Efficacy and Safety of Oral PCSK9 Inhibitors in Adults With Hypercholesterolemia: A Systematic Review and Meta-Analysis of Randomized Controlled Trials.

Introduction: Despite advances with injectable PCSK9 inhibitors, many patients with hypercholesterolemia remain unable to achieve LDL-C goals due to barriers such as cost, access, and adherence. Oral PCSK9 inhibitors represent a promising alternative, but their lipid-lowering efficacy and safety profile have not been systematically evaluated. Methods: We searched PubMed, Embase, and ClinicalTrials.gov through April 2025 and identified four randomized trials of oral PCSK9 inhibitors in hypercholesterolemia, including one Phase 1 and three Phase 2 trials (1,114 participants). The primary outcome was the percent change in LDL-C compared to placebo. Secondary outcomes included changes in lipoprotein(a), apolipoprotein B, total cholesterol, triglycerides, and adverse events. Results were pooled using a random effects model with mean differences and 95% confidence intervals. Results: Oral PCSK9 inhibitors significantly reduced LDL-C compared to placebo (MD –47.09%; 95% CI, –53.22% to –40.96%; p < 0.001). MK-0616 achieved the greatest LDL-C reduction (–53.69%; 95% CI, –61.05% to –46.34%), followed by NNC0385-0434 (–46.23%; 95% CI, –63.15% to –29.31%) and AZD0780 (–38.18%; 95% CI, –45.06% to –31.29%). Lipoprotein(a) (–19.87%; 95% CI, –25.59% to –14.14%; p < 0.001), apolipoprotein B (–37.70%; 95% CI, –43.69% to –31.71%; p < 0.001), and total cholesterol (–24.29%; 95% CI, –27.88% to –20.70%; p < 0.001) were also significantly reduced. Triglyceride reduction was not significant (–3.58%; 95% CI, –7.63% to 0.47%; p = 0.08). Adverse events were similar between groups (RR 1.06; 95% CI, 0.95–1.17; p = 0.32). Conclusions: Oral PCSK9 inhibitors significantly reduced LDL-C, lipoprotein(a), apolipoprotein B, and total cholesterol compared to placebo, with no significant reduction in triglycerides. Among the agents studied, MK-0616 demonstrated the greatest overall LDL-C lowering effect.

To assess the efficacy and safety of Proprotein Convertase Subtilisin/Kexin Type 9 (PCSK9) inhibitors in reducing major adverse cardiovascular events (MACE) in statin-intolerant patients, focusing on low-density lipoprotein cholesterol (LDL-C) reduction and cardiovascular outcomes. A systematic review and meta-analysis were conducted according to the PRISMA guidelines. Randomised control trails (RCTs) and observational studies from PubMed, Cochrane Library, and Web of Science databases were included. Independent reviewers extracted the data, and the analyses were performed using fixed- and random-effects models. Heterogeneity was evaluated using the I2 statistic and publication bias was assessed using Egger's test. Fifteen studies involving 69-18924 participants were included. PCSK9 inhibitors reduced LDL-C levels by 50-70% and lowered the risk of MACE by 12% (OR 0.88). Minimal heterogeneity (I2=0%) indicated consistency across studies. Subgroup analysis showed greater efficacy in high-risk populations (e.g., acute coronary syndrome and familial hypercholesterolemia). Adverse events were mild, with minimal muscle-related side effects. PCSK9 inhibitors are effective and safe alternatives for LDL-C reduction and cardiovascular risk mitigation in patients with statin intolerance. Their efficacy, favorable safety profile, and consistency across studies highlight their potential for managing dyslipidemia, particularly in high-risk groups. Further research on long-term outcomes is required.

The aim of this meta-analysis was to compare the efficacy of PCSK9 and ANGPTL3 inhibitors in patients with homozygous familial hypercholesterolemia (HoFH). We systematically searched selected electronic databases until 30 November 2024. Main end point was the effect of lipid lowering therapy on lipid profile: total cholesterol (TC), triglycerides (TG), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C) and lipoproteins levels. The secondary end point was adverse clinical effects. A total of 12 trials involving 392 patients with HoFH, were finally included in the meta-analysis. At a median follow-up of 12 months, ANGPTL3 inhibitors achieved greater reductions in TC (- 49.9% versus - 21.2%;p for subgroup < 0.001), LDL-C (- 50.77% versus - 17.88%;p for subgroup < 0.001) and TG (- 48.9% versus - 8.2%;p for subgroup < 0.001) compared with PCSK9 inhibitors, but had a smaller impact on HDL-C (- 28.9% versus + 5.2%;pfor subgroup = 0.001). Apolipoprotein B decreased more with ANGPTL3i (- 26.9% versus - 13.2%;pfor subgroup < 0.001), while lipoprotein(a) reductions were similar between groups, and apolipoprotein A remained unaffected with PCSK9i but slightly decreased with ANGPTL3i. In meta-regression, ANGPTL3i produced a greater LDL-C reduction in the negative LDLreceptor (LDLR)genotype (- 34.5%;p = 0.04) and showed a trend toward significance in the defective genotype (- 23.1%;p = 0.07), with no significant difference in the heterozygous type. The rates of adverse events and discontinuations were not significantly different between the groups. PCSK9 inhibitors have lower efficacy in reducing lipid levels in HoFH compared with ANGPTL3 inhibitors, with the greatest difference seen in patients with the negative LDLR genotype. Further studies are needed to clarify efficacy across LDLR functional variants.

The aim of this study is to compare the efficacy and safety of combination containing Atorvastatin plus Fenofibrate (ATO+FENO) and to determine whether combination of Fenofibrate had clinically significant benefit over Atorvastatin alone (ATO) in patients with Hyperlipidemia. This is a single centric, open labelled, prospective study, involving 50 Hyperlipidemic patients of 18 years and older. Data of only Hyperlipidemic patients with Low Density Lipoprotein (LDL –C) ≥ 140 - 60 mg/dl, Total Cholesterol (TC): 200-240 mg/dl and Triglyceride (TG): ≥ 165- < 400 mg/dl and who were prescribed either Atorvastatin 10 mg and Atorvastatin plus Fenofibrate 160 mg were included in the study. Efficacy end points included the change in LDL-C, HDL-C, TC and TG at week 12 and the safety of the treatment was also evaluated based on adverse events. Total of 50 patients were enrolled in the study but 1 patient lost follow up in ATO Group and 2 patients in ATO + FENO Group. Therefore 24 patients in ATO and 23 patients in ATO + FENO group completed study. A statistically significant reduction in LDL-C, TG and TC was seen in both the groups (Atorvastatin 10 mg and Atorvastatin plus Fenofibrate 160 mg). Similarly a statistically significant increase in HDL-C levels was observed in both the groups. ATO + FENO treatment showed a statistically significant reduction in TG at week 12 as compared to ATO alone. Decrease in LDL-C, TC, and TG were 24.86%, 24.81%, and 30.13% respectively and increasing HDL-C 42.37% in ATO + FENO group while the reduction was 21.1%, 21.31%, and 22.84% respectively and increasing HDL-C 38.2% in ATO alone group. The most common adverse events were headache, myalgia and nausea. ATO + FENO treatment showed a greater reduction in lipid parameters as compared to ATO alone (percentage change). Both treatments were well tolerated with similar incidence of adverse events. Study demonstrated that combination treatment was more effective than Atorvastatin alone in reducing LDL-C, Total Cholesterol and Triglyceride. It was also better in increasing HDL-C as compared to Atorvastatin. Statin in combination of fenofibrate may have lesser adverse effects. Thus Combination therapy seems to be a better treatment in patients having Hyperlipidemia.

Background: Turmeric (Curcuma longa) and its main bioactive compound curcumin are widely promoted for cardiometabolic health, yet their efficacy on lipid parameters remains uncertain. Piperine, an alkaloid from black pepper, enhances curcumin bioavailability and may potentiate its effects. This systematic review and meta-analysis aimed to assess the impact of turmeric, alone or combined with piperine, on lipid profiles in adults with metabolic disorders. Methods: A systematic search was conducted (2010–2025) in PubMed, Scopus, and Cochrane CENTRAL. Randomized controlled trials (RCTs) evaluating turmeric supplementation (with or without piperine) on lipid outcomes were included. Methodological quality was assessed with Cochrane RoB 2; certainty of evidence was rated using GRADE. Meta-analyses were performed with random-effects models. The protocol followed PRISMA 2020 guidelines. Results: Ten records were identified; six full texts were assessed; three RCTs (n ≈ 250) were included in quantitative synthesis, and three additional RCTs narratively. Pooled analysis demonstrated significant reductions in triglycerides (WMD −25.5 mg/dL, 95% CI −32.5 to −18.4), total cholesterol (−14.1 mg/dL, 95% CI −22.9 to −5.3), and LDL-C (−17.0 mg/dL, 95% CI −25.2 to −8.8), with an increase in HDL-C (+5.7 mg/dL, 95% CI +2.0 to +9.4). Subgroup analysis suggested greater LDL-C reduction with turmeric+piperine (−29.6 mg/dL) compared to turmeric alone (−16.2 mg/dL). Certainty of evidence was moderate for TG, TC, LDL-C, and low for HDL-C. Conclusions: Turmeric supplementation, particularly when combined with piperine, improves lipid profiles in adults with metabolic disorders. These effects are clinically relevant and comparable to other nutraceuticals, although evidence remains limited by short trial duration and small sample sizes. Larger, long-term RCTs are warranted before turmeric can be recommended in evidence-based dyslipidemia guidelines.

BackgroundAlirocumab and evolocumab (PCSK9-Inhibitors), are new drugs incorporated into the therapeutic arsenal for the treatment of hypercholesterolaemia, having shown effectiveness and safety in the performed clinical trials.PurposeTo assess the effectiveness...

Low-density lipoprotein cholesterol (LDL-C) is a well-established risk factor for atherosclerotic cardiovascular disease. However, the optimal achieved LDL-C level with regard to efficacy and safety in the long term remains unknown. In FOURIER (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk), 27 564 patients with stable atherosclerotic cardiovascular disease were randomized to evolocumab versus placebo, with a median follow-up of 2.2 years. In the open-label extension (FOURIER-OLE), 6635 of these patients were transitioned to open-label evolocumab regardless of initial treatment allocation in the parent trial and were followed for an additional median of 5 years. In this prespecified analysis, we examined the relationship between achieved LDL-C levels (an average of the first 2 LDL-C levels measured) in FOURIER-OLE (available in 6559 patients) and the incidence of subsequent cardiovascular and safety outcomes. We also performed sensitivity analyses evaluating cardiovascular and safety outcomes in the entire FOURIER and FOURIER-OLE patient population. Multivariable modeling was used to adjust for baseline factors associated with achieved LDL-C levels. In FOURIER-OLE, 1604 (24%), 2627 (40%), 1031 (16%), 486 (7%), and 811 (12%) patients achieved LDL-C levels of <20, 20 to <40, 40 to <55, 55 to <70, and ≥70 mg/dL, respectively. There was a monotonic relationship between lower achieved LDL-C levels-down to very low levels <20 mg/dL-and a lower risk of the primary efficacy end point (composite of cardiovascular death, myocardial infarction, stroke, hospital admission for unstable angina or coronary revascularization) and the key secondary efficacy end point (composite of cardiovascular death, myocardial infarction, or stroke) that persisted after multivariable adjustment (adjusted Ptrend<0.0001 for each end points). No statistically significant associations existed in the primary analyses between lower achieved LDL-C levels and increased risk of the safety outcomes (serious adverse events, new or recurrent cancer, cataract-related adverse events, hemorrhagic stroke, new-onset diabetes, neurocognitive adverse events, muscle-related events, or noncardiovascular death). Similar findings were noted in the entire FOURIER and FOURIER-OLE cohort up to a maximum follow-up of 8.6 years. In patients with atherosclerotic cardiovascular disease, long-term achievement of lower LDL-C levels, down to <20 mg/dL (<0.5 mmol/L), was associated with a lower risk of cardiovascular outcomes with no significant safety concerns. URL: https://www. gov; Unique identifier: NCT01764633.

The efficacy and safety of Janus kinase inhibitors in adults with rheumatoid arthritis: a systematic review and cumulative meta-analysis.

The primary objective of this systematic review was to evaluate the therapeutic efficacy and safety profile of intralesional Ionic Contra-Viral Therapy (ICVT)-a combination of digoxin and furosemide-in the treatment of multiple cutaneous warts. This meta-analysis was conducted in accordance with PRISMA guidelines and was prospectively registered in PROSPERO (CRD42024544551). A comprehensive literature search was performed up to April 2024 across PubMed, MEDLINE, Scopus, Cochrane CENTRAL, ClinicalTrials.gov, and Google Scholar. Eligible studies included randomized controlled trials involving adults with ≥2 cutaneous warts treated with intralesional digoxin and furosemide, assessing outcomes, such as complete and partial clearance, wart size reduction, and adverse events. Exclusion criteria included case reports, reviews, and preclinical studies. Data extraction was performed independently by two reviewers, with discrepancies resolved through consensus. The Cochrane RoB 2 tool was used for risk of bias assessment. Meta-analyses were conducted using a random-effects model, and heterogeneity was evaluated using the I² statistic. The quality of evidence was graded using the GRADE framework. Seven randomized trials, including a total of 391 patients, were analyzed. The ICVT group demonstrated significantly higher complete wart clearance compared to placebo (56.8% vs. 2.8%; RR = 13.27, 95% CI = 2.93-60.17; p = 0.0018). Partial response was lower in the ICVT group (5.08% vs. 10%; RR = 0.66, 95% CI = 0.09-5.09; p = 0.69). Adverse events occurred more frequently in the ICVT group (85% vs. 58.8%; RR = 1.33, 95% CI = 0.47-3.79; p = 0.59; I² = 97%). Pain during injection was also more commonly reported in the ICVT group (96.6% vs. 63.3%; RR = 1.45, 95% CI = 0.29-7.22; p = 0.65; I² = 99%). The certainty of evidence was rated as very low for complete clearance, moderate for partial response, and low for adverse events and injection pain. Trial Sequential Analysis (TSA) indicated that the required information size was not met for any of the outcomes. While the results suggest that ICVT may be effective in achieving complete clearance of multiple cutaneous warts, the current evidence is limited by small sample sizes, methodological heterogeneity, and potential biases. The higher incidence of adverse events and injectionrelated pain raises safety concerns. The low to very low certainty of evidence, coupled with the TSA findings, underscores the need for more rigorous investigation. Variability in trial design, dosing protocols, and outcome reporting further limits the applicability of current findings. Intralesional ICVT shows promise as a therapeutic option for multiple cutaneous warts, particularly in achieving complete clearance. However, due to the limited certainty of available evidence and inconsistent safety data, further large-scale, high-quality randomized controlled trials are necessary to validate these findings and establish standardized treatment protocols.

Joint statement from the European Atherosclerosis Society and European Society of Vascular Medicine focuses on patients with peripheral arterial disease

GLP-1 Receptor Agonists and Cardiovascular Outcomes in Adults With Diabetes and Peripheral Artery Disease: An Updated Systematic Review and Meta-Analysis.

Objective: The primary objective of the analysis was to characterize the multivariate relationship between changes in LDL-C, HDL-C and triglycerides (TG) and risk for major coronary events after treatment with statins, fibrates or niacin. Methods: Randomized controlled trials that compared statin, fibrate or niacin treatment with placebo, usual care, or active control and that reported on major coronary events were identified by a literature search, prior meta-analyses and review articles. The dependency of the odds-ratio between active and control arm on the differences in on-treatment LDL-C, HDL-C and TG was determined using a meta-regression analysis. Differences in the risk reduction per unit change in lipid values between drug classes (fibrates, statins and niacin) and drugs within a class were evaluated. Differences in risk reduction per unit change in lipid values for certain patient groups such as diabetes, males, elderly, prior CHD were also evaluated. Results: A total of 70 trials were identified and included in the meta-analysis. The meta-analysis found a significant contribution of lowering TG on top of reducing LDL-C to the risk reduction for a major coronary event after treatment with statins, fibrates or niacin (p&lt;0.001). The risk reduction for major coronary events was estimated to be 18.5% [14.1 to 22.7%] for every 1 mmol/L (38.7 mg/dL) reduction in LDL-C and 27.5% [15.7 to 37.7%] for every 1 mmol/L (88.6 mg/dL) reduction in TG. The reduction in TG was found to explain most (84%) of the risk reduction for treatment with fibrates. For statins, the reduction in LDL-C was found to explain most (71%) of their benefit, but the reduction in TG was found to provide a statistically and clinically significant contribution to their overall risk reduction. The risk reduction per unit change in LDL-C and TG was not dependent on age, gender, diabetes and prior CHD and was not different between fibrates and statins. Conclusions: A significant additional risk reduction is expected by providing a reduction in TG on top of LDL-C changes. The independent effect of TG and LDL-C lowering supports the role for treatment combinations such as statins and fibrates that impact LDL-C and TG differentially.

Control of dyslipidemia in chronic kidney disease (CKD) is not always guaranteed with statins and/or ezetimibe. Proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) have opened up a new era in lipid control, but their effect on renal function and proteinuria in real life have not yet been evaluated. The aim of the present study was to analyze the evolution of renal function and proteinuria in a cohort of CKD patients treated with PCSK9i. This retrospective multicentric cohort study included CKD patients treated with PCSK9i. Baseline epidemiological data, comorbidities and laboratory findings (including estimated glomerular filtration rate [eGFR], proteinuria and lipid profile) were collected. The evolution of renal function, proteinuria and lipid profile was analyzed during the 1-year follow-up. The cohort included 76 patients (68% male, mean age 66 ± 10 years). The mean baseline creatinine was 1.55 ± 0.77 mg/dL, and the mean eGFR was 52 ± 22 mL/min/1.73 m2. Reductions in LDL-cholesterol, total cholesterol and triglycerides during the first month were 51 ± 25%, 32 ± 25% and 11 ± 40%, respectively, levels that remained stable throughout the first year (p < 0.001 for LDL-cholesterol and total cholesterol trends and p = 0.002 for triglyceride trend). During follow-up, proteinuria improved from 57 (9–481) to 30 (7–520) mg/g (p = 0.021). In addition, eGFR remained stable, and no adverse events were reported. In our cohort, dyslipidemia treatment with PCSK9i was associated with decreased proteinuria in CKD patients, an effect that might be due to reduced lipid nephrotoxicity. Clinical trials are needed to further investigate whether this impact on proteinuria can significantly slow CKD progression in the long term.

The efficacy and safety of sodium-glucose co-transporter-2 (SGLT-2) inhibitors in patients with advanced chronic kidney disease (CKD), defined as an estimated glomerular filtration rate (eGFR) <30 ml/min/1.73m2, has not been adequately studied. We conducted a systematic review and meta-analysis of phase 3 randomized controlled trials (RCTs) of SGLT-2 inhibitors in adults. We searched the MEDLINE and Embase databases from inception to April 2024. The primary outcomes were a composite kidney (worsening kidney function, kidney failure, kidney or cardiovascular death) and cardiovascular (cardiovascular death or hospitalization for heart failure) outcome. Secondary outcomes included other reported cardiovascular and kidney outcomes, eGFR slopes, mechanistic and safety outcomes. The relative risks (RR) were estimated using a random effects model. Interaction effects were estimated for treatment effect modification by baseline eGFR (<30 and ≥30 ml/min/1.73m2). A total of 10 RCTs were included (total of 4800 patients with eGFR <30 ml/min/1.73m2). Participants were randomized to receive either placebo or an SGLT-2 inhibitor. Use of SGLT-2 inhibitors was associated with a lower incidence of the primary composite kidney outcome in patients with eGFR <30 ml/min/1.73m2 [RR 0.79, 95% confidence interval (CI) 0.70-0.89] and ≥30 ml/min/1.73m2 (RR 0.71, 95% CI 0.64-0.79). The incidence of the primary cardiovascular outcome was numerically lower in the SGLT-2 inhibitor arm in patients with eGFR <30 ml/min/1.73m2 (RR 0.88, 95% CI 0.71-1.10). In patients with eGFR ≥30 ml/min/1.73m2, SGLT-2 inhibitor use was associated with a lower incidence of the composite cardiovascular outcome (RR 0.77, 95% CI 0.71-0.83). However, there was no interaction between advanced CKD status and the effect of SGLT-2 inhibitors on any of the primary or secondary outcomes. The incidence of adverse events was similar in both arms. SGLT-2 inhibitors retain their kidney and cardiovascular protective effect in patients with advanced CKD, with no added safety concerns.

A six-month, multicenter, open-label, noncomparative, prospective, observational study of the efficacy and tolerability of atorvastatin in the primary care setting(estudio del control de las hiperlipidemiasen atención primaria): the cheap study