Two Phase 3 Trials of Inclisiran in Patients with Elevated LDL Cholesterol.

BACKGROUND: Inclisiran inhibits hepatic synthesis of proprotein convertase subtilisin-kexin type 9. Previous studies suggest that inclisiran might provide sustained reductions in low-density lipoprotein (LDL) cholesterol levels with infrequent dosing. METHODS: We enrolled patients with atherosclerotic cardiovascular disease (ORION-10 trial) and patients with atherosclerotic cardiovascular disease or an atherosclerotic cardiovascular disease risk equivalent (ORION-11 trial) who had elevated LDL cholesterol levels despite receiving statin therapy at the maximum tolerated dose. Patients were randomly assigned in a 1:1 ratio to receive either inclisiran (284 mg) or placebo, administered by subcutaneous injection on day 1, day 90, and every 6 months thereafter over a period of 540 days. The coprimary end points in each trial were the placebo-corrected percentage change in LDL cholesterol level from baseline to day 510 and the time-adjusted percentage change in LDL cholesterol level from baseline after day 90 and up to day 540. RESULTS: A total of 1561 and 1617 patients underwent randomization in the ORION-10 and ORION-11 trials, respectively. Mean (±SD) LDL cholesterol levels at baseline were 104.7±38.3 mg per deciliter (2.71±0.99 mmol per liter) and 105.5±39.1 mg per deciliter (2.73±1.01 mmol per liter), respectively. At day 510, inclisiran reduced LDL cholesterol levels by 52.3% (95% confidence interval [CI], 48.8 to 55.7) in the ORION-10 trial and by 49.9% (95% CI, 46.6 to 53.1) in the ORION-11 trial, with corresponding time-adjusted reductions of 53.8% (95% CI, 51.3 to 56.2) and 49.2% (95% CI, 46.8 to 51.6) (P<0.001 for all comparisons vs. placebo). Adverse events were generally similar in the inclisiran and placebo groups in each trial, although injection-site adverse events were more frequent with inclisiran than with placebo (2.6% vs. 0.9% in the ORION-10 trial and 4.7% vs. 0.5% in the ORION-11 trial); such reactions were generally mild, and none were severe or persistent. CONCLUSIONS: Reductions in LDL cholesterol levels of approximately 50% were obtained with inclisiran, administered subcutaneously every 6 months. More injection-site adverse events occurred with inclisiran than with placebo. (Funded by the Medicines Company; ORION-10 and ORION-11 ClinicalTrials.gov numbers, NCT03399370 and NCT03400800.).

Selective Serotonin Reuptake Inhibitors.

The first antidepressants were created by chance but brought the idea that central serotonin agonism produced an antidepressant effect. SSRIs were the first class of psychotropic medications to be rationally designed, meaning that researchers intended to utilize a specific mechanism of action while avoiding adverse effects. In this way, SSRIs were created to be safer and more tolerable than previous antidepressants. SSRIs share many similarities, but differ in terms of pharmacokinetics and effects on CYP450 enzymes, which is detailed in this chapter. Further information will be provided regarding safety, clinical indications/uses, and dosing recommendations.

An Individualized Music-Based Intervention for Acute Neuropsychiatric Symptoms in Hospitalized Older Adults With Cognitive Impairment: A Prospective, Controlled, Nonrandomized Trial.

Background: Neuropsychiatric symptoms are common features of dementia, and these occur in three fourths of patients on psychogeriatric inpatient units. These symptoms have traditionally been treated with pharmacological agents, but many medications are as likely to harm patients with dementia as to help them. As a result, nonpharmacological interventions are increasingly being investigated as ways to reduce these symptoms. Objective: The current study evaluated the impact of an individualized music-based intervention on agitation, negative mood, positive mood, compliance with care, need for one-on-one nursing staff intervention, and need for PRN medication. Method: Participants in this study were older adults who were admitted to a geriatric behavioral inpatient unit for acute agitation or behavioral disturbance. Twenty patients were in a treatment as usual group and 21 were in the individualized music group. Results: Agitation, negative mood, and positive mood all benefited from the music-based intervention, with resulting large effect sizes. Resisting care level also significantly benefited from the intervention, with a resulting medium effect size. Conclusion: These findings indicate that an easily implemented and reproducible music-based intervention, which is well tolerated and without adverse side effects, can be an effective way to reduce neuropsychiatric symptoms associated with dementia on a hospital unit.

Clinically relevant treatment considerations regarding lithium use in bipolar disorder.

INTRODUCTION: The goal of this paper is to provide a practical, clinically oriented review of lithium, a salt widely used to treat mania since the 1870s and formally approved as a mood stabilizer in 1970. Although lithium is still considered a first-line treatment for bipolar mania in most practice guidelines, its use may be overshadowed by newer psychotropic medications. Areas covered: This paper addresses the historical use of lithium, modern indications for its use, guidelines for prescribing and monitoring continued lithium use, drug-drug interactions, and pharmacodynamics/pharmacokinetic properties. The paper also reviews the unique properties of lithium and their potential clinical importance. Expert opinion: While the use of lithium does involve some unique risks to the patient, it may also has some unique advantages in certain patient populations. Two major findings that make lithium unique are its potential neuroprotective benefits and decreased risk of suicide in patients with mood disorders.

The prevalence of adverse cardiometabolic responses to exercise training with evidence-based practice is low.

BACKGROUND: The purpose of this study was to determine the prevalence of individuals who experienced exercise-induced adverse cardiometabolic response (ACR), following an evidence-based, individualized, community exercise program. METHODS: Prevalence of ACR was retrospectively analyzed in 332 adults (190 women, 142 men) before and after a 14-week supervised community exercise program. ACR included an exercise training-induced increase in systolic blood pressure of ≥10 mmHg, increase in plasma triglycerides (TG) of >37.0 mg/dL (≥0.42 mmol/L), or decrease in high-density lipoprotein cholesterol (HDL-C) of >4.0 mg/dL (0.12 mmol/L). A second category of ACR was also defined - this was ACR that resulted in a metabolic syndrome component (ACR-risk) as a consequence of the adverse response. RESULTS: According to the above criteria, prevalence of ACR between baseline and post-program was systolic blood pressure (6.0%), TG (3.6%), and HDL-C (5.1%). The prevalence of ACR-risk was elevated TG (3.2%), impaired fasting blood glucose (2.7%), low HDL-C (2.2%), elevated waist circumference (1.3%), and elevated blood pressure (0.6%). CONCLUSION: Evidence-based practice exercise programming may attenuate the prevalence of exercise training-induced ACR. Our findings provide important preliminary evidence needed for the vision of exercise prescription as a personalized form of preventative medicine to become a reality.

A community-based exercise intervention transitions metabolically abnormal obese adults to a metabolically healthy obese phenotype.

BACKGROUND: Lower habitual physical activity and poor cardiorespiratory fitness are common features of the metabolically abnormal obese (MAO) phenotype that contribute to increased cardiovascular disease risk. The aims of the present study were to determine 1) whether community-based exercise training transitions MAO adults to metabolically healthy, and 2) whether the odds of transition to metabolically healthy were larger for obese individuals who performed higher volumes of exercise and/or experienced greater increases in fitness. METHODS AND RESULTS: Metabolic syndrome components were measured in 332 adults (190 women, 142 men) before and after a supervised 14-week community-based exercise program designed to reduce cardiometabolic risk factors. Obese (body mass index ≥30 kg · m(2)) adults with two to four metabolic syndrome components were classified as MAO, whereas those with no or one component were classified as metabolically healthy but obese (MHO). After community exercise, 27/68 (40%) MAO individuals (P<0.05) transitioned to metabolically healthy, increasing the total number of MHO persons by 73% (from 37 to 64). Compared with the lowest quartiles of relative energy expenditure and change in fitness, participants in the highest quartiles were 11.6 (95% confidence interval: 2.1-65.4; P<0.05) and 7.5 (95% confidence interval: 1.5-37.5; P<0.05) times more likely to transition from MAO to MHO, respectively. CONCLUSION: Community-based exercise transitions MAO adults to metabolically healthy. MAO adults who engaged in higher volumes of exercise and experienced the greatest increase in fitness were significantly more likely to become metabolically healthy. Community exercise may be an effective model for primary prevention of cardiovascular disease.