Efficacy and safety of standard dose triple combination of telmisartan 80 mg/amlodipine 5 mg/chlorthalidone 25 mg in primary hypertension: A randomized,double-blind,active-controlled,multicenter phase 3 trial

The authors evaluated the efficacy, safety, and characteristics of patients who respond well to standard dose triple combination therapy including chlorthalidone 25 mg with telmisartan 80 mg plus amlodipine 5 mg in hypertensive patients. This is a multicenter, double-blind, active-controlled, phase 3, randomized trial. Patients are randomized to triple combination (telmisartan 40 mg/amlodipine 5 mg/chlorthalidone 12.5 mg, TEL/AML/CHTD group) or dual combination (telmisartan 40 mg/amlodipine 5 mg, TEL/AML group) treatment and then dose up titration to TEL 80/AML5/CHTD25mg and TEL80/AML5, respectively. The primary endpoint is the change of mean sitting systolic blood pressure (MSSBP) at week 8. A Target BP achievement rate, a response rate, and the safety endpoints are also evaluated. Total 374 patients (mean age = 60.9 ± 10.7 years, male = 78.3%) were randomized to the study. The baseline MSSBPs/diastolic BPs were 149.9 ± 12.2/88.5 ± 10.4 mm Hg. After 8 weeks treatment, the change of MSSBPs at week 8 are −19.1 ± 14.9 mm Hg (TEL/AML/CHTD) and −11.4 ± 14.7 mm Hg (TEL/AML) (p < .0001). The achievement rates of target BP (53.8% vs. 37.8%, p = .0017) and responder rate (54.8% vs. 35.6%, p = .0001) at week 8 were significantly higher in TEL/AML/CHTD. There are no serious adverse event and no one discontinued medication due to adverse event. Among the TEL 80/AML5/CHTD25mg treatment group, patients of female or age ≥ 65 years old showed higher rate of target BP achievement than relatively young male. (61.4 vs. 46.8%, p = .042) Our study showed standard dose triple combination of telmisartan 80 mg/amlodipine 5 mg/chlorthalidone 25 mg is efficacious and safe in treatment of primary hypertension. Target BP achievement with triple therapy would be facilitated in female or old age.     

Discovery Belux: comparison of rosuvastatin with atorvastatin in hypercholesterolaemia

METHODS: Discovery Belux is an open-label, multicentre, randomised, phase IIIb, parallel group study comparing the efficacy of rosuvastatin (RSV) and atorvastatin (ATV) on changes in lipid levels and the achievement of European Atherosclerosis Society (EAS) lipid goals. Patients (> or = 18 years) with primary hypercholesterolaemia, with a low-density lipoprotein (LDL-C) level > 120 mg/dl (on treatment) or > 135 mg/dl (naive subjects), and with a statin indication, were randomised to receive RSV 10 mg/day or ATV 10 mg/day for 12 weeks. Patients not at goal after 12 weeks and receiving ATV 10 were further switched to RSV 10 mg for another 12 weeks. Patients not at goal with RSV 10 mg were further titrated to RSV 20 mg. RESULTS: 938 patients were randomised to the two treatment groups. After 12 weeks of treatment, a significantly greater percentage of patients receiving RSV 10 compared with ATV 10 achieved EAS LDL-C target goal (< 115 mg/dl) (85% vs. 67%). LDL-C was reduced by 47% and total cholesterol (TC) by 33% with RSV 10.This was 38% and 27% for ATV 10, respectively. After 24 weeks, an additional 57% of patients initially taking RSV 10 and uncontrolled, reached the target with RSV 20. In the patient group, initially taking ATV 10 and uncontrolled, 65% reached the target with RSV 10 after 24 weeks. Both treatments were well tolerated with a similar incidence of adverse events. In addition, a health economic analysis was performed. As RSV 10 is available at a lower cost in Belgium and as it is more effective, compared to ATV 10, it appeared to be the option of choice from a cost-effectiveness perspective. CONCLUSIONS: Rosuvastatin 10 mg treatment is significantly more effective than atorvastatin 10 mg at achieving European LDL-C goals, at lowering LDL-C and TC. These results were obtained with a similar safety profile. From a cost-effectiveness perspective RSV 10 is the preferred therapeutic option in comparison with ATV 10. Uptitration of uncontrolled patients to RSV 20 mg and switch from ATV 10 to RSV 10 allowed significantly more patients to reach the LDL-C and TC target goal.     

The effects of green coffee bean extract supplementation on lipid profile in humans: A systematic review and meta-analysis of randomized controlled trials

Background and aimThis systematic review and meta-analysis aimed to assess the effects of green coffee bean extract (GCBE) supplementation on lipid profile in adults.Methods and resultsThe PubMed/Medline, Scopus, Web of sciences, and Google Scholar were systematically searched for randomized controlled trials available in English and published before February 2019. The meta-analysis was conducted using fixed effects models, and between-study heterogeneity was assessed by Cochran's Q test and I². A total of 17 effect sizes were included in the meta-analysis. Combined effect sizes on serum total cholesterol concentrations revealed significant effects of GCBE supplementation on serum total cholesterol [weighted mean difference (WMD): −4.51 mg/dL, 95% confidence interval (CI): −6.89, −2.12, p < 0.001], low density lipoprotein-cholesterol (LDL-C) (WMD: −4.38 mg/dL, 95% CI: −6.44, −2.31, p < 0.001), and high density lipoprotein-cholesterol (HDL-C) (WMD: 2.63 mg/dL, 95% CI: 2.20, 3.07, p < 0.001) compared to controls. Nevertheless, no significant changes were observed in serum triglycerides levels (WMD: −4.34 mg/dL, 95% CI: −9.00, 0.32, p = 0.068).ConclusionThe evidence from available studies suggests that the GCBE supplementation leads to significant reductions in total cholesterol, HDL-C, and LDL-C levels, and has modest, but, non-significant effects on triglycerides levels.     

Safety and efficacy of AK0529 in respiratory syncytial virus-infected infant patients: A phase 2 proof-of-concept trial

Background

Respiratory syncytial virus (RSV) infection is a cause of substantial morbidity and mortality in young children. There is currently no effective therapy available.

Methods

This was a Phase 2 study of the oral RSV fusion protein inhibitor AK0529 in infants aged 1–24 months, hospitalized with RSV infection. In Part 1, patients (n = 24) were randomized 2:1 to receive a single dose of AK0529 up to 4 mg/kg or placebo. In Part 2, patients (n = 48) were randomized 2:1 to receive AK0529 at 0.5, 1, or 2 mg/kg bid or placebo for 5 days. Sparse pharmacokinetic samples were assessed using population pharmacokinetics modelling. Safety, tolerability, viral load, and respiratory signs and symptoms were assessed daily during treatment.

Results

No safety or tolerability signals were detected for AK0529: grade ≥3 treatment-emergent adverse events occurring in 4.1% of patients in AK0529 and 4.2% in placebo groups, respectively, and none led to death or withdrawal from the study. In Part 2, targeted drug exposure was reached with 2 mg/kg bid. A numerically greater reduction in median viral load with 2 mg/kg bid AK0529 than with placebo at 96 h was observed. A −4.0 (95% CI: −4.51, −2.03) median reduction in Wang Respiratory Score from baseline to 96 h was observed in the 2 mg/kg group compared with −2.0 (95% CI: −3.42, −1.82) in the placebo group.

Conclusions

AK0529 was well tolerated in hospitalized RSV-infected infant patients. Treatment with AK0529 2 mg/kg bid was observed to reduce viral load and Wang Respiratory Score.

Clinical Trials Registration

NCT02654171.     

Effects of dehydroepiandrosterone (DHEA) supplementation on the lipid profile: A systematic review and dose-response meta-analysis of randomized controlled trials

Background and aimsDehydroepiandrosterone (DHEA) supplementation has gained attention in individuals with adrenal insufficiency, and as a tool for increasing androgens and estrogens whereby is proposed to improve the accretion of muscle and bone mass. However, DHEA supplementation has demonstrated negative effects on the lipid profile and, thus, we aimed to analyze the body of evidence in this regard.Methods and resultsA systematic review and dose-response meta-analysis of randomized controlled trials (RCTs) was performed employing in Scopus, PubMed/Medline, Web of Science, Embase and Google Scholar, then including relevant articles that addressed the effects of DHEA supplementation on the lipid profile, up to February 2020. Combined findings were generated from 23 eligible articles. Hence, total cholesterol (TC) (weighted mean difference (WMD): −3.5 mg/dl, 95% confidence interval (CI): −8.5 to 1.6)), low-density lipoprotein-cholesterol (LDL-C) (WMD: 0.34 mg/dl, 95% CI: −3 to 3.7) and triglycerides (TG) levels (WMD: −2.85 mg/dl, 95% CI: −9.3 to 3.6) did not alter in DHEA group compared to the control, but HDL-C levels significantly reduced in DHEA group (WMD: −3.1 mg/dl, 95% CI: −4.9 to −1.3). In addition, a significant reduction in HDL-C values was observed in studies comprising women (WMD: −5.1 mg/dl, 95% CI: −7.2 to −3) but not in males (WMD: 0.13 mg/dl, 95% CI: −1.4 to 1.7).ConclusionsOverall, supplementation with DHEA did not change circulating values of TC, LDL-C and TG, whereas it may decrease HDL-C levels. Further long-term RCTs are required to investigate the effects of DHEA particularly on major adverse cardiac events.     

Effects of guar gum supplementation on the lipid profile: A systematic review and meta-analysis of randomized controlled trials

Background and aimsGuar gum can be used as an adjuvant in the treatment of dyslipidemia. However, based on data from different studies, the effectiveness of this product is not uniform. Therefore, we conducted a dose–response meta-analysis between guar gum supplementation and lipid profile.Methods and resultsFive databases (Scopus, Web of Science, PubMed/Medline, Embase, and Google Scholar) were searched to identify relevant articles published up to July 2020. The weighted mean difference (WMD) was derived based on the random-effects model. Overall findings were generated from 25 eligible trials. Patients’ conditions included hyperlipidemia, diabetes, metabolic syndrome, hypertension, overweight, carotid endarterectomy, and menopausal women. Prescribed gum dose varied between 100 mg/d and 30 g/d for 1–24 months. Compared with control groups, guar gum supplementation decreased total cholesterol (TC) by −20.41 mg/dL (95% CI: −26.76 to −14.07; P < 0.001) and low-density lipoprotein-cholesterol (LDL-C) by −17.37 mg/dL (95% CI: −23.60 to −11.13; P < 0.001), but did not change triglycerides (TG) (WMD: −6.53 mg/dL, 95% CI: −16.03 to 2.97; P = 0.178) and high-density lipoprotein-cholesterol (HDL-C) (WMD: −0.62 mg/dL, 95% CI: −1.68 to 0.44, P = 0.252).ConclusionsGuar gum supplementation significantly reduced serum LDL-C and TC levels in patients with cardiometabolic problems, but had neutral effects on TG and HDL-C levels.     

Doppler parameters of ophthalmic artery in women with preeclampsia: A meta-analysis

Preeclampsia is a progressive and severe cardiovascular disorder in pregnant women. To determine the potential significance of ophthalmic Doppler parameters in preeclamptic women and to provide evidence-based hints for clinical practice and scientific investigation. We searched PubMed, Embase, Web of Science, and the Cochrane Library till July 31, 2022. Pooled standardized mean difference (SMD) with 95% confidence intervals (CIs) were calculated using the random effects model. Heterogeneity across included studies was evaluated utilizing the Q test and I² statistic. We identified 8 observational studies that met the inclusion criteria. The pooled SMD for peak systolic velocities (PSV) was .12 (95% CI: −.82, 1.06, p = .8071; I² = 94%, p < .0001). The overall SMD for time-averaged mean peak velocities (MV) was 1.79 (95% CI: .87, 2.71, p = .0001; I² = 60%, p = .1152). Regarding the pulsatility index (PI), the pooled SMD was −2.05 (95% CI: −3.12, −.98, p = .0002; I² = 92%, p < .0001). Overall SMD for end-diastolic velocities (EDV) was 1.11 (95% CI: .23, 1.98, p = .0136; I² = 92%, p < .0001). The pooled SMDs for resistance index (RI) and peak ratio (PR) was −.18 (95% CI: −1.90, 1.53, p = .8333; I² = 96%, p < .0001) and 1.46 (95% CI: −1.30, 4.22, p = .2994; I² = 99%, p < .0001), respectively. Publication bias was not identified. MV, PI, and EDV showed significant differences between patients with preeclampsia and non-hypertensive pregnant participants. Studies on the predictive performance of ophthalmic artery Doppler parameters are warranted.     

Effect of coconut oil on cardio-metabolic risk: A systematic review and meta-analysis of interventional studies

Background and aimsHigh total cholesterol (TC) and low density lipoprotein cholesterol (LDL-C) could be major risk factors for cardiovascular disease burden among high risk populations especially in South Asians. This systematic review and meta-analysis aimed to quantify the effects of coconut oil compared with other oils and fats on cardio-metabolic parameters.MethodsPubMed, Scopus and Web of Science were systematically searched. The main outcomes included are lipid and glycemic parameters. Subgroup analyses were performed to evaluate individual comparisons of vegetable oils and animal fat with coconut oil. Data were pooled using random-effects meta-analysis.ResultsCoconut oil consumption significantly increased TC by 15.42 mg/dL (95% CI, 8.96–21.88, p < 0.001), LDL-C by 10.14 mg/dL (95% CI, 4.44–15.84, p < 0.001) and high density lipoprorein cholesterol (HDL-C) by 2.61 mg/dL (95% CI, 0.95–4.26, p = 0.002), and significantly decreased glycosylated hemoglobin (HbA1c) by 0.39 mg/dL (95% CI, −0.50 to −0.27, p < 0.001) but, it had no effects on triglycerides (TG), (4.25 mg/dL; 95% CI, −0.49-8.99, p = 0.08) when compared with the control group. Sub-group analysis demonstrated that coconut oil significantly increased TC and LDL-C over corn, palm, soybean and safflower oils and not over olive oil. Compared with butter, coconut oil showed a better pattern in cardio-metabolic markers by significantly increasing HDL-C (4.38 mg/dL, 95% CI, 0.40 to 8.36, p = 0.03) and decreasing LDL-C (−14.90 mg/dL, 95% CI, −23.02 to-6.77, p < 0.001).ConclusionsOur results suggest that coconut oil consumption results in significantly higher TC, LDL-C and HDL-C than other oils. Consumption of coconut oil can be one of the risk factors for CVDs in South Asians.     

Cholesterol-lowering effects of rosuvastatin compared with atorvastatin in patients with type 2 diabetes -- CORALL study

OBJECTIVES: To compare the efficacy of the newest cholesterol-lowering drug, rosuvastatin (RSV) with atorvastatin (ATV) in subjects with type 2 diabetes. DESIGN: A 24-week, open-label, randomized, parallel-group, phase IIIb, multicentre study. SETTING: Diabetes outpatient clinics of 26 hospitals in The Netherlands. SUBJECTS: A total of 263 patients with type 2 diabetes treated with oral agents or insulin, age (mean +/- SD) 60 +/- 10 years, body mass index (BMI) 31.4 +/- 6.1 kg m(-2), 46% males. INTERVENTION: After a 6-week dietary lead-in period, patients were randomized to RSV (n = 131) or ATV (n = 132) treatment in a dose escalation scheme (RSV: 10, 20 and 40 mg or ATV: 20, 40 and 80 mg for 6 weeks each sequentially). MAIN OUTCOME MEASURES: Primary outcome was the change in apolipoprotein B (apoB) and apoB/apolipoprotein A1 (apoA1) ratio, which has been suggested a better predictor for cardiovascular events than total (TC) or low-density lipoprotein cholesterol (LDL-C). Secondary outcomes were the changes in other lipid parameters. RESULTS: Baseline LDL-C in the RSV and ATV groups was 4.23 +/- 0.98 mmol L(-1) and 4.43 +/-0.99 mmol L(-1), whilst apoB/apoA1 was 0.86 +/-0.22 and 0.92 +/- 0.35, respectively. A greater reduction in apoB/apoA1 was seen with RSV (-34.9%, -39.2% and -40.5%) than with ATV (-32.4%, -34.7% and -35.8%, P < 0.05 at weeks 12 and 18). Significantly greater reductions in LDL-C were also seen with RSV (-45.9%, -50.6% and -53.6%) than with ATV (-41.3%, -45.6% and -47.8%, all P < 0.05). The American Diabetes Association (ADA) LDL-C goal of < 2.6 mmol L(-1) was reached by 82%, 84% and 92% of patients with RSV and 74%, 79% and 81% with ATV. Triglyceride reductions ranged from 16 to 24% and were not different between treatments. Both treatments were well-tolerated: nine patients in the RSV and 11 in the ATV group withdrew from treatment because of adverse events after randomization. CONCLUSION: In subjects with type 2 diabetes, greater improvements of apoB/apoA1 and across the lipid profile were observed with RSV compared with ATV.     

Impact of measurable residual disease on outcomes of unrelated donor haematopoietic cell transplantation with post-transplant cyclophosphamide in AML in first complete remission

Pre-transplant measurable residual disease (MRD) predicts relapse and outcome of allogeneic haematopoietic cell transplantation (allo-HCT). The impact of MRD on the outcomes of post-transplant cyclophosphamide (PTCy)-based allo-HCT from a matched unrelated donor (UD) is unknown. This study assessed the impact of MRD in acute myeloid leukaemia (AML) in the first complete remission (CR1). A total of 272 patients (MRD negative [MRD−], n = 165; MRD positive [MRD+], n = 107) with a median follow-up of 19 (range: 16–24) months were studied. The incidence of grades II–IV and grades III–IV acute GVHD at day 180 was 25.2% and 25% (p = 0.99), and 10.6% and 6.8% (p = 0.29), respectively, and 2-year chronic GVHD was 35% and 30.4% (p = 0.96) in MRD+ and MRD− cohorts, respectively. In multivariate analysis, MRD+ status was associated with a higher incidence of relapse (RI) (hazard ratio [HR] = 2.56, 95% CI: 1.39–4.72), lower leukaemia-free survival (LFS) (HR = 2.04, 95% CI: 1.23–3.39), overall survival (OS) (HR = 1.83, 95% CI: 1.04–3.25) and GVHD-free, relapse-free survival (GRFS) (HR = 1.69, 95% CI: 1.10–2.58). MRD status did not have a significant impact on non-relapse mortality (NRM), or acute or chronic GVHD risk. Among patients with AML undergoing UD allo-HCT with PTCy, pre-transplant MRD+ status predicted a higher relapse rate, lower LFS, OS and GRFS.     

Mediterranean dietary pattern,inflammation and endothelial function: A systematic review and meta-analysis of intervention trials

BackgroundHigh adherence to a Mediterranean diet (MD) is associated with reduced all-cause and cardiovascular mortality risk. To our knowledge, there is no systematic review and meta-analysis of randomized controlled trials that has compared the effects of an MD on outcomes of endothelial function and inflammation.Methods and resultsLiterature search was performed using the electronic databases MEDLINE, EMBASE, and the Cochrane Trial Register. Inclusion criteria were: randomized controlled trials, 19 + years of age, and minimum intervention period of 12 weeks. Study specific weighted mean differences (WMD) were pooled using a random effect model. Seventeen trials including 2300 subjects met the objectives. MD regimens resulted in a significantly more pronounced increase in flow mediated dilatation [WMD: 1.86%, 95% CI 0.23 to 3.48, p = 0.02; I² = 43%], and adiponectin [WMD: 1.69 μg/ml, 95% CI 0.27 to 3.11, p = 0.02; I² = 78%], while high-sensitive C reactive protein [WMD: −0.98 mg/l, 95% CI −1.48 to −0.49, p < 0.0001; I² = 91%], interleukin-6 [WMD: −0.42 pg/ml, 95% CI −0.73 to −0.11, p = 0.008; I² = 81%], and intracellular adhesion molecule-1 [WMD: −23.73 ng/ml, 95% CI −41.24 to −6.22 p = 0.008; I² = 34%] turned out to be significantly more decreased.ConclusionThe results of the present meta-analysis provide evidence that an MD decreases inflammation and improves endothelial function.     

Combined use of amlodipine and folic acid are significantly more efficacious than amlodipine alone in lowering plasma homocysteine and blood pressure among hypertensive patients with hyperhomocysteinemia and intolerance to ACEI: A multicenter,randomized, double-blind,parallel-controlled clinical trial

Hyperhomocysteinemia with hypertension can synergistically increase the risk of stroke. The China stroke primary prevention trial showed that combining 0.8 mg folic acid (FA) with angiotensin-converting enzyme inhibitor (ACEI) can effectively lower plasma total homocysteine (tHcy) and blood pressure (BP); and reduce first stroke risk by additional 21% compared to ACEI alone. However, intolerance to ACEI is common in Asians and amlodipine can be alternative. This is a multicenter, randomized, double-blind, parallel-controlled clinical trial (RCT) which evaluated whether amlodipine combined with FA is more efficacious than amlodipine alone in lowering tHcy and BP among Chinese hypertensive with hyperhomocysteinemia and intolerance to ACEI. 351 Eligible patients were randomly assigned by 1:1:1 ratio to receive amlodipine-FA tablet daily (amlodipine 5 mg/FA 0.4 mg, A group); amlodipine 5 mg/FA 0.8 mg tablet daily (B group); amlodipine 5 mg daily (C group, control group). Follow-up was conducted at 2, 4, 6, and 8 weeks. The primary outcome was efficacy of lowering both tHcy and BP at the end of 8-week treatment. Compared with C group, A group had a significantly higher rate of lowering both tHcy and BP (23.3% vs. 6.0%; Odds Ratio [OR], 8.68; 95% CI, 3.04-24.78, P < .001); B group also had a higher rate of lowering both tHcy and BP (20.3% vs. 6.0%; OR: 5.90; 95% CI, 2.11-16.47, P < .001). This RCT showed amlodipine combined with FA compared with amlodipine alone, each had significantly higher efficacy of lowering both tHcy and BP. No difference was found in BP-lowering and occurrence of adverse events between the three groups.     

Clinical- and cost-effectiveness of LDL particle-guided statin therapy: A simulation study

We used the Archimedes Model, a mathematical simulation model (Model) to estimate the clinical- and cost-effectiveness of using LDL particle concentration (LDL-P) as an adjunct or alternative to LDL cholesterol (LDL-C) to guide statin therapy. LDL-P by NMR has been shown to be a better measure of cardiovascular disease (CVD) risk than LDL-C, and may therefore be a better gauge of the need for and response to statin treatment. Using the Model, we conducted a virtual clinical trial comparing the use of LDL-C alone, LDL-P alone, and LDL-C and LDL-P together to guide treatment in the general adult population, and in high-risk, dyslipidemic subpopulations. In the general population, the 5-year major adverse cardiovascular event (MACE) relative risk reduction (RRR) of LDL-P alone compared to the control arm (LDL-C alone) was 5.0% (95% CI, 4.7–5.3; p < .0001); using both LDL-C and LDL-P (dual markers) led to 3.0% RRR compared to the control arm (95% CI, 2.8–3.3; p < .0001). For individuals with diabetes, the RRR was 7.3% (95% CI, 6.4–8.2; p < .0001) for LDL-P alone and 6.9% for dual markers (95% CI, 6.1–7.8; both, p < .0001).     

Efficacy and safety of PCSK9 inhibitors in patients with diabetes: A systematic review and meta-analysis

AimsIndividuals with diabetes have increased cardiovascular risk. Although PCSK9 inhibitors bring about a wide reduction in lipids, there is uncertainty about the effects for diabetic patients. We conducted a systematic review and meta-analysis to assess the efficacy and safety of PCSK9 inhibitors for diabetes.Data synthesisWe performed a meta-analysis comparing treatment with PCSK9 inhibitors versus controls up to July 2022. Primary efficacy endpoints were percentage changes in lipid profile parameters. We used random effects meta-analyses to combine data. Subgroups of diabetic patients (by diabetes type, baseline LDL-C, baseline HbA1c and follow-up time) were also compared. We included 12 RCTs comprising 14,702 patients. Mean reductions in LDL-C were 48.20% (95% CI: 35.23%, 61.17%) in patients with diabetes. Reductions observed with PCSK9 inhibitors were 45.23% (95% CI: 39.43%, 51.02%) for non-HDL-cholesterol, 30.39% (95% CI: 24.61%, 36.17%) for total cholesterol, 11.96% (95% CI: 6.73%, 17.19%) for triglycerides, 27.87% (95% CI: 22.500%, 33.17%) for lipoprotein(a), 42.43% (95% CI: 36.81%, 48.06%) for apolipoprotein B; increases in HDL-C of 5.97% (95% CI: 4.59%, 7.35%) were also observed. There was no significant difference in fasting plasma glucose (FPG) (WMD: 2.02 mg/mL; 95% CI: −1.83, 5.87) and HbA1c (WMD: 1.82%; 95% CI: −0.63, 4.27). Use of a PCSK9 inhibitor was not associated with increased risk of treatment-emergent adverse event (TEAE) (p = 0.542), serious adverse event (SAE) (p = 0.529) and discontinuations due to AEs (p = 0.897).ConclusionsPCSK9 inhibitor therapy should be considered for all diabetic individuals at high risk of atherosclerotic cardiovascular disease.Registration code in prosperoCRD42022339785.     

Tirzepatide 10 and 15 mg compared with semaglutide 2.4 mg for the treatment of obesity: An indirect treatment comparison

Aim

To compare the efficacy of tirzepatide 10 and 15 mg with semaglutide 2.4 mg using an indirect treatment comparison.

Materials and Methods

Using SURMOUNT-1 and STEP 1 trial data, mean percentage change in body weight from baseline and odds ratio (OR) of achieving 5% or greater weight loss were compared between tirzepatide 10 and 15 mg at week 72 and semaglutide 2.4 mg at week 68 using matching-adjusted indirect comparison of the efficacy estimand. Sensitivity analyses were completed using different methods, including the Bucher method, also using different estimands and/or time points.

Results

Greater reductions in percentage change in body weight were observed with tirzepatide 10 and 15 mg versus semaglutide 2.4 mg (tirzepatide 10 mg mean difference: −4.67% [95% CI −5.91%, −3.43%]; tirzepatide 15 mg mean difference: −5.92% [95% CI −7.16%, −4.68%]; both P < .001). Similarly, more participants achieved 5% or greater weight loss with tirzepatide 10 mg (OR 2.61 [95% CI 1.48, 4.57]; P < .001) and 15 mg (OR 2.75 [95% CI 1.57, 4.81]; P < .001) compared with semaglutide 2.4 mg. All sensitivity analyses were consistent, except for an OR of achieving 5% or greater weight loss with tirzepatide 10 mg using the Bucher method to analyse the treatment regimen estimand (P = .074).

Conclusions

Currently there are no direct comparisons of tirzepatide and semaglutide for weight management. Using the matching-adjusted indirect treatment comparison method to compare the efficacy of tirzepatide and semaglutide for chronic weight management, this analysis showed greater weight loss with tirzepatide 10 and 15 mg versus semaglutide 2.4 mg.     

Long-term outcomes of patients with conjunctival extranodal marginal zone lymphoma

Comprehensive information on clinical features and long-term outcomes of primary conjunctival extranodal marginal zone lymphoma (PCEMZL) is scarce. We present a large single-institution retrospective study of 72 patients. The median age was 64 years, and 63.9% were female. Stage I was present in 87.5%. Radiation therapy (RT) alone was the most common treatment (70.8%). Complete response (CR) was 87.5%, and 100% in RT-treated patients. With a median follow-up of 6.7 years, relapse/progression and death occurred in 19.4% each, with one relapse within the RT field. The 10-year progression-free survival (PFS) and overall survival (OS) were 68.4% (95% CI 52.8%–79.8%) and 89.4% (95% CI 77.4%–95.2%), respectively. The 10-year rate for time to progression from diagnosis was 22.5% (95% CI 11.6%–35.7%). The 10-year PFS and OS of MALT-IPI 0 versus 1–2 were 83.3% versus 51.3%, (p = .022) and 97.6% versus 76.6%, (p = .0052), respectively. The following characteristics were associated with shorter survival: age > 60 years (PFS: HR = 2.93, 95% CI 1.08–7.95; p = .035, OS: HR = 9.07, 95% CI 1.17–70.26; p = .035) and MALT-IPI 1–2 (PFS: HR = 2.67, 95% CI 1.12–6.31; p = .027, OS: HR = 6.64, 95% CI 1.45–30.37; p = .015). CR following frontline therapy was associated with longer PFS (HR = 0.13, 95% CI 0.04–0.45; p = .001), but not OS. Using the Fine and Gray regression model with death without relapse/progression as a competing risk, RT and CR after frontline therapy were associated with lower risk of relapse (SHR = 0.34, 95% CI 0.12–0.96 p = .041 and SHR = 0.11, 95% CI 0.03–0.36; p < .001, respectively). Patients with PCEMZL treated with frontline RT exhibit excellent long-term survival, and the MALT-IPI score appropriately identifies patients at risk for treatment failure.     

Progression patterns and therapeutic sequencing following immune checkpoint inhibition for hepatocellular carcinoma: An international observational study

Background and Aims

Different approaches are available after the progression of disease (PD) to immune checkpoint inhibitors (ICIs) for hepatocellular carcinoma (HCC), including the continuation of ICI, treatment switching to tyrosine kinase inhibitors (TKIs) and cessation of anticancer therapy. We sought to characterise the relationship between radiological patterns of progression and survival post-ICI, also appraising treatment strategies.

Methods

We screened 604 HCC patients treated with ICIs, including only those who experienced PD by data cut-off. We evaluated post-progression survival (PPS) according to the treatment strategy at PD and verified its relationship with radiological patterns of progression: intrahepatic growth (IHG), new intrahepatic lesion (NIH), extrahepatic growth (EHG), new extrahepatic lesion (NEH) and new vascular invasion (nVI).

Results

Of 604 patients, 364 (60.3%) experienced PD during observation. Median PPS was 5.3 months (95% CI: 4.4–6.9; 271 events). At the data cut-off, 165 patients (45%) received no post-progression anticancer therapy; 64 patients (17.6%) continued ICI beyond PD. IHG (HR 1.64 [95% CI: 1.21–2.22]; p = .0013) and nVI (HR 2.15 [95% CI: 1.38–3.35]; p = .0007) were associated with shorter PPS. Multivariate models adjusted for progression patterns, treatment line and albumin-bilirubin grade and Eastern Cooperative Oncology Group performance status at PD confirmed receipt of ICI beyond PD with (HR 0.17, 95% CI: 0.09–0.32; p < .0001) or without subsequent TKI (HR 0.39, 95% CI: 0.26–0.58; p < .0001) as predictors of prolonged PPS versus no anticancer therapy.

Conclusions

ICI-TKI sequencing is a consolidated option in advanced HCC. nVI and IHG predict a poorer prognosis. Despite lack of recommendation, the continuation of ICI beyond progression in HCC is adopted clinically: future efforts should appraise which patients benefit from this approach.     

Effects of zinc supplementation on lipid profile in patients with type 2 diabetes mellitus: A systematic review and meta-analysis of randomized controlled trials

Background and aimFindings on the effects of zinc supplementation on the lipid profile in patients with type 2 diabetes mellitus (T2DM) are conflicting. The current comprehensive systematic review and meta-analysis aimed to summarize available evidence in this regard.Methods and resultsAfter a systematic search in the online databases, we included the randomized controlled trials (RCTs) investigating the effect of zinc supplementation on lipid profile [total cholesterol (TC), low-density lipoprotein cholesterol (LDL-C), high-density lipoprotein cholesterol (HDL-C), and triglyceride (TG)] in patients with T2DM. Altogether, 9 studies with a total sample size of 424 patients with T2DM were included in the analysis. Combining 9 effect sizes from 9 RCTs, we found a significant lowering effect of zinc supplementation on serum levels of TG (weighted mean difference (WMD): −17.08, 95% CI: −30.59, −3.58 mg/dL, P = 0.01) and TC (WMD: −26.16, 95% CI: −49.69, −2.62 mg/dL, P = 0.02). Although the overall effect of zinc supplementation on LDL-C levels was not significant, a beneficial effect was seen in studies that administered <100 mg/d zinc. Based on the non-linear dose–response analysis, a greater reduction in serum levels of TC and LDL-C following zinc supplementation was seen at <12 weeks’ duration of intervention. Unlike the overall effect size, we found a significant increasing effect of zinc supplementation on serum HDL-C concentrations in most subgroups of RCTs according to the subgroup analyses.ConclusionWe found that zinc supplementation may beneficially influence lipid profile in patients with T2DM.     

Efficacy of ezetimibe/simvastatin 10/20 and 10/40 mg compared with atorvastatin 20 mg in patients with type 2 diabetes mellitus

AIM: This randomized, double-blind study evaluated the efficacy of switching from atorvastatin (ATV) 10 mg to ezetimibe/simvastatin (EZE/SIMVA) 10/20 mg, EZE/SIMVA 10/40 mg or doubling the dose of ATV from 10 to 20 mg in patients with type 2 diabetes (T2D). METHODS: Eligible patients had haemoglobin A(1C)< or =10%, were aged > or =18 years and were on ATV 10 mg for > or =6 weeks before study entry. After a 4-week open-label ATV 10 mg run-in, patients were randomized to EZE/SIMVA 10/20 mg (n = 220), EZE/SIMVA 10/40 mg (n = 222) or ATV 20 g (n = 219) daily for 6 weeks. RESULTS: Greater (p < or = 0.001) reductions in low-density lipoprotein cholesterol (LDL-C) (the primary end-point) were achieved by switching to EZE/SIMVA 10/20 mg (26.2%) or 10/40 mg (30.1%) than by doubling the dose of ATV to 20 mg (8.5%). EZE/SIMVA 10/20 mg and 10/40 mg produced greater (p < or = 0.001) reductions in total cholesterol, non-high-density lipoprotein cholesterol (HDL-C) and apolipoprotein B relative to ATV 20 mg. A reduction (p < or = 0.050) in C-reactive protein was observed with EZE/SIMVA 10/40 mg vs. ATV 20 mg. Similar reductions in triglycerides were observed across the three groups, and none of the treatments produced a significant change in HDL-C. A greater (p < or = 0.001) proportion of patients achieved LDL-C <2.5 mmol/l with EZE/SIMVA 10/20 mg (90.5%) and 10/40 mg (87.0%) than with ATV 20 mg (70.4%). Both EZE/SIMVA doses were generally well tolerated, with an overall safety profile similar to ATV 20 mg. CONCLUSIONS: EZE/SIMVA 10/20 and 10/40 mg provided greater lipid-altering efficacy than doubling the dose of ATV from 10 to 20 mg and were well tolerated in patients with T2D.     

COVID-19 is associated with increased care needs and a decreased likelihood of returning home following a hip fracture: The IMPACT frailty study

Purpose

The primary aim was to evaluate the impact of COVID-19 on frailty in patients surviving a hip fracture. Secondary aims were to assess impact of COVID-19 on (i) length of stay (LoS) and post-discharge care needs, (ii) readmissions, and (iii) likelihood of returning to own home.

Methods

This propensity score-matched case-control study was conducted in a single centre between 01/03/20–30/11/21. A ‘COVID-positive’ group of 68 patients was matched to 141 ‘COVID-negative’ patients. ‘Index’ and ‘current’ Clinical Frailty Scale (CFS) scores were assigned for frailty at admission and at follow-up. Data were extracted from validated records and included: demographics, injury factors, COVID-19 status, delirium status, discharge destination, and readmissions. For subgroup analysis controlling for vaccination availability, the periods 1 March 2020–30 November 2020 and 1 February 2021–30 November 2021 were considered pre-/post-vaccine periods.

Results

Median age was 83.0 years, 155/209 (74.2%) were female and median follow-up was 479 days (interquartile range [IQR] 311). There was an equivalent median increase in CFS in both groups (+1.00 [IQR 1.00–2.00, p = 0.472]). However, adjusted analysis demonstrated COVID-19 was independently associated with a greater magnitude change (Beta coefficient [β] 0.27, 95% confidence interval [95% CI] 0.00–0.54, p = 0.05). COVID-19 in the post-vaccine availability period was associated with a smaller increase versus pre-vaccine (β −0.64, 95% CI −1.20 to −0.09, p = 0.023). COVID-19 was independently associated with increased acute LoS (β 4.40, 95% CI 0.22–8.58, p = 0.039), total LoS (β 32.87, 95% CI 21.42–44.33, p < 0.001), readmissions (β 0.71, 95% CI 0.04–1.38, p = 0.039), and a four-fold increased likelihood of pre-fracture home-dwelling patients failing to return home (odds ratio 4.52, 95% CI 2.08–10.34, p < 0.001).

Conclusions

Hip fracture patients that survived a COVID-19 infection had increased frailty, longer LoS, more readmissions, and higher care needs. The health and social care burden is likely to be higher than prior to the COVID-19 pandemic. These findings should inform prognostication, discharge-planning, and service design to meet the needs of these patients.