Stable Statin Therapy Research Articles

Recaticimab as Add-On Therapy to Statins for Nonfamilial Hypercholesterolemia: The Randomized, Phase 3 REMAIN-2 Trial

BackgroundCurrently available antiproprotein convertase subtilisin/kexin type 9 monoclonal antibodies can effectively decrease low-density lipoprotein cholesterol (LDL-C) levels, but require frequent dosing. Recaticimab is a novel humanized monoclonal antibody against proprotein convertase subtilisin/kexin type 9. In a phase 1b/2 trial, recaticimab as add-on to stable statins showed robust LDL-C reduction with a dosing interval up to every 12 weeks (Q12W) in patients with hypercholesterolemia. ObjectivesREMAIN-2 (REcaticiMab Add-on therapy In patients with Nonfamilial hypercholesterolemia) aimed to assess the efficacy and safety of 48-week treatment with recaticimab as add-on therapy to statins in nonfamilial hypercholesterolemia. MethodsREMAIN-2 was a multicenter, randomized, double-blind, placebo-controlled, phase 3 trial. During the run-in period, patients received stable moderate or high-intensity statin, with or without cholesterol absorption inhibitors (ezetimibe) or fenofibrate, for ≥4 weeks. Patients with an LDL-C of ≥1.8 mmol/L (if with atherosclerotic cardiovascular disease [ASCVD]) or ≥2.6 mmol/L (if without ASCVD) were then randomized (2:2:2:1:1:1) to receive recaticimab 150 mg every 4 weeks (Q4W), 300 mg every 8 weeks (Q8W), or 450 mg Q12W, or matching placebo injections (Q4W, Q8W, or Q12W) for 48 weeks. The primary efficacy endpoint was percentage change from baseline to week 24 in LDL-C level. ResultsA total of 689 randomly assigned patients received treatment (mean age, 55.8 years; male, 64.4%; ASCVD history, 69.5%; concomitant ezetimibe, 11.2%; mean baseline LDL-C, 2.8 mmol/L). Percentage change in LDL-C from baseline to week 24 was significantly more pronounced with recaticimab vs placebo (P < 0.0001), with least-squares mean differences of −62.2% (95% CI: −67.0% to −57.4%), −59.7% (95% CI: −65.0% to −54.4%), and −53.4% (95% CI: −58.7% to −48.2%) for the 150 mg Q4W, 300 mg Q8W, and 450 mg Q12W regimens, respectively. The decreases in LDL-C with recaticimab were maintained through week 48. Secondary lipid variables, including non–high-density lipoprotein cholesterol, apolipoprotein B, and lipoprotein(a) also favored the recaticimab groups. During the treatment period, the incidence of treatment-related adverse events (28.5% vs 26.6%) and serious treatment-related adverse events (0.4% vs 0.4%) was similarly low in both the recaticimab and placebo groups. ConclusionsRecaticimab as add-on to stable statin therapy significantly decreased LDL-C levels at week 24 and sustained the decreases through week 48, providing a novel therapeutic alternative with a dosing interval of up to every 12 weeks in patients with nonfamilial hypercholesterolemia.

Obicetrapib as an Adjunct to Stable Statin Therapy in Japanese Subjects: Results from a Randomized Phase 2 Trial.

Obicetrapib is a highly selective cholesteryl ester transfer protein (CETP) inhibitor shown to reduce low-density lipoprotein cholesterol (LDL-C) and apolipoprotein B (apoB), when taken as monotherapy and in combination with ezetimibe on a background of statins, in clinical trials predominantly conducted in Northern European/Caucasian participants. We characterized the efficacy, safety, and tolerability of obicetrapib within an Asian-Pacific region population. This double-blind, randomized, phase 2 trial examined obicetrapib 2.5, 5, and 10 mg/d, compared with placebo, for 8 weeks as an adjunct to stable statin therapy (atorvastatin 10 or 20 mg/d or rosuvastatin 5 or 10 mg/d) in Japanese men and women who had not achieved 2022 Japan Atherosclerosis Society Guidelines and had LDL-C ＞70 mg/dL or non-high-density lipoprotein cholesterol (non-HDL-C) ＞100 mg/dL and triglycerides (TG) ＜400 mg/dL. Endpoints included LDL-C, non-HDL-C, HDL-C, very low-density lipoprotein cholesterol, apolipoproteins, TG, steady state pharmacokinetics (PK) in obicetrapib arms, safety, and tolerability. In the 102 randomized subjects (mean age 64.8 y, 71.6% male), obicetrapib significantly lowered median LDL-C, apoB, and non-HDL-C, and raised HDL-C at all doses; responses in the obicetrapib 10 mg group were -45.8%, -29.7%, -37.0%, and +159%, respectively (all p＜0.0001 vs. placebo). The PK profile demonstrated near complete elimination of drug by 4 weeks. Obicetrapib was well tolerated and there were no adverse safety signals. All doses of obicetrapib taken as an adjunct to stable statin therapy significantly lowered atherogenic lipoprotein lipid parameters, showed near complete elimination of drug by 4 weeks, and were safe and well tolerated in a Japanese population, similar to previous studies of obicetrapib conducted in predominantly Caucasian participants.

Abstract 15201: Obicetrapib as an Adjunct to Stable Statin Therapy Significantly Lowers LDL-C, Non-HDL-C, and Apolipoprotein B in Japanese Patients: Results From the Japan Phase 2 Study

Background: Obicetrapib is a selective CETP inhibitor that has been shown to reduce LDL-C, non-HDL-C, lipoprotein particles, and apolipoproteins when used as monotherapy, and in combination with ezetimibe, on background high-intensity statins. Previous studies of obicetrapib were conducted in predominantly Caucasian participants. There is a lack of clinical experience with obicetrapib when used in combination with stable statin therapy among Asian population. Objectives: This study was designed to fill the gap in clinical experience and to characterize the safety, efficacy profile of obicetrapib within the Asian population. Methods: The Phase 2 study is a trial of Japanese participants who had not achieved treatment goal in accordance with the 2022 Japan Atherosclerosis Society Guidelines and with LDL-C &gt;70 mg/dL or non-HDL-C &gt; 100 mg/dL and TG &lt; 400 mg/dL, while receiving stable statin background therapy. Participants were randomized 1:1:1:1 to obicetrapib 2.5 mg (n=25), obicetrapib 5 mg (n=25), obicetrapib 10 mg (n=26), or placebo (n=26). The primary endpoint was percent change in LDL-C from baseline to week 8. Key secondary endpoints included changes in ApoB, non-HDL-C, and HDL-C. Standard safety assessments were conducted. Results: Obicetrapib produced significant lowering of median LDL-C (45.8%, P&lt;0.0001), ApoB (29.7%, P&lt;0.0001), non-HDL-C (37.0%, P&lt;0.0001) and raising of HDL-C (158.9%, P&lt;0.0001). Placebo demonstrated median change of -0.9%, -0.4%, -0.4% and +5.2% for these parameters respectively. Obicetrapib was well tolerated with similar treatment emergent adverse events compared to placebo. There were no clinically significant changes in laboratory parameters, vital signs, or physical examinations in any treatment group. Conclusions: Similar to previous studies, obicetrapib 2.5 mg, 5 mg, and 10 mg resulted in significant reductions in LDL-C, ApoB, and non-HDL-C in the Asian population. All doses of obicetrapib were safe and well tolerated.

Abstract 11893: Efficacy and Safety of Ongericimab in Chinese Patients With Primary Hypercholesterolemia and Mixed Dyslipidemia

Background: Ongericimab, a monoclonal antibody that inhibits proprotein convertase subtilisin/kexin type 9 (PCSK9), significantly reduced low-density lipoprotein cholesterol (LDL-C) levels in the phase 2 trial. A phase 3 trial was conducted to evaluate the efficacy and safety of ongericimab in Chinese patients with primary hypercholesterolemia and mixed dyslipidemia on background lipid-lowering therapy (LLT). Methods: This was a randomized, double-blind, placebo-controlled, 52-week trial conducted in China (NCT02662569). Eligible patients receiving stable statin (±ezetimibe) therapy but not achieving LDL-C goals were enrolled. Patients were randomly assigned in a 2:1:2:1 ratio to receive either ongericimab 150 mg or placebo subcutaneously every 2 weeks (Q2W), or ongericimab 300 mg or placebo subcutaneously every 4 weeks (Q4W) for 52 weeks. The primary endpoint was percent change in LDL-C from baseline to week 24. Results: A total of 806 patients were randomized, 802 patients received at least one dose of ongericimab or placebo. The least-squares (LS) mean difference between ongericimab and placebo in LDL-C from baseline to week 24 was -67.7% (95% CI: -72.49%, -62.99%; p &lt; 0.0001) in Q2W group and -61.2% (95% CI: -67.09%, -55.21%; p &lt; 0.0001) in Q4W group. LDL-C reductions were maintained to Week 52. Ongericimab also favorably altered other lipid parameters (Table 1). The overall incidence of adverse events was similar between ongericimab and placebo. Conclusion: Ongericimab on stable background LLT significantly reduced LDL-C and was well tolerated in Chinese patients with primary hypercholesterolemia and mixed dyslipidemia.

Effectiveness and Safety of Fenofibrate in Routine Treatment of Patients with Hypertriglyceridemia and Metabolic Syndrome.

A non-interventional study was conducted among routine healthcare providers. Patients with TG levels of >2.3 mmol/L on stable statin therapy starting fenofibrate treatment were enrolled. Data on medical history, fenofibrate treatment, change in lipid levels, and C-reactive protein (CRP) were collected from medical records every 3 months for 6 to 7 months of observation. Overall, 988 patients receiving fenofibrate were enrolled (median age [95% CI] 60 [26.0-86.0] years), and 46.4% of the participants were females. Most patients had concomitant cardiovascular disease. A baseline TG level of 3.6 ± 1.5 mmol/L was reduced by 50.1% to 1.7 ± 0.58 mmol/L at 6 months of treatment (p < 0.001). Baseline non-high-density lipoprotein cholesterol (non-HDL-C) levels decreased by 33.7% at 6 months. Total cholesterol and low-density lipoprotein levels by the end of follow-up were reduced by 24.7 and 25.5% (p < 0.001 for both). C-reactive protein level decreased more than 39% from baseline. Fenofibrate in a real-world setting significantly reduced TG, LDL-C, and non-HDL-C levels. In addition, a C-reactive protein level reduction of 39% was achieved.

Efficacy and safety of evolocumab in chinese patients with primary hypercholesterolemia and mixed dyslipidemia: primary results of the Hua Tuo _ clinical trial

Background and Aims : The prevalence of dyslipidemia in China is approximately 40%, and many patients treated with lipid-lowering therapies fail to achieve LDL-C goals. This study evaluated the effect of evolocumab on LDL-C levels in Chinese patients with primary hypercholesterolemia and mixed dyslipidemia with baseline LDL-C levels of ≥80 mg/dL or ≥130 mg/dL despite optimal stable statin therapy.

Cost-effectiveness of Icosapent Ethyl for High-risk Patients With Hypertriglyceridemia Despite Statin Treatment

The Reduction of Cardiovascular Events With Icosapent Ethyl-Intervention Trial (REDUCE-IT) demonstrated the efficacy of icosapent ethyl (IPE) for high-risk patients with hypertriglyceridemia and known cardiovascular disease or diabetes and at least 1 other risk factor who were treated with statins. To estimate the cost-effectiveness of IPE compared with standard care for high-risk patients with hypertriglyceridemia despite statin treatment. An in-trial cost-effectiveness analysis was performed using patient-level study data from REDUCE-IT, and a lifetime analysis was performed using a microsimulation model and data from published literature. The study included 8179 patients with hypertriglyceridemia despite stable statin therapy recruited between November 21, 2011, and May 31, 2018. Analyses were performed from a US health care sector perspective. Statistical analysis was performed from March 1, 2018, to October 31, 2021. Patients were randomly assigned to IPE, 4 g/d, or placebo and were followed up for a median of 4.9 years (IQR, 3.5-5.3 years). The cost of IPE was $4.16 per day after rebates using SSR Health net cost (SSR cost) and $9.28 per day with wholesale acquisition cost (WAC). Main outcomes were incremental quality-adjusted life-years (QALYs), total direct health care costs (2019 US dollars), and cost-effectiveness. A total of 4089 patients (2927 men [71.6%]; median age, 64.0 years [IQR, 57.0-69.0 years]) were randomly assigned to receive IPE, and 4090 patients (2895 men [70.8%]; median age, 64.0 years [IQR, 57.0-69.0 years]) were randomly assigned to receive standard care. Treatment with IPE yielded more QALYs than standard care both in trial (3.34 vs 3.27; mean difference, 0.07 [95% CI, 0.01-0.12]) and over a lifetime projection (10.59 vs 10.35; mean difference, 0.24 [95% CI, 0.15-0.33]). In-trial, total health care costs were higher with IPE using either SSR cost ($18 786) or WAC ($24 544) than with standard care ($17 273; mean difference from SSR cost, $1513 [95% CI, $155-$2870]; mean difference from WAC, $7271 [95% CI, $5911-$8630]). Icosapent ethyl cost $22 311 per QALY gained using SSR cost and $107 218 per QALY gained using WAC. Over a lifetime, IPE was projected to be cost saving when using SSR cost ($195 276) compared with standard care ($197 064; mean difference, -$1788 [95% CI, -$9735 to $6159]) but to have higher costs when using WAC ($202 830) compared with standard care (mean difference, $5766 [95% CI, $1094-$10 438]). Compared with standard care, IPE had a 58.4% lifetime probability of costing less and being more effective when using SSR cost and an 89.4% probability of costing less than $50 000 per QALY gained when using SSR cost and a 72.5% probability of costing less than $50 000 per QALY gained when using WAC. This study suggests that, both in-trial and over the lifetime, IPE offers better cardiovascular outcomes than standard care in REDUCE-IT participants at common willingness-to-pay thresholds.

Insulin as Monotherapy and in Combination with Other Glucose-Lowering Drugs Is Related to Increased Risk of Diagnosis of Pneumonia: A Longitudinal Assessment over Two Years.

Objective: Patients with type 2 diabetes mellitus (T2DM) are at an increased risk of developing infectious diseases such as pneumonia. Hitherto, there has been uncertainty as to whether there is a relationship between different antidiabetic drug combinations and development of pneumonia in this specific cohort. Research Design and Methods: In this longitudinal retrospective study we used multiple logistic regression analysis to assess the odds ratios (ORs) of pneumonia during an observational period of 2 years in 31,397 patients with T2DM under previously prescribed stable antidiabetic drug combinations over a duration of 4 years in comparison to 6568 T2DM patients without drug therapy over 4 years adjusted for age, sex and hospitalization duration. Results: Of the 37,965 patients with T2DM, 3720 patients underwent stable monotherapy treatment with insulin (mean age: 66.57 ± 9.72 years), 2939 individuals (mean age: 70.62 ± 8.95 y) received stable statin and insulin therapy, and 1596 patients were treated with a stable combination therapy of metformin, insulin and statins (mean age: 68.27 ± 8.86 y). In comparison to the control group without antidiabetic drugs (mean age: 72.83 ± 9.96 y), individuals undergoing insulin monotherapy (OR: 2.07, CI: 1.54–2.79, p < 0.001); insulin and statin combination therapy (OR: 2.24, CI: 1.68–3.00, p < 0.001); metformin, insulin and statin combination therapy (OR: 2.27, CI: 1.55–3.31, p < 0.001); statin, insulin and dipeptidyl peptidase-4 inhibitor (DPP-IV inhibitor) combination therapy (OR: 4.31, CI: 1.80–10.33, p = 0.001); as well as individuals treated with metformin and sulfonylureas (OR: 1.70, CI: 1.08–2.69, p = 0.02) were at increased risk of receiving a diagnosis of pneumonia. Conclusions: Stable monotherapy with insulin, but also in combination with other antidiabetic drugs, is related to an increased risk of being diagnosed with pneumonia during hospital stays in patients with type 2 diabetes mellitus compared to untreated controls.

Effect of icosapent ethyl on progression of coronary atherosclerosis in patients with elevated triglycerides on statin therapy: a prospective, placebo-controlled randomized trial (EVAPORATE): interim results.

Though statin therapy is known to slow coronary atherosclerosis progression and reduce cardiovascular (CV) events, significant CV risk still remains. In the REDUCE-IT study, icosapent ethyl (IPE) added to statin therapy reduced initial CV events by 25% and total CV events by 30%, but its effects on coronary atherosclerosis progression have not yet been fully investigated. Therefore, this study is to determine whether IPE 4 g/day will result in a greater change from baseline in plaque volume measured by serial multidetector computed tomography than placebo in statin-treated patients. EVAPORATE is a randomized, double-blind, placebo-controlled trial. Patients had to have coronary atherosclerosis by coronary computed tomographic angiography (CCTA) (≥1 angiographic stenoses with ≥20% narrowing), on stable statin therapy with low-density lipoprotein cholesterol levels 40-115 mg/dL, and persistently high triglyceride levels (135-499 mg/dL). Patients underwent an interim scan at 9 months and were followed for an additional 9 months with CCTA at 0, 9, and 18 months. Here, we present the protocol-specified interim efficacy results. A total of 80 patients were enrolled, with 67 completing the 9-month visit and having interpretable CCTA at baseline and at 9 months (age = 57 ± 6 years, male = 36, 63%). At the 9-month interim analysis, there was no significant change in low attenuation plaque (LAP) between active and placebo groups (74% vs. 94%, P = 0.469). However, there was slowing of total non-calcified plaque (sum of LAP, fibrofatty, and fibrous plaque) (35% vs. 43%, P = 0.010), total plaque (non-calcified + calcified plaque) (15% vs. 26%, P = 0.0004), fibrous plaque (17% vs. 40%, P = 0.011), and calcified plaque (-1% vs. 9%, P = 0.001), after adjustment by baseline plaque, age, sex, diabetes, baseline triglyceride levels, and statin use. EVAPORATE is the first study using CCTA to evaluate the effects of IPE as an adjunct to statin therapy on atherosclerotic plaque characteristics in a high-risk CV population with persistently high triglyceride levels. It provides important mechanistic data in regards to the reduction in CV events in the REDUCE-IT clinical trial. NCT029226027.

Liraglutide in combination with metformin may improve the atherogenic lipid profile and decrease C-reactive protein level in statin treated obese patients with coronary artery disease and newly diagnosed type 2 diabetes: A randomized trial

Background and aimsAtherosclerosis in obesity and type 2 diabetes (T2DM) is associated with low-grade inflammation (LGI) and dyslipidemia, where especially small, dense lipoprotein particles are atherogenic. The glucagon-like peptide-1 receptor agonist, liraglutide, reduces cardiovascular events by poorly understood mechanisms. We investigated the effect of liraglutide combined with metformin on LGI and lipoprotein density profiles in patients with stable coronary artery disease (CAD) and newly diagnosed T2DM. MethodsWe conducted a randomized, double-blind, placebo-controlled, cross-over trial over a 12 + 12-week period, with ≥2-week wash-out. Intervention: liraglutide/metformin vs. placebo/metformin. Lipoproteins were separated by continuous density gradient ultracentrifugation, and LDL divided into five subfractions between 226 and 270 Å, considering particle size ≤255 Å as the atherogenic pattern. Plasma C-reactive protein and tumor necrosis factor-α were assessed by the enzyme-linked immunosorbent-assay. Results28 out of 41 randomized patients completed all visits. Intention-to-treat analysis was performed but one patient had statin dosage and was excluded from the analysis. 95% of the patients were on statin therapy. Overall, liraglutide did not affect lipid subfractions or markers of LGI compared to placebo. The combination of liraglutide and metformin reduced the total LDL subfractions, primarily by reducing the most atherogenic subfraction LDL5, and reduced CRP but not TNF-α. Explorative analyses suggested that the subfraction LDL5 during the wash-out period rebounded significantly at least in a per-protocol analysis of the sub-group of patients starting the liraglutide therapy. ConclusionsIn patients with CAD and newly diagnosed T2DM on stable statin therapy, liraglutide combined with metformin may improve the atherogenic LDL lipid profile and CRP.

Effect of Alirocumab and Rosuvastatin or Rosuvastatin Alone on Lipid Core Plaque in Coronary Artery Disease Seen on Near-Infrared Spectroscopy Intravascular Ultrasound (ANTARES).

Background: Despite evidence of the effects of alirocumab on the incidence of acute coronary events, its impact on plaque stabilization remains uncertain. The present study will investigate the effect of alirocumab on fibroatheroma in patients who underwent recent percutaneous coronary intervention (PCI). Methods and Results: This phase IV, open-label, randomized, blinded near-infrared spectroscopy plus intravascular ultrasound (NIRS-IVUS) analysis, parallel-group, single-center study will enroll Japanese adults recently hospitalized for PCI with suboptimal low-density lipoprotein cholesterol (LDL-C) control (>70 mg/dL) despite stable statin therapy. Thirty patients will be randomized to receive either alirocumab or standard of care. The alirocumab group will receive alirocumab 75 mg every 2 weeks plus 10 mg rosuvastatin per day. The standard-of-care group will receive 10 mg rosuvastatin per day with dose adjustment to achieve LDL-C <70 mg/dL. Post-treatment NIRS-IVUS will be performed at week 36. The primary endpoint is the change in maximum lipid core burden index in 4-mm pullback compartments (maxLCBI[4 mm]) between baseline and week 36. Secondary endpoints include change in LCBI (lesion), angle of lipid core, plaque burden, and serum lipids and biomarkers related to atherosclerosis and inflammation. Conclusions: The study will clarify the effects of alirocumab on thin-cap fibroatheroma in patients who underwent recent PCI and who have suboptimal LDL-C control with stable statin therapy.

Effect of Alirocumab and Rosuvastatin or Rosuvastatin Alone on Lipid Core Plaque in Coronary Artery Disease Seen on Near-Infrared Spectroscopy Intravascular Ultrasound (ANTARES)

Background: Despite evidence of the effects of alirocumab on the incidence of acute coronary events, its impact on plaque stabilization remains uncertain. The present study will investigate the effect of alirocumab on fibroatheroma in patients who underwent recent percutaneous coronary intervention (PCI). Methods and Results: This phase IV, open-label, randomized, blinded near-infrared spectroscopy plus intravascular ultrasound (NIRS-IVUS) analysis, parallel-group, single-center study will enroll Japanese adults recently hospitalized for PCI with suboptimal low-density lipoprotein cholesterol (LDL-C) control (>70 mg/dL) despite stable statin therapy. Thirty patients will be randomized to receive either alirocumab or standard of care. The alirocumab group will receive alirocumab 75 mg every 2 weeks plus 10 mg rosuvastatin per day. The standard-of-care group will receive 10 mg rosuvastatin per day with dose adjustment to achieve LDL-C <70 mg/dL. Post-treatment NIRS-IVUS will be performed at week 36. The primary endpoint is the change in maximum lipid core burden index in 4-mm pullback compartments (maxLCBI[4 mm]) between baseline and week 36. Secondary endpoints include change in LCBI (lesion), angle of lipid core, plaque burden, and serum lipids and biomarkers related to atherosclerosis and inflammation. Conclusions: The study will clarify the effects of alirocumab on thin-cap fibroatheroma in patients who underwent recent PCI and who have suboptimal LDL-C control with stable statin therapy.

Efficacy and Safety of Prescription Omega-3 Fatty Acids Added to Stable Statin Therapy in Korean Patients with Type 2 Diabetes and Hypertriglyceridemia: a Randomized Controlled Trial.

ObjectiveThe aim of this study was to investigate the effects of omega-3 fatty acids added to statin monotherapy in Korean patients with type 2 diabetes who have persistent hypertriglyceridemia despite statin therapy.MethodsThis study was a randomized controlled trial conducted in 4 clinical sites between February 2009 and February 2011. The inclusion criteria were patients with type 2 diabetes who had received ≥6 weeks of statin therapy and had fasting triglyceride (TG) levels ≥1.7mmol/L and low-density lipoprotein (LDL) cholesterol levels <2.6 mmol/L. The study regimen consisted of 16 weeks of randomized treatment with omega-3 fatty acids (4 g/day) plus a statin (n=26) or statin only (n=30). The primary endpoint was the change from baseline to final visit in mean TG level.ResultsA total of 56 participants were analyzed. At week 16, the change in the TG level in the combination therapy group differed significantly from the change in the statin monotherapy group (−34.8% vs. −15.2%, p=0.0176). Treatment with omega-3 fatty acids plus a statin was also associated with a significant decrease in non-high-density lipoprotein cholesterol compared with baseline, but the difference was not significant compared with the statin monotherapy group (−8.0% vs. −2.5%, p=0.165). The changes in LDL cholesterol and HbA1c levels did not differ significantly between groups. The study medications were well tolerated, and adverse events were comparable between two groups.ConclusionAdding omega-3 fatty acids to statin treatment reduced TG levels more effectively than statin monotherapy without undesirable effects in Korean type 2 diabetic patients who had hypertriglyceridemia despite well-controlled LDL cholesterol on stable statin therapy.Trial RegistrationClinicalTrials.gov Identifier: NCT02305355

Efficacy of alirocumab for reducing plaque vulnerability: Study protocol for ALTAIR, a randomized controlled trial in Japanese patients with coronary artery disease receiving rosuvastatin

BackgroundAlthough a recent clinical trial demonstrated that alirocumab, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, significantly reduces the incidence of acute coronary events, the impact of alirocumab on plaque stabilization remains uncertain. The Efficacy of ALirocumab for Thin-cap fibroatheroma in patients with coronary Artery disease estImated by optical coherence tomogRaphy (ALTAIR) study will investigate the effect of alirocumab on thin-cap fibroatheroma (TCFA) in Japanese patients who underwent recent percutaneous coronary intervention (PCI). Methods and designALTAIR is a phase IV, open-label, randomized, parallel-group, single-center study involving blinded optical coherence tomography (OCT) image analysis in Japanese adults hospitalized for PCI and having suboptimal control of low-density lipoprotein cholesterol (LDL-C) levels (>70mg/dL) despite statin therapy. Patients will be randomized (1:1) to the alirocumab arm (alirocumab 75mg every 2 weeks added to rosuvastatin 10mg/day) or the standard-of-care arm (rosuvastatin 10mg/day, with initiation and/or dose adjustment of non-statin lipid-lowering to achieve an LDL-C target of <70mg/dL). OCT imaging will be conducted at baseline and at week 36 (post-treatment). The primary objective is to compare the alirocumab and standard-of-care arms regarding the change in TCFA fibrous-cap thickness after 9 months of treatment. ConclusionThe outcomes of ALTAIR (ClinicalTrials.gov identifier: NCT03552432) will provide insights into the effect of alirocumab on plaque vulnerability following PCI in patients with suboptimal LDL-C control despite stable statin therapy.

Late-Breaking Science Abstracts From the American Heart Association's Scientific Sessions 2018 and Late-Breaking Abstracts in Resuscitation Science From the Resuscitation Science Symposium 2018.

Late-Breaking Science Abstracts From the American Heart Association's Scientific Sessions 2018 and Late-Breaking Abstracts in Resuscitation Science From the Resuscitation Science Symposium 2018.

Efficacy and Safety of Alirocumab in Japanese Patients with Diabetes Mellitus: Post-hoc Subanalysis of ODYSSEY Japan.

Aim: To examine the efficacy and safety of alirocumab in Japanese patients with dyslipidemia with or without diabetes mellitus (DM).Methods: Patients (n = 216) with heterozygous familial hypercholesterolemia (heFH), non-FH at high cardiovascular risk with coronary artery disease (CAD), or category III (primary prevention) were enrolled; 148 (68.5%) patients had a diagnosis of DM at baseline. Patients were randomized (2:1), with stratification factor (heFH, non-FH), to alirocumab (75 mg every 2 weeks [Q2W] with increase to 150 mg if week 8 LDL-C was above predefined limits) or placebo subcutaneously for 52 weeks on top of stable statin therapy.Results: At Week 24, least square (LS) mean ± standard error changes in low-density lipoprotein cholesterol (LDL-C) concentration from baseline in alirocumab-treated patients were −63.1 ± 1.6% and −60.8 ± 2.7% in those with and without DM. These LDL-C reductions were maintained to Week 52: −63.0 ± 1.6% (LS mean difference vs placebo −62.4 ± 3.0%; P < 0.0001) with DM and −61.3 ± 2.8% (LS mean difference vs placebo − 53.4 ± 4.0%; P < 0.0001) without DM. The most common adverse events in the alirocumab group were nasopharyngitis, back pain, injection site reaction, and fall. No particular safety signals or concerns were noted between DM and non-DM groups at 52 weeks. A dose-increase in alirocumab from 75 to 150 mg Q2W was necessary in two heFH patients, neither of whom had DM.Conclusions: In high-cardiovascular-risk Japanese patients with hypercholesterolemia on stable statin therapy, alirocumab produced substantial and sustained LDL-C reductions throughout the 52-week study regardless of DM status at baseline, with a similar safety profile to placebo.Abbreviations: Apo: apolipoprotein, CAD: coronary artery disease, DM: diabetes mellitus, FH: familial hypercholesterolemia, FPG: fasting plasma glucose, HbA1c: glycated hemoglobin, HDL-C: high-density lipoprotein cholesterol, JAS: Japan Atherosclerosis Society, LDL-C: low-density lipoprotein cholesterol, heFH: heterozygous familial hypercholesterolemia, ITT: intention to treat, LDL-C: low-density lipoprotein cholesterol, LLT: lipid-lowering therapy, Lp(a): lipoprotein(a), LS: least square, PCSK9: proprotein convertase subtilisin/kexin 9, Q2W: every 2 weeks, SC: subcutaneous, SE: standard error, SD: standard deviation, TG: triglycerides

A Prospective, Multicentric Study to Evaluate the Effects of Saroglitazar on Non-HDL Cholesterol and Small Dense LDL Particles in Patients with Diabetic Dyslipidemia

Saroglitazar, a dual PPAR α/γ agonist, is approved in India for the treatment of diabetic dyslipidemia (DD) not controlled with statins. DD is highly atherogenic as it is associated with high triglycerides (TG), high small dense LDL (sdLDL) and low HDL-C. In this, prospective multi-centric study conducted in patients with type 2 diabetes and triglycerides (TG) ≥200 mg/dL after lifestyle and stable statin therapy for at least 3 months, efficacy and safety of saroglitazar has been evaluated. Total 104 patients (78% male) with mean age of 59.1 ± 11.4 years were enrolled. All subjects were given saroglitazar 4mg once daily for 24 weeks. The effects of saroglitazar were evaluated at 24 weeks by using paired t-test. Six months follow-up data is available from 73 patients. At 24 weeks the primary end point showed a significant reduction in non-HDL-C (from 138 ± 51 mg/dL to 113 ± 44 mg/dL; p&amp;lt;0.001) and sdLDL (from 31.7 ± 11.8 mg/dL to 26.0 ± 11.9 mg/dL; p&amp;lt;0.001). Of the secondary end points the values of TG, HDL-C, total cholesterol and HbA1c were also significantly improved at 24 weeks (Table). No major adverse event reported during the study period. This is the first study evaluating the effect of saroglitazar on sdLDL in patients with DD. The results indicate that saroglitazar is safe and well tolerated and effectively reduces sdLDL particles along with non-HDL-C.Change in laboratory parameters at 24 weeks follow-up (All values are Mean±SD)Laboratory parametersBaseline24 weeks follow-upP-valueNon HDL-C (mg/dL)138±51113±44&amp;lt;0.001TG (mg/dL)351±360247±445&amp;lt;0.001LDL-C (mg/dL)90±3882±240.074sdLDL (mg/dL)31.7±11.826.0±11.9&amp;lt;0.001HDL-C (mg/dL)35.6±7.540.6±8.0&amp;lt;0.001Total cholesterol (mg/dL)172±52154±43&amp;lt;0.001HbA1c (%)7.98±1.666.95±0.71&amp;lt;0.001 Disclosure U. Kaul: None. P. Jain: None. R. Kachru: None. V. Bhatia: None. P. Arambam: None. S. Shekhawat: None. Y. Diana: None. K. Rawat: None. S. Singh: None. A. Jaiswal: Employee; Self; Zydus Cadila.

VESS27. Statin Intensity One Year After Revascularization for Chronic Limb-Threatening Ischemia Is Associated With Higher Long-Term Survival

Statin therapy and dosing intensity at hospital discharge are associated with higher long-term survival after vascular procedures. Discontinuation of statins and dosing changes are common, but the effect of these changes has yet to be characterized. We evaluated the association between statin intensity and long-term survival 1 year after lower extremity revascularization for chronic limb-threatening ischemia (CLTI). We reviewed consecutive patients undergoing first-time endovascular or open revascularization for CLTI at a single institution from 2005 to 2014. We classified statin intensity by the American College of Cardiology/American Heart Association guidelines and evaluated change in statin intensity from discharge to 1-year follow-up. We compared long-term mortality beyond 1 year using Cox regression. We identified 1336 first-time revascularizations in 1195 patients with CLTI, of which 884 revascularizations in 792 patients had follow-up through 1 year. At 1 year, 165 patients (19%) were not taking a statin, 71 (8.3%) were receiving low-intensity therapy, 403 (47%) were receiving moderate-intensity therapy, and 221 (28%) were receiving high-intensity therapy. From discharge to 1-year follow-up, 101 patients (12%) had never taken a statin, 106 (12%) had their statin stopped or intensity decreased, 134 (16%) had a statin started or intensity increased, and 512 (60%) remained on stable statin therapy. In multivariable analysis, high- and moderate-intensity statin therapy at 1 year was associated with lower mortality compared with no statin therapy (high: hazard ratio [HR], 0.58 [95% confidence interval, 0.39-0.88; P = .01]; moderate: HR, 0.61 [0.42-0.89; P = .01]). There was no difference between low-intensity therapy and no statin therapy (HR, 1.02 [0.56-1.85]; P = .96). Furthermore, stable statin therapy and having a statin started or intensity increased were associated with lower mortality compared with never taking a statin postoperatively (stable: HR, 0.55 [0.36-0.84; P < .01]; started/increased: HR, 0.51 [0.29-0.91; P = .02]; Fig). There was no difference in survival if the statin was stopped or intensity decreased postoperatively (HR, 0.82 [0.48-1.4]; P = .46; Fig). High- or moderate-intensity statin therapy at 1 year after revascularization for CLTI is associated with higher long-term survival. However, a significant proportion of these patients had their statin stopped or intensity of therapy decreased within the first postoperative year, resulting in a loss of this survival difference. These results demonstrate the importance not only of discharging this population on high- or moderate-intensity statin therapy but also of maintaining this therapy postoperatively.

Effect of alirocumab on coronary atheroma volume in Japanese patients with acute coronary syndromes and hypercholesterolemia not adequately controlled with statins: ODYSSEY J-IVUS rationale and design

BackgroundSerial intravascular ultrasound (IVUS) imaging can be used to evaluate the effect of cholesterol-lowering on coronary atheroma progression and plaque volume, with evidence of potential incremental effects with more aggressive lipid-lowering treatments. Alirocumab is a highly specific, fully human monoclonal antibody to proprotein convertase subtilisin/kexin type 9 (PCSK9). This study will investigate the effect of alirocumab on coronary artery plaque volume in Japanese patients with a recent acute coronary syndrome (ACS) and hypercholesterolemia while on stable statin therapy. MethodsODYSSEY J-IVUS is a phase IV, open-label, randomized, blinded IVUS analysis, parallel-group, multicenter study in Japanese adults recently hospitalized for an ACS and who have elevated low-density lipoprotein cholesterol (LDL-C) values [≥100mg/dL (2.6mmol/L)] at ACS diagnosis and suboptimal LDL-C control on stable statin therapy. Patients will be randomized (1:1) to receive alirocumab or standard-of-care (SOC). The alirocumab arm will receive alirocumab 75mg every 2 weeks (Q2W) added to statin therapy (atorvastatin ≥10mg/day or rosuvastatin ≥5mg/day), with a dose increase to 150mg Q2W in patients whose LDL-C value remains ≥100mg/dL at week 12. The SOC arm will receive atorvastatin ≥10mg/day or rosuvastatin ≥5mg/day, with dose adjustment to achieve LDL-C <100mg/dL. Post-treatment IVUS imaging will be done at week 36±2. The primary objective is to compare the effect of alirocumab versus SOC on coronary atheroma progression (percent change in normalized total atheroma volume) after 9 months of treatment. ConclusionODYSSEY J-IVUS will provide insights into the effect of alirocumab on coronary atherosclerotic plaque volume in patients with a recent ACS and hypercholesterolemia while on stable statin therapy.ClinicalTrials.gov number: NCT02984982.

Abstract 23082: Gemcabene Add-On Therapy to High- and Moderate-Intensity Statin Stratums in Hypercholesterolemic Subjects (ROYAL-1, a Phase 2b Study)

Introduction: Recent large cardiovascular event outcome trials with ezetimibe and a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor added to statins demonstrated benefit from additional LDL-C reduction. Despite availability of approved injectable PCSK9 inhibitors, there still remains a need for novel, efficacious, safe, well-tolerated, and cost-effective oral LDL-C lowering therapies. Gemcabene (GEM) has been shown to significantly lower LDL-C, non-HDL-C, ApoB, and hsCRP further in hypercholesterolemic subjects when added to background statin therapy. GEM neither interacts pharmacokinetically nor has shown increased adverse effects with statins. Hypothesis: GEM added to high- or moderate-intensity statin +/-ezetimibe therapy will provide additional LDL-C reduction for subjects not at goal. Methods: High-risk subjects including those with heterozygous familial hypercholesterolemia or atherosclerotic cardiovascular disease on appropriate diet and stable statin therapy for at least 12 weeks and LDL-C ≥ 100 mg/dL (2.59 mmol/L) and triglycerides &lt; 500 mg/dL (5.65 mmol/L) were randomized into a 12-week, placebo-controlled, parallel-group, double-blind study to assess the efficacy of GEM 600 mg QD on LDL-C and other lipoproteins and hsCRP. Safety and tolerability were evaluated. The subjects were stratified by high- or moderate-intensity statin therapy, with or without ezetimibe, with a target of 52 subjects (26 GEM; 26 placebo) in each stratum. The study (NCT02634151) enrolled 105 subjects (53% women, 77% Caucasian, mean age 61 years). Mean baseline LDL-C for all subjects was approximately 134 mg/dL (3.48 mmol/L) with most subjects in the high-intensity statin stratum on atorvastatin and most subjects in the moderate-intensity stratum on either simvastatin or atorvastatin. Results: Data for the full cohort was previously reported. Data by statin-intensity stratum (high and moderate) including LDL-C, non-HDL-C, ApoB, Lp(a) and hsCRP as well as safety and tolerability will now be reported. Conclusion: The trial and data analysis by statin-intensity stratification, including efficacy and safety, will be completed in October 2017 in time for presentation at the American Heart Association Scientific Sessions.