With Current Safety and Efficacy Data, Should Statins Be Made Available as Nonprescription Over-the-Counter Drugs?

PURPOSE OF REVIEW: Statins inhibit the enzyme 3-hydroxy-3-methylglutaryl-coenzyme A reductase in the liver and reduce atherosclerotic cardiovascular disease (ASCVD) risk by enhancing low-density lipoprotein (LDL) clearance from the circulation. In this review, we discuss their efficacy, safety, and real-world utilization to make a case for reclassifying statins as nonprescription over-the-counter drugs to improve access and availability with the overarching goal of increasing statin utilization in patients most likely to benefit from this class of therapy. RECENT FINDINGS: Statin efficacy for reducing risk in primary and secondary ASCVD prevention populations as well as their safety and tolerability has been thoroughly investigated in large-scale clinical trials over the past 3 decades. Despite the overwhelming scientific evidence, statins are underutilized even among those at the highest ASCVD risk. We propose a nuanced approach to use statins as nonprescription drugs that leverages a multi-disciplinary clinical model. It integrates lessons learned from experiences outside the USA with a proposed Food and Drug Administration rule change that allows nonprescription drug products with an additional condition for nonprescription use.

Remnant cholesterol predicts cardiovascular disease beyond LDL and ApoB: a primary prevention study.

AIMS: Emerging evidence suggests that remnant cholesterol (RC) promotes atherosclerotic cardiovascular disease (ASCVD). We aimed to estimate RC-related risk beyond low-density lipoprotein cholesterol (LDL-C) and apolipoprotein B (apoB) in patients without known ASCVD. METHODS AND RESULTS: We pooled data from 17 532 ASCVD-free individuals from the Atherosclerosis Risk in Communities study (n = 9748), the Multi-Ethnic Study of Atherosclerosis (n = 3049), and the Coronary Artery Risk Development in Young Adults (n = 4735). RC was calculated as non-high-density lipoprotein cholesterol (non-HDL-C) minus calculated LDL-C. Adjusted Cox models were used to estimate the risk for incident ASCVD associated with log RC levels. We also performed discordance analyses examining relative ASCVD risk in RC vs. LDL-C discordant/concordant groups using difference in percentile units (>10 units) and clinically relevant LDL-C targets. The mean age of participants was 52.3 ± 17.9 years, 56.7% were women and 34% black. There were 2143 ASCVD events over the median follow-up of 18.7 years. After multivariable adjustment including LDL-C and apoB, log RC was associated with higher ASCVD risk [hazard ratio (HR) 1.65, 95% confidence interval (CI) 1.45-1.89]. Moreover, the discordant high RC/low LDL-C group, but not the low RC/high LDL-C group, was associated with increased ASCVD risk compared to the concordant group (HR 1.21, 95% CI 1.08-1.34). Similar results were shown when examining discordance across clinical cutpoints. CONCLUSIONS: In ASCVD-free individuals, elevated RC levels were associated with ASCVD independent of traditional risk factors, LDL-C, and apoB levels. The mechanisms of RC association with ASCVD, surprisingly beyond apoB, and the potential value of targeted RC-lowering in primary prevention need to be further investigated.

Lipoprotein (a): Recent Updates on a Unique Lipoprotein.

PURPOSE OF REVIEW: Genetic, epidemiological, and translational data indicate that Lipoprotein (a) [Lp(a)] is likely in the causal pathway for atherosclerotic cardiovascular diseases as well as calcification of the aortic valves. RECENT FINDINGS: Lp(a) is structurally similar to low-density lipoprotein, but in addition to apolipoprotein B-100, it has a glycoprotein apolipoprotein(a) [apo(a)], which is attached to the apolipoprotein B-100. Several distinctive properties of Lp(a) can be attributed to the presence of apo(a). This review discusses the current state of literature on pathophysiological and clinical aspects of Lp(a). After five decades of research, the understanding of Lp(a) structure, biochemistry, and pathophysiology of its cardiovascular manifestations still remains less than fully understood. Universally, Lp(a) elevation may be the most predominant monogenetic lipid disorder with approximate prevalence of Lp(a)>50 mg/dL among estimated >1.4 billion people. This makes a compelling rationale for diagnosing and managing Lp(a)-mediated risk. In addition to discussing various cardiovascular phenotypes of Lp(a) and associated morbidity, we also outline current and emerging therapies aimed at identifying a definitive treatment for elevated Lp(a) levels.

Triglycerides and ASCVD Risk Reduction: Recent Insights and Future Directions.

PURPOSE OF REVIEW: This review focuses on recent evidence examining the role triglycerides (TG) and triglyceride-enriched lipoproteins (TGRL) play in atherosclerotic cardiovascular disease (ASCVD). It also provides a succinct overview of current and future TG-lowering therapies for ASCVD risk reduction. RECENT FINDINGS: Epidemiological and Mendelian randomization studies have consistently shown that TGRL are strongly associated with ASCVD. REDUCE-IT demonstrated cardiovascular benefit with icosapent ethyl in high-risk patients with hypertriglyceridemia on statin therapy. Polymorphisms in APOC3 and ANGPTL3 are associated with ASCVD and use of RNA-interfering therapies to target these proteins has shown TG lowering in early phase trials. TG and TGRL are causally associated with ASCVD. Lifestyle modifications and statin therapy can lower TG/TGRL and are considered first-line treatment for hypertriglyceridemia. Icosapent ethyl has been shown to reduce residual ASCVD risk in high-risk patients on maximally tolerated statins. Ongoing clinical trials will better define optimal therapy for patients on statins with residual hypertriglyceridemia.

Cardiovascular Disease Prevention: Training Opportunities, the Challenges, and Future Directions.

PURPOSE: Cardiovascular diseases (CVDs) are a leading cause of morbidity and mortality worldwide, necessitating major efforts in prevention. This review summarizes the currently available training opportunities in CVD prevention for fellows-in-training (FITs) and residents. We also highlight the challenges and future directions for CVD prevention as a field and propose a structure for an inclusive CVD prevention training program. RECENT FINDINGS: At present, there is a lack of centralized training resources for FITs and residents interested in pursuing a career in CVD prevention. Training in CVD prevention is not an accredited subspecialty fellowship by the American Council of Graduate Medical Education (ACGME). Although there are several independent training programs under the broad umbrella of CVD prevention focusing on different aspects of prevention, there is no unified curriculum or training. More collaborative efforts are needed to identify CVD prevention as an ACGME-accredited subspecialty fellowship. Providing more resources can encourage and produce more leaders in this essential field.

Correction to: Cardiovascular Disease Prevention: Training Opportunities, the Challenges, and Future Directions.

The original version of this article contains errors in Table 3. "At least 1 project/publication in the year" and "> 1 publication per year" have been switched under the titles of "Clinical Track" and "Physician-Scientist track".

Assessing Cardiovascular Risk and Testing in Type 2 Diabetes.

PURPOSE OF REVIEW: Type 2 diabetes confers approximately twofold-increased risk for cardiovascular disease. Early risk stratification of these patients may help reduce cardiovascular events. This review discusses the state of the art of risk factors, biomarkers, and subclinical disease parameters potentially useful in cardiovascular risk assessment in type 2 diabetes. RECENT FINDINGS: Scientific progress in the past decade has identified a spectrum of risk in diabetic individuals rather than categorizing diabetes as a coronary heart disease equivalent as previously done. Recent data on emerging biomarkers and diagnostic imaging, along with traditional risk factors, provide evidence to help inform individualized cardiovascular risk assessment. Comprehensive assessment of traditional risk factors, biomarkers, complications of diabetes, and subclinical atherosclerosis may help classify diabetic individuals as low, intermediate, or high risk for determining the intensity of lifestyle modification and pharmacotherapy. Further research may lead to a comprehensive pathway for cardiovascular disease risk assessment in diabetic patients.

Sex-Based Utilization of Guideline Recommended Statin Therapy and Cardiovascular Disease Outcomes: A Primary Prevention Healthcare Network Registry.

Background: In the US, women have similar cardiovascular death rates than men. Less is known about sex differences in statin use for primary prevention and associated atherosclerotic cardiovascular disease (ASCVD) outcomes. Methods: Statin prescriptions using electronic health records were examined in patients without ASCVD (myocardial infarction (MI), revascularization or ischemic stroke) between 2013-2019. Guideline-directed statin intensity (GDSI) at index and follow-up visits were compared among sexes across ASCVD risk groups, defined by pooled-cohort equation. Cox regression hazard ratios (HR) [95% CI] were calculated for statin use and outcomes (myocardial infarction, stroke/transient ischemic attack (TIA), and all-cause mortality) stratified by sex. Interaction terms (statin and sex) were applied. Results: Among 282,298 patients, (mean age ∼ 50 years) 17.1% women and 19.5% men were prescribed any statin at index visit. Time to GDSI was similar between sexes, but the proportion of high-risk women on GDSI at follow-ups was lower compared to high-risk men (2-years: 27.7 vs 32.0%, and 5-years: 47.2 vs 55.2%, p<0.05). When compared to GDSI, no statin use was associated with higher risk of MI and ischemic stroke/TIA amongst both sexes. High-risk women on GDSI had a lower risk of mortality (HR=1.39 [1.22-1.59]) versus men (HR=1.67 [1.50-1.86]) of similar risk (p value interaction=0.004). Conclusion: In a large contemporary healthcare system, there was underutilization of statins across both sexes in primary prevention. High-risk women were less likely to be initiated on GDSI compared with high-risk men. GDSI significantly improved the survival in both sexes regardless of ASCVD risk group. Future strategies to ensure continued use of GDSI, specifically among women, should be explored.

Sex-based utilization of guideline recommended statin therapy and cardiovascular disease outcomes: Data from a multisite healthcare network primary prevention cohort.

Background: In the US, women have similar cardiovascular death rates as men. However, less is known about sex differences in statin use for primary prevention and associated atherosclerotic cardiovascular disease (ASCVD) outcomes. Methods: Statin prescriptions using electronic health records were examined in patients without ASCVD (myocardial infarction (MI), revascularization or ischemic stroke) between 2013 and 2019. Guideline-directed statin intensity (GDSI) at index (at least moderate intensity, defined per pooled-cohort equation) and follow-up visits were compared between sexes across ASCVD risk groups, defined by the pooled-cohort equation. Cox regression hazard ratios were calculated for statin use and outcomes (myocardial infarction, stroke/transient ischemic attack (TIA), and all-cause mortality) stratified by sex. Interaction terms (statin and sex) were applied. Results: Among 282,298 patients, (mean age ∼ 50 years) 17.1 % women and 19.5 % men were prescribed any statin at index visit. Time to GDSI was similar between sexes, but the proportion of high-risk women on GDSI at follow-up were lower compared to high-risk men (2-years: 27.7 vs 32.0 %, and 5-years: 47.2 vs 55.2 %, p < 0.05). When compared to GDSI, no statin use was associated with higher risk of MI and ischemic stroke/TIA among both sexes. High-risk women on GDSI had a lower risk of mortality (HR=1.39 [1.22-1.59]) vs. men (HR=1.67 [1.50-1.86]) of similar risk (p value interaction=0.004). Conclusion: In a large contemporary healthcare system, there was underutilization of statins across both sexes in primary prevention. High-risk women were less likely to remain on GDSI compared to high-risk men. GDSI significantly improved the survival in both sexes regardless of ASCVD risk group. Future strategies to ensure continued use of GDSI, specifically among women, should be explored.

Early Onset Atherosclerotic Cardiovascular Disease.

Recent trends indicate a concerning increase in early-onset atherosclerotic cardiovascular disease (ASCVD) among younger individuals (age < 55 in men and <65 in women). These findings highlight the pathobiology of ASCVD as a disease process that begins early in life and underscores the need for more tailored screening methods and preventive strategies. Increasing attention has been placed on the growing burden of traditional cardiometabolic risk factors in young individuals while also recognizing unique factors that mediate risk of premature atherosclerosis in this demographic such as substance use, socioeconomic disparities, adverse pregnancy outcomes, and chronic inflammatory states that contribute to the increasing incidence of early ASCVD. Additionally, mounting evidence has pointed out significant disparities in the diagnosis and management of early ASCVD and cardiovascular outcomes based on sex and race. Moving toward a more personalized approach, emerging data and technological developments using diverse tools such as polygenic risk scores and coronary artery calcium scans have shown potential in earlier detection of ASCVD risk. Thus, we review current evidence on causal risk factors that drive the increase in early ASCVD and highlight emerging tools to improve ASCVD risk assessment in young individuals.

Statin utilization and cardiovascular outcomes in a real-world primary prevention cohort of older adults.

Background: Statins are a cost-effective therapy for prevention of atherosclerotic cardiovascular disease (ASCVD). Guidelines on statins for primary prevention are unclear for older adults (>75 years). Objective: Investigate statin utility in older adults without ASCVD events, by risk stratifying in a large healthcare network. Methods: We included 8,114 older adults, without CAD, PVD or ischemic stroke. Statin utilization based on ACC/AHA 10-year ASCVD risk calculation, was evaluated in intermediate (7.5%-19.9%) and high-risk patients (≥ 20%); and categorized using low and 'moderate or high' intensity statins with a follow up period of ∼7 years. Cox regression models were used to calculate hazard ratios for incident ASCVD and mortality across risk categories stratified by statin utilization. Data was adjusted for competing risk using Elixhauser Comorbidity Index. Results: Compared with those on moderate or high intensity statins, high-risk older patients not on any statin had a significantly increased risk of MI [HR 1.51 (1.17-1.95); p<0.01], stroke [HR 1.47 (1.14-1.90); p<0.01] and all-cause mortality [HR 1.37 (1.19-1.58); p<0.001] in models adjusted for Elixhauser Comorbidity Index. When comparing the no statin group versus the moderate or high intensity statin group in the intermediate risk cohort, although a trend for increased risk was seen, it did not meet statistical significance thresholds for MI, stroke or all-cause mortality. Conclusion: Lack of statin use was associated with increased cardiovascular events and mortality in high-risk older adults. Given the benefits appreciated, statin use may need to be strongly considered for primary ASCVD prevention among high-risk older adults. Future studies will assess the risk-benefit ratio of statin intervention in older adults.

Apolipoprotein E and Alzheimer's disease pathology in African American older adults.

The apolipoprotein-E4 (APOE*4) and apolipoprotein-E2 (APOE*2) alleles are more common in African American versus non-Hispanic white populations, but relationships of both alleles with Alzheimer's disease (AD) pathology among African American individuals are unclear. We measured APOE allele and ß-amyloid (Aß) and tau using blood samples and positron emission tomography (PET) images, respectively. Individual regression models tested associations of each APOE allele with Aß or tau PET overall, stratified by racialized group, and with a racialized group interaction. We included 358 older adults (42% African American) with Aß PET, 134 (29% African American) of whom had tau PET. APOE*4 was associated with higher Aß in non-Hispanic white (P < 0.0001), but not African American (P = 0.64) participants; racialized group modified the association between APOE*4 and Aß (P < 0.0001). There were no other racialized group differences. These results suggest that the association of APOE*4 and Aß differs between African American and non-Hispanic white populations. Other drivers of AD pathology in African American populations should be identified as potential therapeutic targets.

Cardiovascular Disease and Alzheimer's Disease: The Heart-Brain Axis.

Cardiovascular disease (CVD) remains one of the leading causes of morbidity and mortality in aging adults across the United States. Prior studies indicate that the presence of atherosclerosis, the pathogenic basis of CVD, is linked with dementias. Alzheimer's disease (AD) and AD-related dementias are a major public health challenge in the United States. Recent studies indicate that ≈3.7 million Americans ≥65 years of age had clinical AD in 2017, with projected increases to 9.3 million by 2060. Treatment options for AD remain limited. Development of disease-modifying therapies are challenging due, in part, to the long preclinical window of AD. The preclinical incubation period of AD starts in midlife, providing a critical window for identification and optimization of AD risk factors. Studies link AD with CVD risk factors such as hypertension, inflammation, and dyslipidemia. Both AD and CVD are progressive diseases with decades-long development periods. CVD can clinically manifest several years earlier than AD, making CVD and its risk factors a potential predictor of future AD. The current review focuses on the state of literature on molecular and metabolic pathways modulating the heart-brain axis underlying the potential association of midlife CVD risk factors and their effect on AD and related dementias. Further, we explore potential CVD/dementia preventive strategies during the window of opportunity in midlife and the future of research in the field in the multiomics and novel biomarker use era.

Impact of Guideline-Directed Statin Intervention for Primary Prevention in Patients With Diabetes.

OBJECTIVE: We examined guideline-directed statin intensity (GDSI) use and atherosclerotic cardiovascular disease (ASCVD) outcomes in patients with diabetes across a contemporary health care system. RESEARCH DESIGN AND METHODS: Patients without preexisting ASCVD were categorized by diabetes status and 10-year ASCVD risk (borderline [5-7.4%], intermediate [7.5-19.9%], high [≥20%]). Mean ±SD time to start of or change to GDSI was calculated. Incident ASCVD and all-cause mortality association, stratified by ASCVD risk, was calculated using Cox regression. RESULTS: Among 282,298 patients, 28,807 (10.2%) had diabetes and 253,491 (89.8%) did not. Only two-thirds of intermediate- and high-risk patients with diabetes were receiving GDSI therapy at 5-year follow-up. In fully adjusted models, patients with diabetes not taking a statin (vs. GDSI) had a significantly higher risk of stroke and mortality in the intermediate- and high-risk groups (hazard ratio for mortality 1.81 [95% CI 1.58-2.07] vs. 1.41 [1.26-1.57]; P for interaction < 0.01). CONCLUSIONS: Significant gaps remain in GDSI use for high-risk patients with diabetes, conferring an increased risk of ASCVD outcomes and all-cause mortality.

Dietary Effects on Monocyte Phenotypes in Subjects With Hypertriglyceridemia and Metabolic Syndrome.

In patients with hypertriglyceridemia, a short-term low-saturated fat vs high-saturated fat diet induced lower plasma lipids and improved monocyte phenotypes. These findings highlight the role of diet fat content and composition for monocyte phenotypes and possibly cardiovascular disease risk in these patients. (Effects of Dietary Interventions on Monocytes in Metabolic Syndrome; NCT03591588).

Regression of severe Behcet's eye disease with infliximab therapy; .first two cases treated in Pakistan.

We present two cases of Behcet's Disease with severe eye problems along with oral and genital ulcerations. Both cases, initially were treated with steroids and oral immunosuppressive agents, but did not show a response and ocular disease became worse. Both the cases were kept on Infliximab therapy. an immediate positive response with improvement in vision and symptoms was seen. After initial infusions the ocular damage in both the cases stopped.

Awareness and ethical views regarding life support among doctors working in tertiary care facilities of Karachi, Pakistan.

OBJECTIVE: To assess the knowledge of Life Support (LS) among doctors and to determine their ethical beliefs for the continuation or termination of Basic and Advanced Life Support services. METHODS: This cross-sectional study was done from March to June 2009 that involved 110 doctors of three teaching Hospitals in Karachi (Jinnah Postgraduate Medical Centre, Aga Khan University and Ziauddin University hospitals). All the subjects were selected by random sampling and were then analysed on the basis of self-administered questionnaires. RESULTS: Out of the 110 doctors who took the survey, 109 (99%) had heard of Life Support. In the breakdown of doctors, 1 out of the 18 consultants (5.6%), 5 of 45 PGs (11%) and 2 out of 47 House Officers (4%) who took part in this study were unable to correctly identify the right definition of LS. Out of the total number (n = 110) of doctors, 94 (85%) said they would use Life Support in their patients and 41 (43%) of them thought life support was the only way the doctor can "do what he is supposed to do i.e. save a life", while the other reason for using LS was "Religiously, the right way". CONCLUSION: LS is still a highly sensitive subject that needs still more awareness in Karachi, Pakistan. It was surprising to find out that the knowledge of LS by residents, postgraduates and even consultants was not as high as expected. Making Basic Life Support as a part of the undergraduate course might help in clarifying the discrepancies present in the knowledge of Life Support.

PCSK9 Inhibitors in the Management of Cardiovascular Risk: A Practical Guidance.

Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors are potent medications in the toolkit for treatment of atherosclerotic cardiovascular disease. These agents have been well studied in clinical trials supporting their efficacy in dramatically reducing low-density lipoprotein cholesterol (LDL-C) and impact on cardiovascular outcomes. Since the approval of commercial use for PCSK9 inhibitors in 2015, we have also gained significant experience in the use of these therapeutics in the real-world setting. In this article, we review current guideline recommendations, clinical trial evidence on efficacy and safety as well as data on cost-effectiveness, prescription and adherence. We focus primarily on the monoclonal antibody class of PCSK9 inhibitors in this review while also touching on other types of therapeutics that are under development.

Lipoprotein(a) and ethnicities.

The initial studies focusing on lipoprotein(a) [Lp(a)] and its role in atherosclerotic cardiovascular disease were conducted exclusively in Whites. Subsequently, multiple large-scale, independent investigations have established clear race/ethnic differences in plasma Lp(a) concentration and population distribution over the last four decades. Blacks have the highest Lp(a) level of all race/ethnic groups studied followed by South Asians, Whites, Hispanics and East Asians. The mechanisms underlying these differences have been sought and genetics plays an important role in providing insights into the observed differences. The association of elevated Lp(a) level with cardiovascular disease risk in different race/ethnic groups has also been studied. These studies show that, in general, elevated Lp(a) level is associated with cardiovascular risk in all groups. However, given race/ethnic differences in Lp(a) level and distribution, finding an appropriate Lp(a) threshold that predicts risk, meaningfully categorizes risk among individuals, and guides preventive therapy use has been challenging. In this review, we discuss the available evidence regarding race/ethnic differences in Lp(a) and the underlying mechanisms. Additionally, the association of Lp(a) with cardiovascular risk in various race/ethnic groups and the nuances of identifying the appropriate Lp(a) threshold are discussed. The key points on Lp(a) and ethnicities are described in Box 1.