Obicetrapib for dyslipidemia with or without cardiovascular risk: A GRADE-assessed meta-analysis of randomized trials with trial sequential evidence.

Background: Guideline-directed lipid-lowering still leaves up to one-third of high-risk patients above LDL-C targets, sustaining residual cardiovascular risk. Obicetrapib—an oral cholesteryl-ester transfer-protein inhibitor has produced promising results in LDL-C reductions in recent phase 2/3 trials. We aim to quantify the efficacy and safety of Obicetrapib versus placebo in statin-treated adults. Methods: We searched PubMed, Embase, Cochrane, Scopus, and Web of Science (inception to 15 May 2025) for randomised controlled trials (RCTs) that enrolled adults with dyslipidemia (with or without atherosclerotic cardiovascular disease risk (ASCVD) receiving statins and compared Obicetrapib (1, 2.5, 5, or 10 mg) against placebo. Dichotomous outcomes were pooled as risk ratios (RRs), and continuous outcomes as mean differences (MDs), each with 95 % confidence intervals (CIs). Results: A total of 3,386 patients were included across six RCTs. Obicetrapib, compared to placebo, was associated with a significantly greater reduction in LDL-C (MD: -27.29 mg/dL; 95% CI: -33.65 to -20.93; P < 0.0001) and a significantly greater increase in HDL-C (MD: 70.96 mg/dL; 95% CI: 64.71 to 77.20; P < 0.0001). Obicetrapib also significantly increased the likelihood of achieving LDL-C targets of <55 mg/dL (RR: 6.42; 95% CI: 5.15 to 8.01; P < 0.0001), <70 mg/dL (RR: 2.56; P < 0.0001), and <100 mg/dL (RR: 1.34; P < 0.0001). Additionally, apolipoprotein B levels were significantly reduced with Obicetrapib (MD: -14.34 mg/dL; 95% CI: -19.28 to -9.41; P < 0.0001). Additionally, there was no significant difference in total adverse events (AEs) (P= 0.4124), serious AEs (P= 0.3712), and AEs leading to discontinuation of medication (P=0.4035). Conclusion: Our analysis shows that Obicetrapib, a selective CETP inhibitor, significantly improves lipid profiles in statin-treated patients with dyslipidemia, with or without ASCVD. It led to marked reductions in LDL-C, non-HDL-C, and apoB, and substantial increases in HDL-C. These effects significantly increased the achievement of LDL-C targets. Obicetrapib’s safety profile was similar to that of the placebo. Further RCTs are needed to confirm these findings.

Background: Obicetrapib is a next-generation cholesteryl ester transfer protein (CETP) inhibitor. It has emerged as a promising agent for improving lipid parameters and potentially reducing risk of atherosclerotic cardiovascular disease (ASCVD). Methods: A systematic search of databases, including PubMed, Scopus, Embase, Web of Science, Clinical Trials, and Cochrane Library, was conducted to identify relevant randomized controlled trials (RCTs). Outcomes included the assessment of LDL-C reduction, changes in ApoB, non-HDL-C, HDL-C, triglycerides, Lp(a), MACE, as well as the safety and tolerability profile of Obicetrapib in patients with dyslipidemia or ASCVD. Standardized mean differences (SMD) with 95% confidence intervals (CI) were pooled using random-effects. Results: Seven RCTs encompassing 3483 patients were included. Obicetrapib significantly improved lipid parameters. It reduced LDL-C (MSD: –35.43; 95% CI: –40.14 to –30.17; I2 = 93.26%), non-HDL-C (MSD: –36.42; 95% CI: –42.77 to –30.07; I2 = 99.06%), ApoB (MSD: –23.38; 95% CI: –30.68 to –16.08; I2 = 88.56%), and Lp(a) (MSD: –23.95; 95% CI: –35.26 to –12.63; I2 = 77.14%). Obicetrapib also led to a reduction in TG levels (MSD: –0.12; 95% CI: –0.19 to –0.05; I2 = 0.00%). In contrast, favorable increases were observed in HDL-C (MSD: 77.35; 95% CI: 64.56 to 90.13; I2 = 95.82%) and ApoA1 (MSD: 63.93; 95% CI: 53.65 to 74.21; I2 = 81.89%). Despite high heterogeneity, these results support Obicetrapib’s effectiveness in improving atherogenic lipid markers. Obicetrapib demonstrated a safety profile comparable to placebo. The overall risk of any adverse event was slightly reduced in the Obicetrapib group compared to placebo, but the 95% CI included 1, (RR: 0.96; 95% CI: 0.76 to 1.21; I2 = 66.3%; p = 0.01). Specific adverse events such as diarrhea (OR: 1.56; 95% CI: 0.34 to 7.11; I2 = 5.16%; p = 0.57), headache (OR: 1.17; 95% CI: 0.74 to 1.84; I2 = 0.00%; p = 0.50), and back pain (RR: 0.36; 95% CI: 0.11 to 1.16; I2 = 18.3%; p = 0.26) were also not significantly different between groups. Overall, Obicetrapib appears well-tolerated without increased adverse events. Conclusion: Obicetrapib significantly improved lipid parameters, notably reducing LDL-C, non-HDL-C, ApoB, Lp(a), and triglycerides, while increasing HDL-C and ApoA1, with a favorable and comparable safety profile.

Targeting High-density Lipoproteins to Reduce Cardiovascular Risk: What Is the Evidence?

Non-steroidal anti-inflammatory drugs for acute gout.

Hypertension is a chronic condition associated with an increased risk of mortality and morbidity. Renin is the enzyme responsible for converting angiotensinogen to angiotensin I, which is then converted to angiotensin II. Renin inhibitors are a new class of drugs that decrease blood pressure (BP) by preventing the formation of both angiotensin I and angiotensin II. To quantify the dose-related BP lowering efficacy of renin inhibitors compared to placebo in the treatment of primary hypertension.To determine the change in BP variability, pulse pressure, and heart rate and to evaluate adverse events (mortality, non-fatal serious adverse events, total adverse events, withdrawal due to adverse effects and specific adverse events such as dry cough, diarrhoea and angioedema). The Cochrane Hypertension Information Specialist searched the following databases for randomized controlled trials (RCTs) up to February 2017: the Cochrane Hypertension Specialized Register, the Cochrane Central Register of Controlled Trials (CENTRAL) (2017, Issue 2), MEDLINE (from 1946), Embase (from 1974), the World Health Organization International Clinical Trials Registry Platform, and ClinicalTrials.gov. There was no restriction by language or publication status. We also searched the European Medicines Agency (EMA) for clinical study reports, the Novartis Clinical Study Results Database, bibliographic citations from retrieved references, and contacted authors of relevant papers regarding further published and unpublished work. We included randomized, double-blinded, placebo-controlled studies evaluating BP lowering efficacy of fixed-dose monotherapy with renin inhibitor compared with placebo for a minimum duration of three to 12 weeks in adult patients with primary hypertension. This systematic review is a comprehensive update which includes four additional studies and extensive detail from nine clinical study reports (CSRs) of previously included studies obtained from EMA. The remaining three CSRs are not available.Two review authors independently assessed study eligibility and extracted data. In all cases where there was a difference between the CSR and the published report, data from the CSR was used. Dichotomous outcomes were reported as risk ratio (RR) with 95% confidence intervals (CIs) and continuous outcomes as mean difference (MD) with 95% CIs. 12 studies (mean duration of eight weeks) in 7439 mostly Caucasian patients (mean age 54 years) with mild-to-moderate uncomplicated hypertension were eligible for inclusion in the review. Aliskiren was the only renin inhibitor evaluated. All included studies were assessed to have high likelihood of attrition, reporting and funding bias.Aliskiren has a dose-related systolic/diastolic blood pressure (SBP/DBP) lowering effect as compared with placebo MD with 95% CI: aliskiren 75 mg (MD -2.97, 95% CI -4.76 to -1.18)/(MD -2.05, 95% CI -3.13 to -0.96) mm Hg (moderate-quality evidence), aliskiren 150 mg (MD -5.95, 95% CI -6.85 to -5.06)/ (MD -3.16, 95% CI -3.74 to -2.58) mm Hg (moderate-quality evidence), aliskiren 300 mg (MD -7.88, 95% CI -8.94 to -6.82)/ (MD -4.49, 95% CI -5.17 to -3.82) mm Hg (moderate-quality evidence), aliskiren 600 mg (MD -11.35, 95% CI -14.43 to -8.27)/ (MD -5.86, 95% CI -7.73 to -3.99) mm Hg (low-quality evidence). There was a dose-dependent decrease in blood pressure for aliskiren 75 mg, 150 mg and 300 mg. The blood pressure lowering effect of aliskiren 600 mg was not different from 300 mg (MD -0.61, 95% CI -2.78 to 1.56)/(MD -0.68, 95% CI -2.03 to 0.67). Aliskiren had no effect on blood pressure variability. Due to very limited information available regarding change in heart rate and pulse pressure, it was not possible to meta-analyze these outcomes.Mortality and non-fatal serious adverse events were not increased. This review found that in studies of eight week duration aliskiren may not increase withdrawal due to adverse events (low-quality evidence). Diarrhoea was increased in a dose-dependent manner (RR 7.00, 95% CI 2.48 to 19.72) with aliskiren 600 mg (low-quality evidence). The most frequent adverse events reported were headache, nasopharyngitis, diarrhoea, dizziness and fatigue. Compared to placebo, aliskiren lowered BP and this effect is dose-dependent. This magnitude of BP lowering effect is similar to that for angiotensin-converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs). There is no difference in mortality, nonfatal serious adverse events or withdrawal due to adverse effects with short term aliskiren monotherapy. Diarrhoea was considerably increased with aliskiren 600 mg.

Editorial group: Cochrane Gut Group. Publication status and date: New search for studies and content updated (conclusions changed), published in Issue 7, 2023.

Background: Dyslipidemia is a major risk factor for Atherosclerotic Cardiovascular Disease (ASCVD). Statin is a crucial intervention to fix dyslipidemia and reduce the ASCVD risk. Still, there are several regimens to achieve blood lipid level targets, including increasing the statin dose or adding ezetimibe to the statin used. However, the best option between the two regimens is still a matter of debate. Research Question: We aim to evaluate the efficacy and safety of Ezetimibe plus any type of statin versus a double dose of the same statin in patients with ASCVD risk. Methods: A systematic review and meta-analysis based on randomized controlled trials (RCTs) obtained from PubMed, Embase Cochrane, Scopus, and WOS till December 2023. We used the random-effects model to report dichotomous outcomes using odds ratio (OR) and continuous outcomes using mean difference (MD), with a 95% confidence interval (CI). Results: Forty-seven studies with a total of 18592 patients were included. Ezetimibe plus statin was associated with a decrease in low-density lipoprotein (LDL) levels [MD: -13.69 with 95% CI (-15.64, -11.74), P <0.01], and more patients achieving their targeted LDL levels [OR: 2.89 with 95% CI (2.40, 3.47), P <0.01]. However, there was no significant difference between the two groups regarding any adverse events [OR: 0.98 with 95% CI (0.89, 1.08), P =0.62], and the composite endpoint of cardiovascular death, major coronary events, or nonfatal stroke [OR: 0.72 with 95% CI (0.39, 1.32), P = 0.29], although there was a trend towards better results for patients with the combination regimen. Conclusion: Ezetimibe plus statin combination led to more reduced LDL levels and more patients achieving their goal levels than double dose statin, without a significant difference in the rate of any adverse events occurrence. More RCTs are mandatory to assess the effect of both regimens on major clinical events such as stroke, coronary events, and death.

Cholesteryl ester transfer protein (CETP) deficiency and lipoprotein phenotypes with CETP inhibitors were compared. The effects on atherosclerotic cardiovascular disease (ASCVD) and the recently suggested retinal disease of age-related macular degeneration (ARMD) were summarized and discussed in relation to CETP deficiency and extremely increased high-density lipoprotein (HDL) cholesterol levels (＞100 mg/dL). In CETP truncated variants leading to reduced low-density lipoprotein cholesterol levels, ASCVD risk was decreased in heterozygotes. ASCVD prevalence did not increase in homozygotes with CETP deficiency. However, the association between ASCVD and ARMD risks in cases of very high HDL cholesterol level found in multifactorial hyperalphalipoproteinemia needs to be clarified on an etiological basis. The hurdles facing the development of CETP inhibitors are summarized, including a new result for obicetrapib.

Disclosure: A. Jaber: None. J. Zapen: None. Z. Al-Abed: None. J. Abu Zayed: None. H. Ayesh: None.Introduction: Cholesteryl ester transfer protein (CETP) inhibitors represent an innovative therapeutic approach to dyslipidemia management by modulating lipid profiles, including increasing HDL and reducing LDL cholesterol. Anacetrapib and Obicetrapib are the most promising agents within this class, showing potential for improving lipid parameters associated with cardiovascular risk. This network meta-analysis evaluates the comparative efficacy of these agents in reducing LDL cholesterol, increasing HDL cholesterol, lowering triglycerides, and reducing apolipoprotein B (ApoB). Methods: A systematic search was conducted using PubMed, Cochrane, Scopus, Web of Science, and ClinicalTrials.gov, yielding 22 eligible trials, of which 10 met inclusion criteria. Data were synthesized using a random-effects model to estimate mean differences (MD) with 95% confidence intervals (CI) across key lipid parameters. Results: Both Anacetrapib and Obicetrapib demonstrated significant LDL cholesterol reductions compared to placebo (Anacetrapib: MD -30.18 mg/dL, 95% CI [-39.28; -21.08], p < 0.0001; Obicetrapib: MD -32.40 mg/dL, 95% CI [-44.02; -20.78], p < 0.0001). HDL cholesterol increased markedly, with Obicetrapib showing superior efficacy (Obicetrapib: MD +156.77 mg/dL, 95% CI [117.41; 196.13]; Anacetrapib: MD +103.81 mg/dL, 95% CI [78.43; 129.19], p < 0.0001). Triglycerides were significantly reduced by Anacetrapib (MD -9.15 mg/dL, 95% CI [-14.37; -3.94], p < 0.001), though no substantial reduction was noted with Obicetrapib (MD -2.78 mg/dL, 95% CI [-12.04; 6.49], p = 0.56). Both agents significantly lowered ApoB, with comparable reductions (Anacetrapib: MD -20.83 mg/dL, 95% CI [-26.45; -15.21], p < 0.0001; Obicetrapib: MD -20.67 mg/dL, 95% CI [-27.43; -13.92], p < 0.0001). Conclusions: Anacetrapib and Obicetrapib significantly improve lipid profiles, with Obicetrapib excelling in HDL elevation and Anacetrapib demonstrating superior triglyceride reduction. Both agents are effective in reducing LDL and ApoB. These findings highlight their clinical potential in cardiovascular risk management and underscore the need for further evaluation in larger trials to confirm their safety and long-term efficacy.Presentation: Saturday, July 12, 2025

Non-steroidal anti-inflammatory drugs for acute gout.

ABSTRACTBackgroundHyperlipidemia, a key risk factor for cardiovascular disease, is characterized by elevated low‐density lipoprotein cholesterol (LDL‐C), triglycerides, and reduced high‐density lipoprotein cholesterol (HDL‐C). Cholesteryl ester transfer protein (CETP) inhibitors, such as anacetrapib, obicetrapib, evacetrapib, dalcetrapib, and torcetrapib, aim to improve lipid profiles by increasing HDL‐C and reducing LDL‐C, but their comparative efficacy remains unclear.MethodsThis systematic review and frequentist network meta‐analysis, conducted per PRISMA‐NMA guidelines, included 33 randomized controlled trials (RCTs) involving 120,292 adults with hyperlipidemia. We compared CETP inhibitors, alone or with statins, against placebo or other lipid‐lowering therapies. Primary outcome was LDL‐C reduction; secondary outcomes included HDL‐C, triglycerides, and total cholesterol changes. Random‐effects models calculated mean differences (MD) with 95% confidence intervals (CI), and P‐scores ranked interventions.ResultsAtorvastatin + obicetrapib showed the largest reduction in LDL‐C levels (MD: −69.00, 95% CI: −95.96 to −42.04, p < 0.0001), followed by rosuvastatin + obicetrapib (MD: −60.70, 95% CI: −99.28 to −22.12, p = 0.0020). Atorvastatin + obicetrapib yielded highly significant increase in HDL‐C levels (MD: 149.90, 95% CI: 121.70 to 178.10, p < 0.0001), but rosuvastatin + obicetrapib showed the greatest increase (MD: 158.90, 95% CI: 118.59 to 199.21, p < 0.0001) and obicetrapib monotherapy (MD: 139.00, 95% CI: 129.05 to 148.96, p < 0.0001), while rosuvastatin + evacetrapib led triglyceride reductions (MD: −31.70 mg/dL). Rosuvastatin was most effective for total cholesterol (MD: −31.60 mg/dL).ConclusionCETP inhibitors, particularly anacetrapib and obicetrapib combined with statins, significantly improve lipid profiles, offering potential therapeutic benefits for hyperlipidemia management and cardiovascular risk reduction.Trial Registration: The study was registered with PROSPERO to ensure transparency and adherence to methodological rigor (Registration ID: CRD420250652666).

Properly designed and conducted randomized controlled clinical trials (RCTs) are the premier tool for both testing mechanistic hypotheses and critically ascertaining the risks and benefits of a therapy or strategy for clinical care. The sample size of a trial is mainly a function of the rates of its primary objectives and the presumed influence of the intervention. Trials focusing on a primary outcome variable that can be readily quantified in each subject, such as blood pressure or plasma cholesterol levels, require substantially fewer participants and shorter durations to determine whether their predefined measurement is altered compared with a morbidity and mortality trial. Trials designed to determine whether clinical prognosis is altered by an intervention depend on the proportion of patients experiencing the predefined adverse clinical event(s) and often require 100s-fold–greater patient-time exposures to test their primary hypothesis and provide even modest information about safety. These resource-intense morbidity and mortality trials are generally only performed when information from observational studies as well as smaller mechanistic and surrogate- outcomes RCTs are so highly supportive of a favorable outcome that they justify the effort. Despite this understandable stacking of the cards with the best available information, many of the morbidity and mortality trials conducted to test for a potential favorable impact of an intervention conclude by not supporting the prestudy hypothesis-generating data.1 The lessons in humility offered by these neutral or negative outcomes trials underscore the importance of obtaining crucial risk–benefit data before widespread adoption of even an apparently favorable therapy.2 Articles pp 2506 and 2515 For rational therapeutic decision making, we would ideally like to have both a framework of reliable mechanistic information and robust clinical outcomes and safety data. Sometimes major clinical outcomes trials are designed with a complement of embedded ancillary trials to generate a more complete picture …

Plasma levels of high-density lipoprotein cholesterol (HDL-C) are strongly inversely associated with risk of atherosclerotic cardiovascular disease (ASCVD). It has been estimated that for every 1-mg increase in HDL-C, there is a 2% to 3% decrease in cardiovascular risk,1 which suggests that therapy to increase HDL-C levels could be effective in reducing cardiovascular risk. HDL metabolism is therefore a major emerging target for drug discovery.2 The finding more than a decade ago that genetic deficiency of the cholesteryl ester transfer protein (CETP) in humans is associated with markedly elevated plasma HDL-C levels led to the concept that CETP inhibition could be a therapeutic strategy for raising HDL.3 Indeed, 2 small-molecule inhibitors of CETP have been shown to raise HDL-C levels in humans,4–6 and this finding has generated substantial enthusiasm for CETP inhibition as a therapeutic strategy. See p 1418 Important questions remain about whether CETP inhibition, despite its positive effects on HDL-C levels, will reduce ASCVD. One theoretical concern is that CETP inhibition could slow the rate of reverse cholesterol transport (RCT), the process by which macrophage cholesterol in the vessel wall is returned to the liver for excretion. In studies in humans, radiolabeled cholesteryl esters that originated in HDL ultimately appeared in the bile primarily after their transfer (presumably mediated by CETP) to apolipoprotein B-containing lipoproteins,7 which suggests that CETP might play an important physiological role in RCT. Ultimately, randomized controlled trials of CETP inhibitors will definitively address their effect on atherosclerosis and cardiovascular events. In the meantime, observational studies in humans have the potential to provide important insights into this critical question. Such observational studies include careful assessment of cardiovascular risk in CETP-deficient subjects (both homozygous and heterozygous), as well as studies of the association of CETP polymorphisms and plasma CETP levels with …

Cholesteryl ester transfer protein (CETP) transfers cholesteryl esters from nonatherogenic high-density lipoproteins to potentially proatherogenic non-high-density lipoprotein fractions. Human genetic studies and human cohort studies have concluded that CETP gene polymorphisms associated with decreased CETP activity are accompanied by a significantly lower risk of atherosclerotic cardiovascular disease. Inhibition of CETP in rabbits reduces development of diet-induced atherosclerosis. Inhibition of CETP in humans reduces non-high-density lipoprotein cholesterol while increasing high-density lipoproteins cholesterol, consistent with a reduced risk of having an atherosclerotic cardiovascular disease event. The failure of randomized human clinical outcome trials with 3 different CETP inhibitors may have been the consequence of either off-target adverse effects of the drug used or problems with the design of the trials. The hypothesis that CETP inhibition reduces atherosclerotic cardiovascular disease risk is still untested. The future of CETP inhibition as a cardio-protective strategy will depend on the outcome of the ongoing Randomized Evaluation of the Effects of Anacetrapib Through Lipid-Modification (REVEAL) trial with the CETP inhibitor, anacetrapib.

Cholesteryl ester transfer protein (CETP) facilitates the exchange of cholesteryl esters and triglycerides (TG) between high-density lipoprotein (HDL) particles and TG-rich, apolipoprotein (apo) B-containing particles. Initially, these compounds were developed to raise plasma HDL cholesterol (HDL-C) levels, a mechanism that was previously thought to lower the risk of atherosclerotic cardiovascular disease (ASCVD). More recently, the focus changed and the use of pharmacologic CETP inhibitors to reduce low-density lipoprotein cholesterol (LDL-C), non-HDL-C and apoB concentrations became supported by several lines of evidence from animal models, observational investigations, randomized controlled trials and Mendelian randomization studies. Furthermore, a cardiovascular outcome trial of anacetrapib demonstrated that CETP inhibition significantly reduced the risk of major coronary events in patients with ASCVD in a manner directly proportional to the substantial reduction in LDL-C and apoB. These data have dramatically shifted the attention on CETP away from raising HDL-C instead to lowering apoB-containing lipoproteins, which is relevant since the newest CETP inhibitor, obicetrapib, reduces LDL-C by up to 51% and apoB by up to 30% when taken in combination with a high-intensity statin. An ongoing cardiovascular outcome trial of obicetrapib in patients with ASCVD is expected to provide further evidence of the ability of CETP inhibitors to reduce major adverse cardiovascular events by lowering apoB. The purpose of the present review is to provide an up-to-date understanding of CETP inhibition and its relationship to ASCVD risk reduction.