Toward Heart-Healthy and Sustainable Cities: A Policy Statement From the American Heart Association.

Nearly 56% of the global population lives in cities, with this number expected to increase to 6.6 billion or >70% of the world's population by 2050. Given that cardiometabolic diseases are the leading causes of morbidity and mortality in people living in urban areas, transforming cities and urban provisioning systems (or urban systems) toward health, equity, and economic productivity can enable the dual attainment of climate and health goals. Seven urban provisioning systems that provide food, energy, mobility-connectivity, housing, green infrastructure, water management, and waste management lie at the core of human health, well-being, and sustainability. These provisioning systems transcend city boundaries (eg, demand for food, water, or energy is met by transboundary supply); thus, transforming the entire system is a larger construct than local urban environments. Poorly designed urban provisioning systems are starkly evident worldwide, resulting in unprecedented exposures to adverse cardiometabolic risk factors, including limited physical activity, lack of access to heart-healthy diets, and reduced access to greenery and beneficial social interactions. Transforming urban systems with a cardiometabolic health-first approach could be accomplished through integrated spatial planning, along with addressing current gaps in key urban provisioning systems. Such an approach will help mitigate undesirable environmental exposures and improve cardiovascular and metabolic health while improving planetary health. The purposes of this American Heart Association policy statement are to present a conceptual framework, summarize the evidence base, and outline policy principles for transforming key urban provisioning systems to heart-health and sustainability outcomes.

The Urban Environment and Cardiometabolic Health.

Urban environments contribute substantially to the rising burden of cardiometabolic diseases worldwide. Cities are complex adaptive systems that continually exchange resources, shaping exposures relevant to human health such as air pollution, noise, and chemical exposures. In addition, urban infrastructure and provisioning systems influence multiple domains of health risk, including behaviors, psychological stress, pollution, and nutrition through various pathways (eg, physical inactivity, air pollution, noise, heat stress, food systems, the availability of green space, and contaminant exposures). Beyond cardiometabolic health, city design may also affect climate change through energy and material consumption that share many of the same drivers with cardiometabolic diseases. Integrated spatial planning focusing on developing sustainable compact cities could simultaneously create heart-healthy and environmentally healthy city designs. This article reviews current evidence on the associations between the urban exposome (totality of exposures a person experiences, including environmental, occupational, lifestyle, social, and psychological factors) and cardiometabolic diseases within a systems science framework, and examines urban planning principles (eg, connectivity, density, diversity of land use, destination accessibility, and distance to transit). We highlight critical knowledge gaps regarding built-environment feature thresholds for optimizing cardiometabolic health outcomes. Last, we discuss emerging models and metrics to align urban development with the dual goals of mitigating cardiometabolic diseases while reducing climate change through cross-sector collaboration, governance, and community engagement. This review demonstrates that cities represent crucial settings for implementing policies and interventions to simultaneously tackle the global epidemics of cardiovascular disease and climate change.

Air Pollution, Built Environment, and Early Cardiovascular Disease.

As the world's population becomes increasingly urbanized, there is growing concern about the impact of urban environments on cardiovascular health. Urban residents are exposed to a variety of adverse environmental exposures throughout their lives, including air pollution, built environment, and lack of green space, which may contribute to the development of early cardiovascular disease and related risk factors. While epidemiological studies have examined the role of a few environmental factors with early cardiovascular disease, the relationship with the broader environment remains poorly defined. In this article, we provide a brief overview of studies that have examined the impact of the environment including the built physical environment, discuss current challenges in the field, and suggest potential directions for future research. Additionally, we highlight the clinical implications of these findings and propose multilevel interventions to promote cardiovascular health among children and young adults.

Differential Diagnosis of Suspected Chronic Obstructive Pulmonary Disease Exacerbations in the Acute Care Setting: Best Practice.

Patients with chronic obstructive pulmonary disease (COPD) may suffer from acute episodes of worsening dyspnea, often associated with increased cough, sputum, and/or sputum purulence. These exacerbations of COPD (ECOPDs) impact health status, accelerate lung function decline, and increase the risk of hospitalization. Importantly, close to 20% of patients are readmitted within 30 days after hospital discharge, with great cost to the person and society. Approximately 25% and 65% of patients hospitalized for an ECOPD die within 1 and 5 years, respectively. Patients with COPD are usually older and frequently have concomitant chronic diseases, including heart failure, coronary artery disease, arrhythmias, interstitial lung diseases, bronchiectasis, asthma, anxiety, and depression, and are also at increased risk of developing pneumonia, pulmonary embolism, and pneumothorax. All of these morbidities not only increase the risk of subsequent ECOPDs but can also mimic or aggravate them. Importantly, close to 70% of readmissions after an ECOPD hospitalization result from decompensation of other morbidities. These observations suggest that in patients with COPD with worsening dyspnea but without the other classic characteristics of ECOPD, a careful search for these morbidities can help detect them and allow appropriate treatment. For most morbidities, a thorough clinical evaluation supplemented by appropriate clinical investigations can guide the healthcare provider to make a precise diagnosis. This perspective integrates the currently dispersed information available and provides a practical approach to patients with COPD complaining of worsening respiratory symptoms, particularly dyspnea. A systematic approach should help improve outcomes and the personal and societal cost of ECOPDs.

An updated systematic review and meta-analysis on portable air cleaners and blood pressure: Recommendations for users and manufacturers.

Fine particulate matter (PM2.5) air pollution is a leading contributor to the global burden of cardiovascular disease (CVD). One important underlying mechanism is an increase in blood pressure (BP). A growing number of studies have reported a beneficial effect of portable air cleaners (PACs) on systolic and diastolic BP; SBP and DBP. We conducted an updated systematic review and meta-analysis of studies using true versus sham mode filtration reporting the effects on BP. Of 214 articles identified up to February 5, 2023, seventeen (from China, USA, Canada, South Korea and Denmark) enrolling approximately 880 participants (484 female) met the inclusion criteria for meta-analyses. Aside from studies conducted in China, research on PACs and BP has been conducted in relatively low pollution settings. Mean indoor PM2.5 concentrations during the active and sham mode purification were 15.9 and 41.2 µg/m3, respectively. The mean efficiency of PACs against indoor PM2.5 was 59.8 % (ranging from 23 % to 82 %). True mode filtration was associated with a pooled mean difference of - 2.35 mmHg (95 % confidence interval [CI]: - 4.5, - 0.2) and - 0.81 mmHg (95 % CI: - 1.86, 0.24) in SBP and DBP, respectively. After removing the studies with high risk of bias, the magnitude of the pooled benefits on SBP and DBP increased to - 3.62 mmHg (95 % CI: - 6.69, - 0.56) and - 1.35 mmHg (95 % CI: - 2.29, - 0.41), respectively. However, there are several barriers to the use of PACs, specifically in low- and middle-income countries (LMICs), such as the initial purchase cost and filter replacements. There may be several avenues to help overcome these economic burdens and improve cost effectiveness, such as implementing government or other subsidized programs to distribute PACs targeting vulnerable and higher-risk individuals. We propose that environmental health researchers and healthcare providers should be better trained to educate the public regarding the use of PACs to reduce the impacts of PM2.5 on cardiometabolic diseases globally.

Ambient Air Pollution and Atherosclerosis: Insights Into Dose, Time, and Mechanisms.

Ambient air pollution due to particulate matter ≤2.5 µ is the leading environmental risk factor contributing to global mortality, with a preponderant majority of these deaths attributable to atherosclerotic cardiovascular disease (ASCVD) causes such as stroke and myocardial infarction. Epidemiological studies in humans have provided refined estimates of exposure risk, with evidence suggesting that risk association with particulate matter ≤2.5 levels and ASCVD continues at levels well below air quality guidelines in North America and Europe. Mechanistic studies in animals and humans have provided a framework of understanding of the duration and pathways by which air pollution exposure may predispose to atherosclerosis. Although acute exposure to particulate matter ≤2.5 is associated with oxidative stress and inflammation, system transmission of signals from the lungs to extrapulmonary sites may involve direct translocation of components, biologic intermediates, and autonomic nervous system activation. End-organ effector pathways such as endothelial barrier disruption/dysfunction, thrombosis, vasoconstriction/increased blood pressure, and plaque instability, may contribute to ASCVD. The strength of the association of air pollution with ASCVD offers an opportunity to mitigate its consequences. Although elimination of anthropogenic sources of air pollution with a switch to clean energy provides the ultimate solution, this may not be possible in the interim and may require personal protection efforts and an integrated approach to managing risk posed by air pollution for ASCVD.

Optimal dynamic treatment regime estimation using information extraction from unstructured clinical text.

The wide-scale adoption of electronic health records (EHRs) provides extensive information to support precision medicine and personalized health care. In addition to structured EHRs, we leverage free-text clinical information extraction (IE) techniques to estimate optimal dynamic treatment regimes (DTRs), a sequence of decision rules that dictate how to individualize treatments to patients based on treatment and covariate history. The proposed IE of patient characteristics closely resembles "The clinical Text Analysis and Knowledge Extraction System" and employs named entity recognition, boundary detection, and negation annotation. It also utilizes regular expressions to extract numerical information. Combining the proposed IE with optimal DTR estimation, we extract derived patient characteristics and use tree-based reinforcement learning (T-RL) to estimate multistage optimal DTRs. IE significantly improved the estimation in counterfactual outcome models compared to using structured EHR data alone, which often include incomplete data, data entry errors, and other potentially unobserved risk factors. Moreover, including IE in optimal DTR estimation provides larger study cohorts and a broader pool of candidate tailoring variables. We demonstrate the performance of our proposed method via simulations and an application using clinical records to guide blood pressure control treatments among critically ill patients with severe acute hypertension. This joint estimation approach improves the accuracy of identifying the optimal treatment sequence by 14-24% compared to traditional inference without using IE, based on our simulations over various scenarios. In the blood pressure control application, we successfully extracted significant blood pressure predictors that are unobserved or partially missing from structured EHR.

Acute differences in blood lipids and inflammatory biomarkers following controlled exposures to cookstove air pollution in the STOVES study.

Household air pollution is a leading risk factor for morbidity and premature mortality. Numerous cookstoves have been developed to reduce household air pollution, but it is unclear whether such cookstoves meaningfully improve health. In a controlled exposure study with a crossover design, we assessed the effect of pollution emitted from multiple cookstoves on acute differences in blood lipids and inflammatory biomarkers. Participants (n = 48) were assigned to treatment sequences of exposure to air pollution emitted from five cookstoves and a filtered-air control. Blood lipids and inflammatory biomarkers were measured before and 0, 3, and 24 hours after treatments. Many of the measured outcomes had inconsistent results. However, compared to control, intercellular adhesion molecule-1 was higher 3 hours after all treatments, and C-reactive protein and serum amyloid-A were higher 24 hours after the highest treatment. Our results suggest that short-term exposure to cookstove air pollution can increase inflammatory biomarkers within 24 hours.

Personal-Level Protective Actions Against Particulate Matter Air Pollution Exposure: A Scientific Statement From the American Heart Association.

Since the publication of the last American Heart Association scientific statement on air pollution and cardiovascular disease in 2010, unequivocal evidence of the causal role of fine particulate matter air pollution (PM2.5, or particulate matter ≤2.5 µm in diameter) in cardiovascular disease has emerged. There is a compelling case to provide the public with practical personalized approaches to reduce the health effects of PM2.5. Such interventions would be applicable not only to individuals in heavily polluted countries, high-risk or susceptible individuals living in cleaner environments, and microenvironments with higher pollution exposures, but also to those traveling to locations with high levels of PM2.5. The overarching motivation for this document is to summarize the current evidence supporting personal-level strategies to prevent the adverse cardiovascular effects of PM2.5, guide the use of the most proven/viable approaches, obviate the use of ineffective measures, and avoid unwarranted interventions. The significance of this statement relates not only to the global importance of PM2.5, but also to its focus on the most tested interventions and viable approaches directed at particulate matter air pollution. The writing group sought to provide expert consensus opinions on personal-level measures recognizing the current uncertainty and limited evidence base for many interventions. In doing so, the writing group acknowledges that its intent is to assist other agencies charged with protecting public health, without minimizing the personal choice considerations of an individual who may decide to use these interventions in the face of ongoing air pollution exposure.

Guidance to Reduce the Cardiovascular Burden of Ambient Air Pollutants: A Policy Statement From the American Heart Association.

In 2010, the American Heart Association published a statement concluding that the existing scientific evidence was consistent with a causal relationship between exposure to fine particulate matter and cardiovascular morbidity and mortality, and that fine particulate matter exposure is a modifiable cardiovascular risk factor. Since the publication of that statement, evidence linking air pollution exposure to cardiovascular health has continued to accumulate and the biological processes underlying these effects have become better understood. This increasingly persuasive evidence necessitates policies to reduce harmful exposures and the need to act even as the scientific evidence base continues to evolve. Policy options to mitigate the adverse health impacts of air pollutants must include the reduction of emissions through action on air quality, vehicle emissions, and renewable portfolio standards, taking into account racial, ethnic, and economic inequality in air pollutant exposure. Policy interventions to improve air quality can also be in alignment with policies that benefit community and transportation infrastructure, sustainable food systems, reduction in climate forcing agents, and reduction in wildfires. The health care sector has a leadership role in adopting policies to contribute to improved environmental air quality as well. There is also potentially significant private sector leadership and industry innovation occurring in the absence of and in addition to public policy action, demonstrating the important role of public-private partnerships. In addition to supporting education and research in this area, the American Heart Association has an important leadership role to encourage and support public policies, private sector innovation, and public-private partnerships to reduce the adverse impact of air pollution on current and future cardiovascular health in the United States.

Extreme Levels of Air Pollution Associated With Changes in Biomarkers of Atherosclerotic Plaque Vulnerability and Thrombogenicity in Healthy Adults.

RATIONALE: The pathophysiologic mechanisms of air pollution-associated exacerbation of cardiovascular events remain incompletely understood. OBJECTIVE: To assess whether ambient air pollution can be a trigger of the vulnerable plaque and heightened thrombogenicity through systemic inflammatory pathways. METHODS AND RESULTS: In Beijing AIRCHD study (Air Pollution and Cardiovascular Dysfunctions in Healthy Adults Living in Beijing), 73 healthy adults (mean±SD, 23.3±5.4 years) were followed up in 2014 to 2016. We estimated associations between air pollutants and biomarkers relevant to atherosclerotic plaque vulnerability, thrombogenicity, and inflammation using linear mixed-effects models and elucidated the biological pathways involved using mediation analyses. Receiver operating characteristic analyses were conducted to assess the ability of each biomarker to predict ambient air pollution exposures. High average concentrations of particulate matter in diameter <2.5 µm (91.8±63.8 µg/m3) were observed during the study period. Significant increases in circulating biomarkers of plaque vulnerability, namely MMPs (matrix metalloproteinases; MMP-1, 2, 3, 7, 8, and 9), of 8.6% (95% CI, 0.1-17.8) to 141.4% (95% CI, 111.8-171.0) were associated with interquartile range increases in moving averages of particulate matter in diameter <2.5 µm, number concentrations of particles in sizes of 5 to 560 nm and black carbon, during the last 1 to 7 days before each participant's clinic visit. Higher air pollutant levels were also significantly associated with decreases in TIMP (tissue inhibitors of MMPs; TIMP-1 and 2), heightened thrombogenicity (shortened prothrombin time and increases in sCD40L [soluble CD40 ligand], sCD62P [soluble P-selectin], and fibrinogen/fibrin degradation products), and elevations in systemic inflammation (IL-1ß [interleukin-1ß], CRP [C-reactive protein], MIP-1α/ß [macrophage inflammatory protein-1α/ß], sRAGE [soluble receptor for advanced glycation end products], and IGFBP [insulin-like growth factor-binding protein]-1 and 3). Receiver operating characteristic curves showed that several biomarkers can serve as robust pollutant-specific predictors with high versus low black carbon exposure (area under the receiver operating characteristic curve of 0.974 [95% CI, 0.955-0.992] for MMP-8 and 0.962 [95% CI, 0.935-0.988] for sRAGE). Mediation analysis further showed that systemic inflammation can mediate ≤46% of the changes in MMPs and thrombogenicity associated with interquartile range increases in air pollutants. CONCLUSIONS: Our results suggest that air pollution may prompt cardiovascular events by triggering vulnerable plaque along with heightened thrombogenicity possibly through systemic inflammatory pathways.

Fewer patients receive recommendations for pharmacotherapy in primary prevention using the 2018 atherosclerotic cardiovascular disease risk estimator.

Shortly after the introduction of the 2013 original Pooled Cohort Equation (PCE), an overestimation of risk was suggested. As such, the updated 2018 PCE was developed to more accurately assess atherosclerotic cardiovascular disease (ASCVD) risk in the population. Hence, this study aims to compare drug prescribing recommendations in a large, real-world patient population, depending on which PCE is used to estimate 10-year ASCVD risk. This retrospective cohort study identified 20,843 patients aged between 40 and 75 years with no previous ASCVD. The 10-year ASCVD risk score was assessed by using both PCE. Patients were assigned to the four risk categories according to the 2018 ACC/AHA guideline. The percentage of patients qualifying for guideline-recommended primary prevention with statins and/or anti-hypertensives were compared between both PCE. Risk reclassification occurred in 26.7% of patients overall (n = 5571), of which 98.1% (n = 5466) were assigned to lower risk categories with the updated PCE. Non-diabetic (14.0%) patients no longer met the threshold for recommending statins as primary prevention with the updated PCE. Likewise, 13.8% of patients with stage I hypertension no longer met the threshold for recommending antihypertensive drugs with the updated PCE. In conclusion, risk reclassification occurred among 26.7% of patients overall, mostly due to lower risk categories assigned by the updated PCE. Up to 14.0% of patients no longer met the threshold for recommending statin therapy and/or antihypertensive drugs by using the updated PCE. These findings suggest that using the updated PCE could translate into fewer patients receiving pharmacotherapy for ASCVD primary prevention.

Ambient Air Pollution Is Associated With HDL (High-Density Lipoprotein) Dysfunction in Healthy Adults.

Objective- We aimed to assess whether exposure to higher levels of ambient air pollution impairs HDL (high-density lipoprotein) function and to elucidate the underlying biological mechanisms potentially involved. Approach and Results- In the Beijing AIRCHD study (Air Pollution and Cardiovascular Dysfunction in Healthy Adults), 73 healthy adults (23.3±5.4 years) were followed-up with 4 repeated study visits in 2014 to 2016. During each visit, ambient air pollution concentrations, HDL function metrics, and parameters of inflammation and oxidative stress were measured. Average daily concentrations of ambient particulate matter in diameter <2.5 µm were 62.9 µg/m3 (8.1-331.0 µg/m3). We observed significant decreases in HDL cholesterol efflux capacity of 2.3% (95% CI, -4.3 to -0.3) to 5.0% (95% CI, -7.6 to -2.4) associated with interquartile range increases in moving average concentrations of particulate matter in diameter <2.5 µm and traffic-related air pollutants (black carbon, nitrogen dioxide, and carbon monoxide) during the 1 to 7 days before each participant's clinic visit. Higher ambient air pollutant levels were also associated with significant reductions in circulating HDL cholesterol and apoA-I (apolipoprotein A-I), as well as elevations in HDL oxidation index, oxidized LDL (low-density lipoprotein), malondialdehyde, and high-sensitivity C-reactive protein. Conclusions- Higher ambient air pollution concentrations were associated with impairments in HDL functionality, potentially because of systemic inflammation and oxidative stress. These novel findings further our understanding of the mechanisms whereby air pollutants promote cardiometabolic disorders.

Acute differences in pulse wave velocity, augmentation index, and central pulse pressure following controlled exposures to cookstove air pollution in the Subclinical Tests of Volunteers Exposed to Smoke (SToVES) study.

Household air pollution emitted from solid-fuel cookstoves used for domestic cooking is a leading risk factor for morbidity and premature mortality globally. There have been attempts to design and distribute lower emission cookstoves, yet it is unclear if they meaningfully improve health. Using a crossover design, we assessed differences in central aortic hemodynamics and arterial stiffness following controlled exposures to air pollution emitted from five different cookstove technologies compared to a filtered air control. Forty-eight young, healthy participants were assigned to six 2-h controlled treatments of pollution from five different cookstoves and a filtered air control. Each treatment had a target concentration for fine particulate matter: filtered air control = 0 µg/m3, liquefied petroleum gas = 10 µg/m3, gasifier = 35 µg/m3, fan rocket = 100 µg/m3, rocket elbow = 250 µg/m3, three stone fire = 500 µg/m3. Pulse wave velocity (PWV), central augmentation index (AIx), and central pulse pressure (CPP) were measured before and at three time points after each treatment (0, 3, and 24 h). Linear mixed models were used to assess differences in the outcomes for each cookstove treatment compared to control. PWV and CPP were marginally higher 24 h after all cookstove treatments compared to control. For example, PWV was 0.15 m/s higher (95% confidence interval: -0.02, 0.31) and CPP was 0.6 mmHg higher (95% confidence interval: -0.8, 2.1) 24 h after the three stone fire treatment compared to control. The magnitude of the differences compared to control was similar across all cookstove treatments. PWV and CPP had no consistent trends at the other post-treatment time points (0 and 3 h). No consistent trends were observed for AIx at any post-treatment time point. Our findings suggest higher levels of PWV and CPP within 24 h after 2-h controlled treatments of pollution from five different cookstove technologies. The similar magnitude of the differences following each cookstove treatment compared to control may indicate that acute exposures from even the cleanest cookstove technologies can adversely impact these subclinical markers of cardiovascular health, although differences were small and may not be clinically meaningful.

Acute changes in lung function following controlled exposure to cookstove air pollution in the subclinical tests of volunteers exposed to smoke (STOVES) study.

Background: Exposure to household air pollution generated as a result of cooking and heating is a leading contributor to global disease. The effects of cookstove-generated air pollution on adult lung function, however, remain uncertain.Objectives: We investigated acute responses in lung function following controlled exposures to cookstove-generated air pollution.Methods: We recruited 48 healthy adult volunteers to undergo six two-hour treatments: a filtered-air control and emissions from five different stoves with fine particulate matter (PM2.5) targets from 10 to 500 µg/m3. Spirometry was conducted prior to exposure and immediately, and three and 24 h post-exposure. Mixed-effect models were used to estimate differences in post-exposure lung function for stove treatments versus control.Results: Immediately post-exposure, lung function was lower compared to the control for the three highest PM2.5-level stoves. The largest differences were for the fan rocket stove (target 250 µg/m3; forced vital capacity (FVC): -60 mL, 95% confidence interval (95% CI) -135, 15; forced expiratory volume (FEV1): -51 mL, 95% CI -117, 16; mid-expiratory flow (FEF25-75): -116 mL/s, 95% CI -239, 8). At 3 h post-exposure, lung function was lower compared to the control for all stove treatments; effects were of similar magnitude for all stoves. At 24 h post-exposure, results were consistent with a null association for FVC and FEV1; FEF25-75 was lower relative to the control for the gasifier, fan rocket, and three stone fire.Conclusions: Patterns suggesting short-term decreases in lung function follow from exposure to cookstove air pollution even for stove exposures with low PM2.5 levels.

Hypertension.

Recent guidelines on diagnosis and management of high blood pressure (BP) include substantial changes and several new concepts compared with previous guidelines. These are reviewed and their clinical implications are discussed in this article. The goal is to provide a practical reference to assist clinicians with up-to-date management of patients with high BP. Important issues include new diagnostic thresholds, out-of-office BP monitoring, intensified treatment goals, and a different approach to resistant hypertension. Finally, differences among guidelines, the persistent controversies that have led to them, and their implications for clinical practice are discussed.

Exposure to household air pollution from biomass cookstoves and self-reported symptoms among women in rural Honduras.

Household air pollution from combustion of solid fuels is an important risk factor for morbidity and mortality, causing an estimated 2.6 million premature deaths globally in 2016. Self-reported health symptoms are a meaningful measure of quality of life, however, few studies have evaluated symptoms and quantitative measures of exposure to household air pollution. We assessed the cross-sectional association of self-reported symptoms and exposures to household air pollution among women in rural Honduras using stove type (traditional [n = 76]; cleaner-burning Justa [n = 74]) and 24-hour average personal and kitchen fine particulate matter (PM2.5) concentrations. The odds of prevalent symptoms were higher among women using traditional stoves vs Justa stoves (e.g. headache: odds ratio = 2.23; 95% confidence interval = 1.13-4.39). Associations between symptoms and measured PM2.5 were generally consistent with the null. These results add to the evidence suggesting reduced exposures and better health-related quality of life among women using cleaner-burning biomass stoves.

Variation in PCSK9 and HMGCR and Risk of Cardiovascular Disease and Diabetes.

BACKGROUND: Pharmacologic inhibitors of proprotein convertase subtilisin-kexin type 9 (PCSK9) are being evaluated in clinical trials for the treatment of cardiovascular disease. The effect of lowering low-density lipoprotein (LDL) cholesterol levels by inhibiting PCSK9 on the risk of cardiovascular events or diabetes is unknown. METHODS: We used genetic scores consisting of independently inherited variants in the genes encoding PCSK9 and 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMGCR; the target of statins) as instruments to randomly assign 112,772 participants from 14 studies, with 14,120 cardiovascular events and 10,635 cases of diabetes, to groups according to the number of LDL cholesterol-lowering alleles that they had inherited. We compared the effects of lower LDL cholesterol levels that were mediated by variants in PCSK9, HMGCR, or both on the risk of cardiovascular events and the risk of diabetes. RESULTS: Variants in PCSK9 and HMGCR were associated with nearly identical protective effects on the risk of cardiovascular events per decrease of 10 mg per deciliter (0.26 mmol per liter) in the LDL cholesterol level: odds ratio for cardiovascular events, 0.81 (95% confidence interval [CI], 0.74 to 0.89) for PCSK9 and 0.81 (95% CI, 0.72 to 0.90) for HMGCR. Variants in these two genes were also associated with very similar effects on the risk of diabetes: odds ratio for each 10 mg per deciliter decrease in LDL cholesterol, 1.11 (95% CI, 1.04 to 1.19) for PCSK9 and 1.13 (95% CI, 1.06 to 1.20) for HMGCR. The increased risk of diabetes was limited to persons with impaired fasting glucose levels for both scores and was lower in magnitude than the protective effect against cardiovascular events. When present together, PCSK9 and HMGCR variants had additive effects on the risk of both cardiovascular events and diabetes. CONCLUSIONS: In this study, variants in PCSK9 had approximately the same effect as variants in HMGCR on the risk of cardiovascular events and diabetes per unit decrease in the LDL cholesterol level. The effects of these variants were independent and additive. (Funded by the Medical Research Council and the National Heart, Lung, and Blood Institute.).