Project description:Low-density lipoprotein cholesterol (LDL-C) is an important modifiable risk factor for atherosclerotic cardiovascular disease. It is unclear whether the percentage LDL-C lowering with pharmacotherapies differs on the basis of baseline LDL-C levels. To evaluate the association between baseline LDL-C levels and the percentage LDL-C reduction with a statin, ezetimibe, and a PCSK9 inhibitor. This secondary exploratory study analyzed data from 3 randomized placebo-controlled clinical trials (Aggrastat to Zocor-Thrombolysis in Myocardial Infarction 21 [A to Z-TIMI 21], Improved Reduction of Outcomes: Vytorin Efficacy International Trial [IMPROVE-IT], and Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk [FOURIER]) of lipid-lowering therapies (statin, ezetimibe, and a PCSK9 inhibitor) and included participants with atherosclerotic cardiovascular disease. Analyses took place form April to October 2020. In A to Z-TIMI 21, 1:1 randomization to simvastatin, 40 mg, daily for 30 days followed by 80 mg daily thereafter vs placebo for 4 months followed by simvastatin, 20 mg, daily thereafter. In IMPROVE-IT, 1:1 randomization to ezetimibe, 10 mg, daily plus simvastatin, 40 mg, daily vs placebo plus simvastatin, 40 mg, daily. In FOURIER, 1:1 randomization to evolocumab, 140 mg, every 2 weeks or 420 mg monthly vs matching placebo. The percentage LDL-C reduction at either 1 month (A to Z-TIMI 21, IMPROVE-IT) or 3 months (FOURIER) as a function of baseline LDL-C level. Data were modeled using a generalized linear regression model. A total of 3187 patients from A to Z-TIMI 21, 10 680 patients from IMPROVE-IT, and 25 847 patients from FOURIER were analyzed. There was a higher percentage reduction in LDL-C levels with evolocumab in patients with lower baseline LDL-C levels, ranging from 59.4% (95% CI, 59.1%-59.8%) in patients with a baseline LDL-C level of 130 mg/dL to 66.1% (95% CI, 65.6%-66.6%) in patients with a baseline LDL-C level of 70 mg/dL (P < .001). In contrast, across the same range of baseline LDL-C level, there was a more modest difference for simvastatin (44.6% [95% CI, 43.9%-45.2%] vs 47.8% [95% CI, 46.4%-49.2%]; P < .001) and minimal difference with ezetimibe (25.0% [95% CI, 23.3%-26.6%] vs 26.2% [95% CI, 24.2%-28.1%]; P = .007). The percentage LDL-C reduction with statins, ezetimibe, and PCSK9 inhibition is not attenuated in patients starting with lower baseline LDL-C levels and is 6.6% greater for PCSK9 inhibition. These data are encouraging for the use of intensive LDL-C-lowering therapy even for patients with lower LDL-C levels.

Project description:IntroductionInhibition of proprotein convertase subtilisin/kexin 9 (PCSK9) is an efficient strategy for lowering low-density lipoprotein cholesterol (LDL-C). There are, however, scant data on the efficacy and safety of PCSK9 inhibitors in non-cardiovascular diseases, particularly cancer. The present study aimed to evaluate the effect of PCSK9 inhibition using a nanoliposomal antiPCSK9 vaccine on cancer behavior and endpoints in mice bearing breast tumor.Material and methodsTo induce antiPCSK9 antibody in vivo, a nanoliposomal antiPCSK9 vaccine absorbed on 0.4% alum adjuvant was used. To induce tumor, BALB/c mice were subcutaneously inoculated with 4T1 breast carcinoma cells. After the tumor mass was palpable (approximately 10 mm3), the mice were randomly divided into four groups and subjected to different treatment protocols: (1) PBS (untreated control), (2) vaccine group, (3) combination of vaccine and Doxil, and (4) Doxil (positive control) group. Vaccine was subcutaneously administered to mice four times at 2-week intervals. Two weeks after the last administration, the vaccinated and non-vaccinated mice were subcutaneously inoculated with 4T1 breast carcinoma cells. To evaluate therapeutic efficacy, mouse body weight, tumor size, and survival were monitored every other day for 60 days.ResultsThe nanoliposomal antiPCSK9 vaccine was found to efficiently induce specific antibodies against PCSK9 in BALB/c mice, thereby decreasing plasma levels of PCSK9 and inhibiting its function. Tumor size analysis showed that time to reach endpoint (TTE) of the vaccine, combination, Doxil, and control groups was 47 ±10, 57 ±4, 60 ±4 and 39 ±9 days, respectively. Rate of tumor growth in vaccine, combination and Doxil groups was decreased by 21%, 48% and 53%, respectively, compared to the control group. Lifespan was increased by 4.2% in the vaccine group, compared with the control group. Additionally, the survival in the combination and Doxil groups was significantly higher than the vaccine and control groups.ConclusionsOur results revealed that PCSK9 inhibition may moderately improve breast cancer outcomes while having no harmful effects in tumor-bearing mice.

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Cholesterol reduction by immunization with a PCSK9 mimic.

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Cholesterol reduction by immunization with a PCSK9 mimic.

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