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Substantial COVID-19 research investment has been allocated to randomized clinical trials (RCTs) on hydroxychloroquine/chloroquine, which currently face recruitment challenges or early discontinuation. We aim to estimate the effects of hydroxychloroquine and chloroquine on survival in COVID-19 from all currently available RCT evidence, published and unpublished. We present a rapid meta-analysis of ongoing, completed, or discontinued RCTs on hydroxychloroquine or chloroquine treatment for any COVID-19 patients (protocol: https://osf.io/QESV4/ ). We systematically identified unpublished RCTs (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, Cochrane COVID-registry up to June 11, 2020), and published RCTs (PubMed, medRxiv and bioRxiv up to October 16, 2020). All-cause mortality has been extracted (publications/preprints) or requested from investigators and combined in random-effects meta-analyses, calculating odds ratios (ORs) with 95% confidence intervals (CIs), separately for hydroxychloroquine and chloroquine. Prespecified subgroup analyses include patient setting, diagnostic confirmation, control type, and publication status. Sixty-three trials were potentially eligible. We included 14 unpublished trials (1308 patients) and 14 publications/preprints (9011 patients). Results for hydroxychloroquine are dominated by RECOVERY and WHO SOLIDARITY, two highly pragmatic trials, which employed relatively high doses and included 4716 and 1853 patients, respectively (67% of the total sample size). The combined OR on all-cause mortality for hydroxychloroquine is 1.11 (95% CI: 1.02, 1.20; I² = 0%; 26 trials; 10,012 patients) and for chloroquine 1.77 (95%CI: 0.15, 21.13, I² = 0%; 4 trials; 307 patients). We identified no subgroup effects. We found that treatment with hydroxychloroquine is associated with increased mortality in COVID-19 patients, and there is no benefit of chloroquine. Findings have unclear generalizability to outpatients, children, pregnant women, and people with comorbidities.

Background: Obesity enhances hemodynamic alterations that predispose to a subsequent increase in left ventricular (LV) wall stress leading to LV hypertrophy. In obese subjects, weight reduction regresses LV mass (LVM), regardless of blood pressure. Sibutramine can increase blood pressure and heart rate, which may attenuate the reductions in LVM associated with weight loss., Methods: Outpatients (n = 184, age 18-65 y, body mass index > or =30 to <40 kg/m2) were randomly assigned to 6 months of once daily double-blind treatment with sibutramine 10 mg or 20 mg, or placebo. LV dimensions, status and function of the valves, weight loss, blood pressure, heart rate, and electrocardiogram were assessed., Results: For end point data sets, the mean +/- SD LVM index (LVM/height) changes were -3.0 +/- 11.9 g/m for placebo (n = 56), -4.4 +/- 10.7 g/m for sibutramine 10 mg (n = 61), and -4.3 +/- 10.9 g/m for sibutramine 20 mg (n = 56). The reductions observed in the sibutramine groups were statistically significant compared with baseline (P <.01), but pairwise comparison results with placebo were not statistically significant. There was no difference in overall status of the cardiac valves. A statistically significant greater weight loss was found in patients on both doses of sibutramine compared with placebo (P <.001). No statistically significant differences between the groups were observed in respect to blood pressure and electrocardiographic intervals, but a statistically significant increase in pulse rate (7 beats/min) was noted for patients with sibutramine treatment., Conclusion: A 6-month treatment with sibutramine does not affect ventricular dimensions, heart valves, and electrocardiogram variables.

This study compared the structural and functional properties of glucosylated and non-glucosylated LpA-I particle subfractions (GLpA-I and NGLpA-I, respectively) isolated from patients with poorly controlled type 1 (insulin-dependent) diabetes. Compared with NGLpA-I, GLpA-I showed an enrichment in triglycerides (P < .05) and a depletion in phospholipid (P < .05) content. Moreover, the triglycerides-to-cholesteryl esters ratio was increased (P < .05), suggesting an increased cholesteryl ester transfer protein activity and a possible transport defect that accelerates atherogenesis. The surface-to-core constituents ratio, an indirect estimate of particles size, is lower in GLpA-I (P < .01) than in NGLpA-I, correlating well with a larger median size (P < .05) as seen by electron microscopy. The apolipoprotein (apo) A-I conformation was evaluated through determination of the immunological accessibility of three different domains defining specific epitopes for anti-apo A-I monoclonal antibodies. We observed a marked decreased accessibility for two of these regions, which interestingly have already been implicated in the interaction with cells. Cell culture data suggest that nonenzymatic glycosylation occurring on apo A-I can modify lipoprotein function, since it results in a decreased binding of GLpA-I to HeLa cells and impaired cholesterol efflux from Fu5AH rat hepatoma cells.

The physicochemical modifications (composition and conformation) of lipoproteins containing apolipoprotein B-100 (apo B-100) were studied in normocholesterolaemic adequately controlled Type 1 insulin-dependent diabetic patients. Thirty-one normocholesterolaemic (serum cholesterol < 6.50 mmol/l) diabetic male patients and 31 age-and body mass index-adjusted healthy normolipaemic male controls were studied. Cholesterol and choline-containing phospholipids were measured in total serum and in two lipoprotein subfractions containing or not apo B (LpB and LpnoB respectively). These subfractions were separated by precipitation with concanavalin A. Total apo B-100 and two lipoprotein particles defined according to their apo B-100 epitope accessibility were determined using respectively anti-apo B polyclonal and two monoclonal antibodies that reacted with specific epitopes on the apo B molecule. Despite a classical lipid profile (cholesterol and triglyceride levels), which was quite normal in plasma from patients as compared to controls, a depletion of choline-containing phospholipid content in serum and more specifically in LpB particles was observed in diabetic patients. Decreased cholesterol content was also observed in LpB particles. Immunological analysis demonstrated an increased number of lipoprotein particles (a condition previously related to coronary artery disease) and decreased immunoaccessibility of a conformationally expressed apo B-100 epitope. These conformational changes were correlated with modifications of the surface phospholipid environment of LpB particles. It is concluded that subtle abnormalities in the composition and conformation of atherogenic apo-B-containing lipoproteins occur in Type 1 diabetes mellitus. These structural modifications may be one factor accounting for the increased rate of atherosclerosis in diabetes, despite the existence of a normal classical lipid profile.

High-density lipoproteins (HDL) are believed to protect against atherosclerosis by promoting the process of reverse cholesterol transport. This process involves different steps including efflux of cellular cholesterol, cholesterol esterification and lipid transport and exchange. Apolipoprotein (apo) A-I, the major HDL apolipoprotein, and the HDL-associated enzyme lecithin-cholesterol acyltransferase (LCAT), which uses apo A-I as a cofactor, play a crucial role in reverse cholesterol transport. HDL may be classified into species according to their apolipoprotein content. Recent data concerning HDL particles indicate that lipoproteins containing apo A-I but not apo A-II (LpA-I) are more effective carriers of free cholesterol and are associated with a protective effect against coronary heart disease. In vitro studies have shown that glycosylated HDL are functionally abnormal and may be considered atherogenic. Our study considers the different impacts of non-enzymatic glycosylation of apo A-I or protein-HDL on the reverse cholesterol transport process.

The excess risk of cardiovascular disease in Type 1 diabetes mellitus compared to non diabetic subjects is only partially explained by standard risk factors. Several studies suggest that Lp(a) concentrations are increased in Type 1 diabetes mellitus, but data are still controversial. Moreover, a high cardiovascular risk has been reported in diabetic patients with persistent proteinuria. Therefore, the aim of this study was to compare the Lp(a) particle levels in insulin-dependent diabetic patients with or without increased urinary albumin excretion. Cross-sectional study of Lp(a) plasma levels in a population of 140 insulin-dependent diabetic patients: 83 without increased proteinuria, 14 with borderline elevation of urinary albumin excretion, 27 with micro- and 16 with macro-proteinuria. Simultaneous determination of plasma lipids, fasting blood glucose and HbA1c was performed. The mean plasma Lp(a) concentrations and the distribution of the levels were comparable in all of the diabetic patient groups. No relationship existed between Lp(a) and HbA1c, fasting blood glucose or any lipid plasma levels. No influence of albumin excretion rate on Lp(a) levels was observed. These data provide no evidence of a specific contribution of Lp(a) particles to the increased morbidity and mortality from cardiovascular disease observed among patients with nephropathy.