This phase 3 trial evaluated the safety and efficacy of inclisiran, a small interfering RNA that inhibits hepatic PCSK9 synthesis, in 482 adults with heterozygous familial hypercholesterolemia, who ...received subcutaneous injections of inclisiran or placebo on days 1, 90, 270, and 450. Changes in cholesterol were assessed up to day 540.
Dalcetrapib, an inhibitor of cholesteryl ester transfer protein, raises HDL cholesterol levels. In this clinical trial involving patients with an acute coronary syndrome, dalcetrapib had no ...beneficial effect on clinical outcomes, despite raising HDL cholesterol levels.
High-density lipoproteins (HDLs) participate in the process of cellular cholesterol efflux and may have additional protective effects against atherothrombosis.
1
An inverse association between levels of HDL cholesterol and incident events of coronary heart disease has been shown in observational studies
2
,
3
and persists in most post hoc analyses and meta-analyses of trials of statin therapy for patients with cardiovascular risk factors, chronic cardiovascular disease, or recent acute coronary syndrome.
4
–
10
However, it remains uncertain whether pharmacologic intervention that raises HDL cholesterol levels results in decreased cardiovascular risk.
11
–
16
Moreover, changes in HDL cholesterol levels may not reflect changes in the . . .
Inclisiran, a small interfering RNA therapeutic, reduces hepatic synthesis of PCSK9. In two separate randomized trials, subcutaneous injections of inclisiran on day 1, day 90, and then every 6 months ...reduced LDL cholesterol levels by approximately 50% at month 17, with a modest excess of injection-site adverse events.
A sedentary lifestyle and lack of physical activity are well-established risk factors for chronic disease and adverse health outcomes. Thus, there is enormous interest in measuring physical activity ...in biomedical research. Many consumer physical activity monitors, including Basis Health Tracker, BodyMedia Fit, DirectLife, Fitbit Flex, Fitbit One, Fitbit Zip, Garmin Vivofit, Jawbone UP, MisFit Shine, Nike FuelBand, Polar Loop, Withings Pulse O
, and others have accuracies similar to that of research-grade physical activity monitors for measuring steps. This review focuses on the unprecedented opportunities that consumer physical activity monitors offer for human physiology and pathophysiology research because of their ability to measure activity continuously under real-life conditions and because they are already widely used by consumers. We examine current and potential uses of consumer physical activity monitors as a measuring or monitoring device, or as an intervention in strategies to change behavior and predict health outcomes. The accuracy, reliability, reproducibility, and validity of consumer physical activity monitors are reviewed, as are limitations and challenges associated with using these devices in research. Other topics covered include how smartphone apps and platforms, such as the Apple ResearchKit, can be used in conjunction with consumer physical activity monitors for research. Lastly, the future of consumer physical activity monitors and related technology is considered: pattern recognition, integration of sleep monitors, and other biosensors in combination with new forms of information processing.
Inclisiran, an siRNA administered twice-yearly, significantly reduced LDL cholesterol (LDL-C) in Phase III trials. Whether lowering LDL-C with inclisiran translates into a lower risk of ...cardiovascular (CV) events is not yet established.
Patient-level, pooled analysis of ORION-9, -10 and -11, included patients with heterozygous familial hypercholesterolaemia, atherosclerotic CV disease (ASCVD), or ASCVD risk equivalent on maximally tolerated statin-therapy, randomized 1:1 to receive 284 mg inclisiran or placebo on Days 1, 90, and 6-monthly thereafter for 18 months. Prespecified exploratory endpoint of major cardiovascular events (MACEs) included non-adjudicated CV death, cardiac arrest, non-fatal myocardial infarction (MI), and fatal and non-fatal stroke, evaluated as part of safety assessments using a standard Medical Dictionary for Regulatory Activities basket. Although not prespecified, total fatal and non-fatal MI, and stroke were also evaluated. Mean LDL-C at baseline was 2.88 mmol/L. At Day 90, the placebo-corrected percentage reduction in LDL-C with inclisiran was 50.6%, corresponding to an absolute reduction of 1.37 mmol/L (both P < 0.0001). Among 3655 patients over 18 months, 303 (8.3%) experienced MACE, including 74 (2.0%) fatal and non-fatal MIs, and 28 (0.8%) fatal and non-fatal strokes. Inclisiran significantly reduced composite MACE OR (95% CI): 0.74 (0.58-0.94), but not fatal and non-fatal MIs OR (95% CI): 0.80 (0.50-1.27) or fatal and non-fatal stroke OR (95% CI): 0.86 (0.41-1.81).
This analysis offers early insights into the potential CV benefits of lowering LDL-C with inclisiran and suggests potential benefits for MACE reduction. These findings await confirmation in the larger CV outcomes trials of longer duration.
Inclisiran, a small interfering RNA that targets
PCSK9
mRNA, was given as a single injection at baseline or in two doses at baseline and 90 days. At 180 days, LDL cholesterol was significantly ...lowered among persons at high cardiovascular risk who had elevated levels at baseline.
Low-density lipoprotein (LDL) cholesterol is a causal factor in atherosclerotic cardiovascular disease. Statins have been shown to reduce LDL cholesterol levels and cardiovascular events in large outcome trials, findings that have made them the therapeutic cornerstone of clinical practice.
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Despite the proven efficacy of statins, there is considerable variability in individual responses to these drugs.
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Furthermore, some observational data suggest that as many as half of persons who begin statin therapy discontinue it within a year.
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Moreover, among patients receiving statin therapy who are at high risk for cardiovascular disease and who have persistent elevation of LDL cholesterol levels, the . . .
To evaluate the efficacy and safety of inclisiran by diabetes status.
ORION-1 (ClinicalTrials.gov, NCT02597127) randomized 501 subjects with atherosclerotic cardiovascular disease (ASCVD) or ASCVD ...risk equivalents and high LDL cholesterol (LDL-C), despite maximally tolerated LDL-C-lowering therapies, to one or two doses of placebo or inclisiran. Levels of lipids and proprotein convertase subtilisin/kexin type 9 (PCSK9) at baseline and day 180 were compared.
Inclisiran was associated with marked declines in LDL-C (median -28% to -52%,
< 0.0001 and -28% to -55%,
< 0.005 for all doses in the without- and with-diabetes groups, respectively) and PCSK9. The inclisiran-treated groups also had lower apolipoprotein B, non-HDL cholesterol, and lipoprotein(a) but higher HDL cholesterol. Inclisiran had an adverse profile similar to that of placebo, and adverse events were proportionally balanced in the baseline with- and without-diabetes groups.
PCSK9-targeted siRNA-driven strategies may provide a novel therapeutic option for managing dyslipidemia in the presence and absence of diabetes.
Background
Optimal methods of mortality risk stratification in patients in the cardiac intensive care unit (CICU) remain uncertain. We evaluated the ability of the Sequential Organ Failure Assessment ...(SOFA) score to predict mortality in a large cohort of unselected patients in the CICU.
Methods and Results
Adult patients admitted to the CICU from January 1, 2007, to December 31, 2015, at a single tertiary care hospital were retrospectively reviewed. SOFA scores were calculated daily, and Acute Physiology and Chronic Health Evaluation (APACHE)‐III and APACHE‐IV scores were calculated on CICU day 1. Discrimination of hospital mortality was assessed using area under the receiver‐operator characteristic curve values. We included 9961 patients, with a mean age of 67.5±15.2 years; all‐cause hospital mortality was 9.0%. Day 1 SOFA score predicted hospital mortality, with an area under the receiver‐operator characteristic curve value of 0.83; area under the receiver‐operator characteristic curve values were similar for the APACHE‐III score, and APACHE‐IV predicted mortality (P>0.05). Mean and maximum SOFA scores over multiple CICU days had greater discrimination for hospital mortality (P<0.01). Patients with an increasing SOFA score from day 1 and day 2 had higher mortality. Patients with day 1 SOFA score <2 were at low risk of mortality. Increasing tertiles of day 1 SOFA score predicted higher long‐term mortality (P<0.001 by log‐rank test).
Conclusions
The day 1 SOFA score has good discrimination for short‐term mortality in unselected patients in the CICU, which is comparable to APACHE‐III and APACHE‐IV. Advantages of the SOFA score over APACHE include simplicity, improved discrimination using serial scores, and prediction of long‐term mortality.
BACKGROUND:The ORION-1 trial (Trial to Evaluate the Effect of ALN-PCSSC Treatment on Low Density Lipoprotein Cholesterol LDL-C) demonstrated that inclisiran, an siRNA therapeutic that targets ...protease proprotein convertase subtilisin/kexin type 9 mRNA within hepatocytes, produces significant low-density lipoprotein cholesterol reduction. The effects of inclisiran on other lipids are less well described.
METHODS:ORION-1 was a phase 2 trial assessing 6 different inclisiran dosing regimens versus placebo. Participants with elevated low-density lipoprotein cholesterol despite receiving maximally tolerated statin therapy received a single-dose (200, 300, or 500 mg) or 2-dose starting regimen (100, 200, or 300 mg on days 1 and 90) of inclisiran or placebo. This prespecified analysis reports the percentage reductions in non–high-density lipoprotein cholesterol (non–HDL-C), apolipoprotein (apo) B, very-low-density lipoprotein cholesterol, lipoprotein(a), triglycerides, HDL-C, and apo A1 at the primary efficacy time point (day 180) with mixed-effect models for repeated measures. Additional prespecified analyses report time course of changes from baseline at each visit to day 210, interindividual variation in response, and lipid goal attainment.
RESULTS:The mean age of the 501 participants was 63 years, 65% were male, 69% had atherosclerotic cardiovascular disease, 73% used statins, and mean low-density lipoprotein cholesterol was 128 mg/dL. A single dose of inclisiran reduced apo B, non–HDL-C, and very-low-density lipoprotein cholesterol over 210 days. A second dose of inclisiran provided additional lowering of these lipids. At day 180, non–HDL-C was lowered dose-dependentlyby 25% from 148±43 to 110±45 mg/dL in the 200-mg single-dose group and by 46% from 161±58 to 91±58 mg/dL in the 2-dose 300-mg group. For the same dosing regimens, apo B was reduced by 23% from 101±23 to 78±29 mg/dL and by 41% from 106±31 to 65±33 mg/dL (P<0.001 for all groups versus placebo). In the 300-mg 2-dose group, all individuals experienced apo B and non–HDL-C reductions. There was larger interindividual variation in very-low-density lipoprotein cholesterol, triglycerides, and lipoprotein(a) reductions. In the 300-mg 2-dose group, the percentages of patients achieving guideline-recommended apo B goals for high- and very-high-risk patients at day 180 were 78% and 90%; 68% and 83% of participants achieved non–HDL-C <100 and <130 mg/dL.
CONCLUSIONS:Inclisiran produces significant and prolonged reductions in atherogenic lipoproteins, suggesting that inhibiting the synthesis of protease proprotein convertase subtilisin/kexin type 9 through siRNA may be a viable alternative to other approaches that target protease proprotein convertase subtilisin/kexin type 9.
CLINICAL TRIAL REGISTRATION:URLhttps://www.clinicaltrials.gov. Unique identifierNCT02597127.
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