carriage of more than one associated allele (P=0.008) to be the most significant independent predictors for the development of HIVLD. CONCLUSION: Genetic variation in key regulators of adipogenesis could interfere with fat storage and metabolism contributing to the development of HIVLD in HAART-treated HIV patients. These results need replication in other cohorts.

Exacerbation of hereditary warfarin resistance by azathioprine.

A 39-year-old Afro-Caribbean man with Crohn disease with recurrent deep vein thromboses and pulmonary emboli was commenced on lifelong warfarin treatment. The patient required high-dose warfarin (>140 mg/wk), which increased further during azathioprine treatment. Cessation of azathioprine resulted in an increase in the international normalized ratio (INR). Mutation analysis identified a Val66Met substitution in vitamin K epoxide reductase complex subunit 1 (VKORC1), consistent with severe warfarin resistance. This report is the first presentation where the patient had a defined hereditary resistance to warfarin, which was aggravated by concomitant azathioprine. It is important for clinicians to be aware of the interaction between warfarin and azathioprine, to monitor clinical response closely, and to manage the doses of both drugs accordingly.

Polymorphisms in COL15 gene are not associated with systemic sclerosis.

OBJECTIVE: Systemic sclerosis (SSc) is marked by microvascular abnormalities leading to ischemic features such as Raynaud's phenomenon and fingertip ulcers. Digital ischemia in turn results in hypoxia, which is expected to drive compensatory angiogenesis; however, this phenomenon is deregulated in SSc. Vascular basement membrane (VBM) that consists of type IV, XV, and XVIII collagens supports the growth and survival of vascular endothelial cells and plays a key role in regulating angiogenesis. Recent gene expression analyses of skin tissue and dermal fibroblasts from patients with SSc revealed COL15 to be one of the significantly differentially regulated genes. We undertook an association study to explore the role of COL15 single-nucleotide polymorphisms (SNP) in SSc disease development. METHODS: Eleven SNP across COL15 were genotyped in a cohort of 175 UK Caucasian patients with SSc and 190 population-matched unrelated healthy subjects using 2 methods: TaqMan and SNaPshot. Statistical analysis was performed by Pearson's chi-square test and HelixTree software was utilized for haplotype analysis. RESULTS: No difference in genotype or allele frequencies were detected between patients with SSc and controls. None of the haplotype frequencies were found to differ between patients and controls. CONCLUSION: Failure to detect an association may reflect a true lack of association or could be a false-negative result arising as a result of low power of the study. Our study had sufficient power to detect an effect size of 2.1 (p = 0.05); however, larger patient cohorts may be needed for exclusion of COL15 from a possible candidacy in SSc.