Preventing premature cardiovascular mortality: the role of lifestyle interventions and pharmacotherapy—a narrative review

Abstract

Cardiovascular diseases (CVD), including coronary heart disease, cerebrovascular disease, and peripheral artery diseases, are the leading global cause of premature mortality in adults. Addressing CVD aligns with the United Nations Sustainable Development Goals aiming to reduce premature deaths by one-third by 2030 through lifestyle and pharmacological interventions. Major risk factors for CVD are categorized into lifestyle and genetic factors. Lifestyle factors such as elevated cholesterol, hypertension, high body mass index, smoking, poor dietary habits, and physical inactivity significantly increase CVD mortality. Conversely, genetic predisposition strongly influences individual risk, often amplified by unhealthy behaviors. Primary prevention strategies, including adherence to Dietary Approaches to Stop Hypertension (DASH) and Mediterranean Diet (MD), regular physical activity, and smoking cessation, have demonstrated effectiveness in reducing CVD incidence and mortality. Secondary prevention emphasizes pharmacological interventions, specifically aspirin and statin therapies, non-statin agents, antihypertensive, all of which significantly decrease recurrent cardiovascular events among high-risk individuals. Although cardiovascular screening practices remain debated, targeted screening informed by precision medicine approaches and artificial intelligence shows promise in stratifying risk effectively. This review synthesizes evidence on these preventive strategies, underscoring their integrated role in reducing premature CVD-related mortality, while recognizing the need for further implementation research to optimize preventive healthcare outcomes.

1 Introduction

Cardiovascular diseases (CVD) are, as the name indicates, a group of disorders that affect the heart and blood vessels and include coronary heart diseases, cerebrovascular diseases, peripheral artery diseases, pulmonary embolism, and deep vein thrombosis (1). Heart diseases are the leading cause of death in the U.S (2). and globally (3) and are estimated to contribute 28% of premature deaths (1). The United Nations Sustainable Development Goals (SDGs) aim to reduce premature deaths by one third by the year 2030, including premature deaths from CVD (4). Some of the interventions listed under this indicator for SDGs include lifestyle modifications as well as pharmacological interventions (4). The American Heart Association's guidelines on the prevention of CVD focuses on lifestyle modifications (diet, physical activity, smoking) as the foundation of prevention. They also provide guidance on selective use of aspirin in CVD prevention, with recent updates highlighting the role of specific medications in the management of diabetes mellitus, a risk factor of CVD (5, 6). This review focuses on the evidence for dietary modifications, physical activity, smoking cessation, and pharmacological interventions in reducing premature CVD mortality, while also incorporating novel perspectives such as the role of artificial intelligence (AI) in risk prediction and emerging pharmacological therapies within the continuum of prevention (Table 1). Table 2 summarizes the studies described and Figure 1 presents a diagram of the risk factors and prevention strategies discussed in this review.

Figure 1

2 Search strategy and selection criteria

The studies included were identified through searches in multiple databases, including PubMed, Medline, Embase, and Google Scholar, covering publications up to June 2025. Search terms combined cardiovascular disease, premature mortality, prevention, lifestyle interventions, and pharmacological therapies. Higher-level evidence was prioritized, giving preference to systematic reviews and meta-analyses, followed by randomized controlled trials and large prospective cohort studies. Only articles published in English and involving human populations were considered. Final inclusion of studies was determined by consensus among the authors.

3 Risk factors of CVD

Prior to discussing prevention strategies, it is important to consider the different risk factors of CVD which have been extensively studied in the last few decades. The most common risk factors can be lumped into two main categories: lifestyle factors and genetic factors (7).

3.1 Lifestyle factors

Over the years, lifestyle factors have been at the core of understanding CVD incidence and risk of premature mortality; they have demonstrated a major role in mediating such diseases and their progression.

Blood cholesterol levels can negatively affect vascular mortality. In fact, one systematic review (SR) and meta-analysis of 61 prospective studies discussed this association (8). Among 150,000 participants with available data on cholesterol levels, a decrease of 1 mmol/L of total cholesterol showed a 56% decrease, 34%, and 17% decrease in ischemic heart disease (IHD) mortality in the age groups of 40–49, 50–69, and 70–89 years, respectively (8). Additionally, blood pressure (BP) has long been studied as a factor of association with CVD mortality; a large meta-analysis of 61 prospective studies accounting for 112.7 million person-years showed that an increase of systolic BP (SBP) of 20 mmHg and an increase of diastolic BP (DBP) of 10 mmHg doubled the risk of IHD mortality in people aged 40–69 years (9). A similar meta-analysis was conducted on 123 randomized control trials (RCTs) which reported a relative risk (RR) of 0.87 (95% CI 0.84; 0.91) of all-cause mortality for every 10 mmHg reduction in SBP (10). Besides elevated cholesterol levels and BP, body mass index (BMI) was linked to a significant increase in all-cause mortality in a meta-analysis that included 239 prospective studies (11). This association is specifically evident for vascular mortality as reported by a collaborative analysis of 57 prospective cohort studies with 894,576 participants with a mean age of 46 (12). The findings of this study indicate that with each 5 kg/m² increase in BMI, there was an average increase in vascular mortality of 40% (95% CI 1.37;1.45) (12). Other factors have also been investigated in the pursuit of understanding CVD mortality, such as smoking and dietary habits. One prospective cohort study looking at the impact of smoking on CVD, with participants’ mean age of 44.4 and 43.6 years in men and women, respectively, found a significant association between being a current smoker and CVD incidence when compared to never-smokers with a reported hazard ratio (HR) of 2.10 (95% CI 1.65; 2.67) (13). Another SR of 18 SR and meta-analysis studies found that cannabis smoking had a higher damaging impact on the cardiovascular system when compared to tobacco (14). Smoking, in addition to other negative behaviors, contributes to what is referred to as a poor lifestyle in terms of health and wellness. Interestingly, over a 20 year follow-up period, a prospective analysis on 88,940 women examining primordial prevention of CVD revealed that 73% of coronary heart diseases (CHD) can be attributed to failure to adhere to a healthy lifestyle, defined as dietary habits that follow the Healthy Eating Index, not smoking, a normal BMI, engaging in physical activity, and limiting alcohol consumption (15).

3.2 Genetic factors

There is growing evidence in the literature that genetics plays a significant role in the development of CVD; and that this relationship is further strengthened when it interacts with lifestyle factors. A study that aimed to quantify the genetic risk for coronary artery disease (CAD) in three prospective studies, with a total of 33,296 participants, showed that those who are placed in the high genetic risk quintile contributed to 91% of the incidence of coronary events when compared with those in the low genetic risk quintile (HR 1.91 95% CI 1.75; 2.09) (16). Additionally, this study found that among those ranked in the high risk group, following a healthy lifestyle was associated with a 54% decrease in coronary events (95% CI 0.47;0.63) when compared to those following an unhealthy lifestyle (16).

The various risk factors mentioned can influence the incidence and mortality from CVD in the population, thus the importance of implementing effective prevention strategies at the different stages of disease progression. The subsequent sections will address primary and secondary prevention measures that can effectively manage the risk of premature mortality.

4 Primary prevention

Primary prevention aims to prevent the onset of CVD and can be achieved through changes in modifiable factors, which can be mainly categorized as maintaining a healthy diet, smoking cessation, and engaging in physical activity.

4.1 Healthy diet

A healthy diet is a key component of primary prevention of CVD. Two diets have been extensively studied in the literature for that purpose; the Dietary Approaches to Stop Hypertension (DASH) and the Mediterranean diet (MD).

The DASH diet emphasizes the consumption of fruits and vegetables, low-fat dairy, nuts, and legumes and was developed as a means to treat hypertension (HTN) (17). An umbrella review of SR and meta-analysis of prospective studies and RCTs investigated the association between a DASH diet and CVD incidence (17). The primary outcome indicated that the DASH diet was associated with a 20% decrease in the incidence of CVD. For example, the study highlighted that DASH dietary patterns significantly decreased SBP and DBP (17). This evidence is further supported by a SR and meta-analysis that included 15 cohort studies and a sample size of 1,020,642 that found a significant association between the DASH diet and a reduction in the risk of all-cause mortality (RR 0.78, 95% CI 0.75; 0.81) and of cardiovascular mortality (RR 0.78 95% CI 0.75; 0.81) (18).

On the other hand, the MD is based on consumption of fruits, vegetables, and legumes with reliance on olive oil as a source of fat, and poultry and fish as a source of protein (19). The adherence to this diet was found to be associated with a decrease in several CVD risk factors. A SR and meta-analysis of 7 prospective cohort studies reported that a strict adherence to the MD was significantly associated with a 9% decrease in the risk of overweight and obesity (95% CI 0.88; 0.94), which, as discussed above, have been tied to higher CVD mortality (20). Another SR and meta-analysis investigated the effect of a MD in RCTs; the findings showed that adhering to the MD decreased SBP by 1.4 mmHg and DBP by 1.5 mmHg on average, in addition to witnessing a 13% decrease in HTN when compared to low adherence (19). By decreasing risk factors, this was accompanied with a decrease in all-cause mortality and CVD mortality as was shown in yet another SR that looked at the results of 6 RCTs (21). It was reported that the MD was linked to 37% reduction in the risk of major cardiovascular events (MACE) (95% CI 0.53; 0.75) (21).

In addition to overall dietary patterns like DASH and Mediterranean diets, specific nutrient and food-group changes offer powerful levers for CVD prevention. The WHO recommends reducing adult sodium intake to <2 g/day (≈5 g/day salt), a target shown to lower blood pressure and reduce risks of stroke and coronary heart disease (22). Moreover, increasing dietary fiber intake (e.g., to ∼25–30 g/day) has been associated with reductions in CVD incidence and improved cardiometabolic risk factor profiles (23). Additionally, replacing portions of saturated fats with polyunsaturated fats yields substantial benefit. Recent studies report that reducing saturated fat intake and replacing it with polyunsaturated fat lowers cardiovascular disease risk (24, 25). Finally, ultra-processed foods and sugar-sweetened beverages are major policy targets: higher intake of added sugars and SSBs increases risk of CVD and stroke; similarly, ultra-processed foods have been linked with higher overall CVD and coronary heart disease risk in prospective cohorts (26, 27).

4.2 Smoking cessation

The 2021 ESC guidelines identify smoking as a major causal risk factor for CVD and strongly recommend complete cessation at all ages by emphasizing that all forms of tobacco exposure, including e-cigarettes, increase cardiovascular risk (28) and leads to a 10-year decrease in life expectancy, on average (29). When interpreting the relationship of CVD incidence with smoking in a study of 8,770 individuals with a mean age of 42.2, participants who quit smoking within 5 years compared to current smokers had a significantly lower risk with a reported HR negative difference of 4.51 (95% CI −5.90; −2.77) (30). A SR and meta-analysis of 13 studies of adults between 23 and 53 years reported a decrease of 5.2% m/s in arterial fitness, a risk factor of CVD (29). Another meta-analysis comprising of 25 cohorts in the CHANCES consortium, studied the relationship between smoking status and cardiovascular mortality in 503,905 participants aged 60 and above (31). The main finding of the study was the presence of a dose-response decrease in the risk of cardiovascular mortality with a longer cessation period; the HR for trend per 10-years was 0.85 (95% CI 0.82; 0.89) (31).

A large prospective cohort demonstrated that combustible cigarette smoking significantly increases cardiovascular risk across multiple subtypes, with dose–response gradients (e.g., HR = 2.45 for myocardial infarction; HR = 5.06 for peripheral artery disease) and risk reduction after cessation (32). A systematic review and meta-analysis of 8.5 million participants found that risk from e-cigarettes was primarily concentrated among dual users with combustible tobacco (OR = 2.56), while the specific analysis for exclusive e-cigarette use was not significantly associated with cardiovascular events (33). In parallel, a cross-sectional analysis of over 430,000 adults reported that daily cannabis use was linked to increased odds of myocardial infarction (OR = 1.25) and stroke (OR = 1.42), with stronger associations among never-tobacco users (MI OR = 1.49; stroke OR = 2.16), and clear dose–response by frequency of use (34). Collectively, these findings highlight that combustible tobacco remains the dominant causal driver of cardiovascular disease, while e-cigarette risk is largely mediated by dual use, and cannabis carries independent, dose-related associations even after adjustment for tobacco and e-cigarette use.

4.3 Physical activity

Regular physical activity has been well-examined in the literature as an important component of primary prevention of CVD and its risk factors. This was analyzed in a SR of 16 studies looking at the impact of training interventions on cardiovascular risk factors in healthy young and middle-adults; it reported a significant decrease in the participants’ BP and BMI. For instance, reductions in SBP and DBP ranged from 5 to 9 mmHg, and BMI reductions ranged from 1.0 to 1.5 kg/m², both considered clinically significant for reducing cardiovascular event risk (35). A SR and meta-analysis of 16 studies with a minimum of follow-up of two years focused on a more specific intervention, muscle-strengthening, and its impact on mortality from major non-communicable diseases (36). A dose-response decrease in CVD mortality was found with every increase in 10 min/week of muscle-strengthening exercises, with the lowest RR of 0.82 (95% CI 0.76; 0.90) at 60 min/week. When combined with aerobic activities, performing muscle-strengthening exercises was associated with a 46% decrease in the risk of CVD (36). Moreover, a SR and meta-analysis that included 29 prospective studies looking at the association between physical activity and heart failure, found that those who perform high rigorous exercises or high walking intensity compared to lower activity levels had a decrease of 34% and 27% in the risk of heart failure, respectively (37).

Current adult-guidelines recommend 150–300 min/week of moderate-intensity aerobic activity (or 75–150 min/week vigorous, or an equivalent mix) plus muscle-strengthening on ≥2 days/week (38). It further emphasizes that prolonged sedentary time is independently associated with higher risk of all-cause mortality, CVD mortality, type-2 diabetes and adverse cardiometabolic outcomes (38).

4.4 Obesity and weight management

Obesity is a major global driver of CVD and contributes to cardiovascular mortality independently of other risk factors (39). Excess adiposity increases the risk of metabolic disorders and accelerates the development of CAD and heart failure. A SR and meta-analysis that included five studies with 881,692 participants found that obesity was significantly associated with an increased risk of CAD with an OR of 1.20 (95% CI 1.02; 1.41) (40). Similarly, a meta-analysis of 38 studies reported that higher BMI in early life was positively associated with cardiovascular outcomes, with a HR of 1.18 (95% CI 1.07–1.30) for CVD, 1.13 (95% CI 1.07–1.19) for CHD, and 1.16 (95% CI 1.11–1.20) for heart failure (41).

Weight loss and weight control interventions have been shown to significantly improve cardiovascular outcomes. An umbrella review of SRs of 31 articles comprising 47 effect sizes found that weight management strategies were associated with reduced all-cause mortality and improved cardiovascular outcomes. Importantly, high- to moderate-quality evidence highlighted the benefits of GLP-1 receptor agonists (GLP-1 RAs) in individuals with type 2 diabetes or overweight, underscoring their role not only in glycemic control but also in weight management and cardiovascular prevention (42).

5 Secondary prevention

Secondary prevention is considered an essential part of managing the incidence and premature mortality from CVD. Several strategies can be employed for early detection of CVD in high-risk populations to prevent the progression of the disease.

5.1 Screening for CVD

Screening is an important tool of early detection of many burdensome diseases, however, its use to detect CVD to allow early intervention has been a subject of debate with several concerns arising regarding the effectiveness and benefits of this strategy. In fact, a SR of 16 RCTs and cohort studies described the benefits of CVD screening with resting and exercise electrocardiography; the findings highlight that by adding exercise electrocardiography to the risk factors of CVD, such as smoking and cholesterol, there was no significant decrease in cardiovascular events (43). Furthermore, the United States Preventive Service Taskforce recommends screening for blood lipids in men and women before the age of 35 and 45, respectively. The taskforce found inadequate evidence to support the need for CVD screening for men and women below these age thresholds, as well as in children and young adults up to 20 years old (44).

Polygenic risk scores have emerged as powerful tools for cardiovascular risk stratification, summarizing the cumulative effect of numerous genetic variants associated with CAD, and can identify high-risk individuals even before traditional risk factors manifest (45). In parallel, biomarkers such as high-sensitivity C-reactive protein, high-sensitivity troponins, and natriuretic peptides (e.g., NT-proBNP) have shown significant value in detecting subclinical disease and predicting adverse cardiovascular outcomes, potentially enabling earlier initiation of preventive interventions (46–48).

Furthermore, a recent scoping review highlighted how AI algorithms can analyze complex genetic and clinical data to identify individuals at elevated CVD risk, potentially enabling earlier interventions even in patients with subclinical disease (49). AI-based models have also shown strong performance in analyzing electronic health records and imaging data to stratify risk (50–52). However, most of these tools have been validated retrospectively, raising concerns about calibration, transportability across populations, and reliance on surrogate endpoints rather than hard cardiovascular outcomes (52). Bias in training datasets, underrepresentation of marginalized and LMIC populations, and limited regulatory guidance further constrain generalizability and adoption (53).

Ractical applications are emerging, such as AI-enabled ECG analysis and machine learning–enhanced calculators embedded in electronic health records, which may improve risk stratification and resource allocation (51, 52). Nonetheless, large-scale prospective trials are still needed to confirm whether these approaches reduce cardiovascular events. At present, precision medicine and AI should be viewed as complementary to, rather than replacements for, established prevention strategies.

These screening approaches fall under secondary prevention, as they aim to detect risk or subclinical disease in individuals already at elevated risk, rather than preventing the initial development of CVD.

5.2 Aspirin therapy

Aspirin is no longer routinely recommended for primary prevention, as guideline bodies highlight that in older adults the bleeding risk often outweighs cardiovascular benefit; use is individualized for select high-risk patients. In contrast, aspirin remains a cornerstone of secondary prevention following myocardial infarction, stroke, or established CVD (28).

Aspirin is an anti-platelet agent that works on reducing the formation of blood clots that can lead to ischemic stroke or heart failure in people with CVD. Many historical trials have tested for the efficacy of aspirin on preventing CVD, starting with the Cardiff I trial from 1974 conducted on 1,239 men who had a recent myocardial infarction episode; this study reported a relative reduction in mortality of 25% (54). A SR looked at the role of aspirin in secondary prevention of CVD; it included 6 primary prevention trials and 16 secondary prevention RCTs with a total of 112,000 low- and high-risk individuals with 660,000 person-years (55). The study reported a decrease of serious vascular events (6.7% vs. 8.2% per year, p-value < 0.0001) and a decrease in the number of strokes (4.3% vs. 5.3% per year, p-value < 0.0001) (55). These findings were further supported by an RCT exploring the effect of aspirin use in the prevention of first cardiovascular events in diabetes mellitus patients. The study included 15,480 participants; individuals were followed for an average of 7.4 years. The group receiving aspirin experienced a significantly lower incidence of serious vascular events compared to the placebo group (8.5% vs. 9.6%, respectively) with a rate ratio of 0.88 and a 95% CI: 0.79–0.97. However, aspirin use was associated with a higher risk of major bleeding episodes, occurring in 4.1% of participants, compared to 3.2% in the placebo group (rate ratio 1.29; 95% CI: 1.09–1.52). The majority of these bleeding complications were gastrointestinal or other extracranial hemorrhages (56). This trial illustrates the limited role of aspirin in primary prevention, in contrast to its well-established efficacy in secondary prevention.

5.3 Statin therapy

Statins are recommended for both primary prevention, among individuals with elevated LDL cholesterol or high estimated ASCVD risk, and for secondary prevention in patients with established CVD, where the benefits are particularly robust; however, their use is primarily focused on secondary prevention (28).

Statins are a class of drugs that work by lowering lipid-blood levels, specifically LDL. This can help prevent further damage to cardiovascular health. A meta-analysis of 28 RCTs examined major vascular events after statin intervention on 183,419 participants with mild kidney disease (57). The findings of this study indicate that following a statin-therapy decreases the risk of MACE by 21% (RR 0.79, 95% CI 0.77; 0.81) per mmol/L reduction in LDL cholesterol (57). These results are further supported by a more recent SR of 6 RCTs looking at the effect of statin on 53,107 participants with CVD or risk factors of CVD; the study reported a 30% reduction in major coronary events, and a 19% reduction in major cerebrovascular events (58).

5.4 Non-statin agents

For patients at very high cardiovascular risk who do not achieve LDL-cholesterol goals with statin therapy, or who are statin intolerant, non-statin agents provide additional benefit. Ezetimibe, when added to statins, has been shown to further reduce MACE, particularly in secondary prevention populations with established coronary disease. In the IMPROVE-IT trial, which enrolled 18,144 patients post-acute coronary syndrome, adding ezetimibe to simvastatin lowered median LDL levels to 53.7 mg/dL compared to 69.5 mg/dL with statin alone, and reduced the composite endpoint of cardiovascular death, MI, stroke, revascularization, or unstable angina (HR 0.936, 95% CI 0.89;0.99) (59).

More recently, PCSK9 inhibitors have demonstrated robust LDL-lowering effects and significant reductions in recurrent cardiovascular events in high-risk patients. The FOURIER trial randomized 27,564 patients with ASCVD and LDL ≥ 70 mg/dL on statins to evolocumab, a PCSK9 inhibitor, or placebo (60). Evolocumab reduced LDL cholesterol by 59% (to a median of 30 mg/dL) and lowered the risk of MACE (HR 0.85, 95% CI 0.79; 0.92) and the key secondary outcome of CV death, MI, or stroke (HR 0.80, 95% CI 0.73;0.88) over a median 2.2 years of follow-up (60). These therapies are primarily indicated in secondary prevention, especially in those with persistent LDL elevation despite maximally tolerated statins.

Ezetimibe is generally well tolerated, though mild gastrointestinal symptoms such as abdominal discomfort, diarrhea, or excessive gas may occur, along with some joint pain or respiratory tract symptoms in a small proportion of users (61). Meanwhile, PCSK9 inhibitors have favorable safety profiles overall; the most frequent adverse effects are injection-site reactions, sometimes accompanied by mild flu-like symptoms or general musculoskeletal discomfort. Serious adverse events are rare (62). Additional barriers include cost and mode of administration which may limit widespread use (63, 64).

5.5 SGLT2 inhibitors and GLP-1 receptor agonists

Sodium-glucose cotransporter-2 inhibitors (SGLT2i) and GLP-1 RAs are newer therapies with substantial evidence for cardiovascular prevention (65). The strongest evidence for these agents comes from secondary prevention trials in patients with type 2 diabetes and established ASCVD. SGLT2i lower glucose through glycosuria and produce modest reductions in body weight and blood pressure, while also exerting direct cardiovascular benefits (66, 67). GLP-1 RAs improve glycemic control and promote weight loss, with consistent evidence of cardiovascular protection, particularly in patients with type 2 diabetes and obesity (65, 68).

Large cardiovascular outcome trials and meta-analyses have shown that GLP-1 RAs significantly reduce MACE, cardiovascular mortality, stroke, and all-cause mortality across a wide range of patients with and without prior CVD (65, 68, 69). A pooled analysis of 13 CVD outcome trials, including more than 83,000 patients reported reductions in MACE (OR 0.86), cardiovascular mortality (OR 0.87), and stroke (fatal OR 0.74, nonfatal OR 0.87) with GLP-1 RA therapy (68).

SGLT2i have also shown robust and consistent cardioprotective effects. In a large real-world study of over 313,000 patients with type 2 diabetes, SGLT2i use was associated with a 34% lower risk of CVD compared with other second-line therapies (66). A meta-analysis of 13 RCTs involving 90,413 patients found that SGLT2i reduced the composite of first heart failure hospitalization or cardiovascular death by 23%–24% across populations with heart failure, diabetes, or chronic kidney disease, with parallel reductions in cardiovascular mortality (67). Evidence from routine care populations further suggests that SGLT2i may provide greater benefit in patients with a history of heart failure, while GLP-1 RAs may be more effective in reducing atherosclerotic events in those without prior CVD (69).

5.6 Antihypertensives

Pharmacological BP reduction remains a cornerstone of both primary and secondary prevention of CVD. A large systematic review and meta-analysis of randomized controlled trials demonstrated that for every 10-mmHg reduction in systolic BP, the relative risk of MACE decreased by about 20%, with consistent benefit across age groups and baseline risk profiles (10). The 2024 ESC guidelines on the management of HTN recommend initiating drug treatment in individuals with established cardiovascular disease if blood pressure is ≥130/80 mmHg despite lifestyle measures, with a treatment target of 120–129/70–79 mmHg if tolerated, while generally avoiding reductions below 120/70 mmHg (70). First-line agents include thiazide-like diuretics, ACE inhibitors or ARBs, and calcium channel blockers, with choice tailored to comorbidities and tolerability (28, 71). These therapies reduce both first cardiovascular events and recurrent events in patients with prior CVD, underscoring their dual role in primary and secondary prevention.

5.7 Polypill

The concept of combining multiple cardiovascular medications into a single pill has been tested in large-scale randomized trials. The TIPS-3 trial evaluated a polypill containing simvastatin (40 mg), atenolol (100 mg), hydrochlorothiazide (25 mg), and ramipril (10 mg), with or without low-dose aspirin (75 mg), in 5,713 participants followed for a mean of 4.6 years (72). Compared with placebo, the polypill lowered LDL cholesterol by approximately 19 mg/dL and systolic blood pressure by about 5.8 mmHg (72). The primary outcome of MACE occurred in 4.4% of participants in the polypill group vs. 5.5% in the placebo group (HR 0.79; 95% CI 0.63–1.00) (72). When combined with aspirin, the benefit was enhanced (HR 0.69; 95% CI 0.50–0.97) (72). These findings highlight the synergistic effect of combining lipid-lowering, antihypertensive, and antiplatelet therapy into a single formulation, improving adherence while providing clinically meaningful reductions in cardiovascular risk.

Further management strategies such as cardiac rehabilitation, surgical interventions, and revascularization procedures fall under tertiary prevention. These approaches, while important for reducing morbidity and mortality in advanced diseases, are beyond the scope of this review.

6 Discussion

A comprehensive overview of the different risk factors associated with CVD was presented along with potential interventions that could limit premature mortality caused by these diseases. The focus on premature CVD mortality, together with the integration of lifestyle and pharmacological strategies across the full prevention continuum, underscores the relevance of this synthesis. Framing prevention within the SDG 2030 target emphasizes its public health importance, while emerging tools, such as AI-enabled risk prediction and newer cardioprotective medications, illustrate how approaches are evolving beyond traditional strategies.

As with any disease, preventive efforts are multi-leveled. Primary prevention strategies for CVD emphasized adhering to a healthy diet (notably the DASH diet and MD), smoking cessation, and engaging in physical activity, all of which significantly decrease the risk of mortality. At a higher level, secondary prevention strategies for individuals with high-risk CVD highlight the use of different pharmacological therapies in reducing overall risk of CVD mortality. It is important to recognize that all the strategies discussed throughout the review are usually intertwined, and no clear separation is evident. In practice, interventions often offer a synergistic effect in prevention and treatment of CVD, and it is recommended that, even with pharmacological or surgical interventions, patients are still advised and encouraged on the importance of a healthy lifestyle.

AI and machine learning models that integrate clinical, imaging, and genetic data show promise for improving early identification of high-risk individuals and tailoring the intensity of lifestyle counseling and pharmacotherapy. However, most models remain methodologically limited, with challenges in validation, calibration, and generalizability. At present, these tools are best viewed as complementary to guideline-based prevention strategies rather than replacements.

While this review highlights the established role of aspirin and statins in secondary prevention, it also discusses the growing evidence for SGLT2i and GLP-1 RAs and other medications as novel therapies with demonstrated cardiovascular benefits. Their inclusion reflects how prevention strategies are expanding beyond traditional agents, offering additional opportunities to reduce premature CVD mortality when combined with lifestyle interventions.

Despite strong evidence for both lifestyle and pharmacological interventions, translation into clinical practice remains inconsistent. Common challenges include low adherence to lifestyle changes, often influenced by behavioral, cultural, and environmental factors, as well as socioeconomic barriers that restrict access to healthy foods, safe spaces for physical activity, and regular medical care. At the health-system level, resource constraints and persistent disparities between high-income and low- and middle-income countries further hinder equitable implementation of preventive strategies (73–75). Moving forward, efforts may focus on integrated care models that combine patient education, community-based interventions, and access to essential medicines. Additionally, advances in precision medicine and novel pharmacotherapies such as PSCK9 inhibitors provide additional tools but also raise issues of affordability and accessibility.

Emerging opportunities also include digital health interventions, such as telemedicine and mobile-based coaching that may help sustain lifestyle changes, specifically regarding CVD outcomes (76, 77). Those remain understudied across diverse populations and settings, even though studies have highlighted their cost-effectiveness (78). At the policy level, measures like salt reformulation have shown cost-effective cardiovascular benefits, yet their adoption is inconsistent worldwide (79). Importantly, the burden of premature CVD and the feasibility of prevention strategies in low- and middle-income countries remain underrepresented in the literature, highlighting a need for greater equity-focused research (80–82).

This review has some limitations; even though a comprehensive report has been detailed, it is not a SR and hence may have missed some major studies on potential interventions for premature CVD mortality. Moreover, the scope of this review presents a broad overview of possible primary and secondary prevention strategies and sheds light on several interventions that may be useful in preventing premature mortality with little insight on implementation strategies.

7 Conclusion

Premature CVD remains a global public health challenge, but a substantial proportion of this burden is preventable. Evidence consistently supports the benefits of lifestyle modification, particularly healthy dietary patterns, smoking cessation, and physical activity, alongside pharmacologic therapies such as statins, antihypertensives, and novel agents like SGLT2i and GLP-1 RAs. Integrating these interventions across the continuum of primary, secondary, and tertiary prevention can substantially reduce early mortality.

Moving forward, greater attention is needed to equity and implementation: ensuring that proven strategies reach diverse populations, especially in low- and middle-income countries, and addressing barriers related to cost, access, and adherence. Emerging opportunities, including artificial intelligence for risk prediction, digital health tools to support behavior change, and population-level policies (e.g., salt reformulation, trans-fat bans), highlight how prevention is evolving. Future research should focus not only on refining risk stratification and expanding therapeutic options, but also on translating evidence into practice through integrated, scalable, and equitable approaches.

References

• 1.

  WHO. Cardiovascular Diseases (CVDs). World Health Organization (2021). Available online at:https://www.who.int/news-room/fact-sheets/detail/cardiovascular-diseases-(cvds) (Accessed February 15, 2024).

  • Google Scholar
  • View reference in article

• 2.

  CDC. Leading Causes of Death. Center for Disease Control (2023). Available online at:https://www.cdc.gov/nchs/fastats/leading-causes-of-death.htm(Accessed February 15, 2024).

  • Google Scholar
  • View reference in article

• 3.

  WHO. The Top 10 Causes of Death. World Health Organization (2020). Available online at:https://www.who.int/news-room/fact-sheets/detail/the-top-10-causes-of-death(Accessed February 15, 2024).

  • Google Scholar
  • View reference in article

• 4.

  FriedenTRCobbLKLeidigRCMehtaSKassD. Reducing premature mortality from cardiovascular and other non-communicable diseases by one third: achieving sustainable development goal indicator 3.4. 1. Glob Heart. (2020) 15(1). 10.5334/gh.531

  • CrossRef
  • Google Scholar
  • View reference in article

• 5.

  BittnerV. The new 2019 AHA/ACC guideline on the primary prevention of cardiovascular disease. Circulation. (2020) 142(25):2402–4. 10.1161/CIRCULATIONAHA.119.040625

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 6.

  HeidenreichPABozkurtBAguilarDAllenLAByunJJColvinMMet al2022 AHA/ACC/HFSA guideline for the management of heart failure: a report of the American College of Cardiology/American Heart Association joint committee on clinical practice guidelines. Circulation. (2022) 145(18):e895–e1032. 10.1161/CIR.0000000000001063

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 7.

  SaidMAvan de VegteYJZafarMMvan der EndeMYRajaGKVerweijNet alContributions of interactions between lifestyle and genetics on coronary artery disease risk. Curr Cardiol Rep. (2019) 21(9):89. 10.1007/s11886-019-1177-x

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 8.

  KromhoutD. Blood cholesterol and vascular mortality by age, sex, and blood pressure: a meta-analysis of individual data from 61 prospective studies with 55000 vascular deaths (prospective studies collaboration). Lancet. (2007) 370(9602):1829–39. 10.1016/S0140-6736(07)61778-4

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 9.

  LewingtonSClarkeRQizilbashNPetoRCollinsRProspective StudiesC. Age-specific relevance of usual blood pressure to vascular mortality: a meta-analysis of individual data for one million adults in 61 prospective studies. Lancet. (2002) 360(9349):1903–13. 10.1016/S0140-6736(02)11911-8

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 10.

  EttehadDMEmdinCAHKiranAPAndersonSGPCallenderTMBCEmbersonJPet alBlood pressure lowering for prevention of cardiovascular disease and death: a systematic review and meta-analysis. Lancet. (2016) 387(10022):957–67. 10.1016/S0140-6736(15)01225-8

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 11.

  Di AngelantonioEBhupathirajuSNWormserDGaoPKaptogeSde GonzalezABet alBody-mass index and all-cause mortality: individual-participant-data meta-analysis of 239 prospective studies in four continents. Lancet. (2016) 388(10046):776–86. 10.1016/S0140-6736(16)30175-1

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 12.

  WhitlockGLewingtonSSherlikerPClarkeRKromhoutDProspective StudiesCet alBody-mass index and cause-specific mortality in 900 000 adults: collaborative analyses of 57 prospective studies. Lancet. (2009) 373(9669):1083–96. 10.1016/S0140-6736(09)60318-4

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 13.

  BolijnRMuilwijkMNicolaouMGalenkampHStronksKTanHLet alThe contribution of smoking to differences in cardiovascular disease incidence between men and women across six ethnic groups in Amsterdam, The Netherlands: the HELIUS study. Prev Med Rep. (2023) 31:102105. 10.1016/j.pmedr.2022.102105

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 14.

  Abu JadAARavanavenaARavindraCIgweonu-NwakileEOAliSPaulSet alAdverse effects of cannabinoids and tobacco consumption on the cardiovascular system: a systematic review. Cureus. (2022) 14(9):e29208. 10.7759/cureus.29208

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 15.

  ChomistekAKChiuveSEEliassenAHMukamalKJWillettWCRimmEB. Healthy lifestyle in the primordial prevention of cardiovascular disease among young women. J Am Coll Cardiol. (2015) 65(1):43–51. 10.1016/j.jacc.2014.10.024

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 16.

  KheraAVEmdin ConnorADrakeINatarajanPBickAGCookNRet alGenetic risk, adherence to a healthy lifestyle, and coronary disease. N Engl J Med. (2016) 375(24):2349–58. 10.1056/NEJMoa1605086

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 17.

  ChiavaroliLViguilioukENishiSKBlanco MejiaSRahelićDKahleováHet alDASH dietary pattern and cardiometabolic outcomes: an umbrella review of systematic reviews and meta-analyses. Nutrients. (2019) 11(2):338. 10.3390/nu11020338

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 18.

  SchwingshacklLMHoffmannGP. Diet quality as assessed by the healthy eating index, the alternate healthy eating Index, the dietary approaches to stop hypertension score, and health outcomes: a systematic review and meta-analysis of cohort studies. J Acad Nutr Diet. (2015) 115(5):780–800.e5. 10.1016/j.jand.2014.12.009

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 19.

  CowellORMistryNDeightonKMatuJGriffithsAMinihaneAMet alEffects of a Mediterranean diet on blood pressure: a systematic review and meta-analysis of randomized controlled trials and observational studies. J Hypertens. (2021) 39(4):729–39. 10.1097/HJH.0000000000002667

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 20.

  LotfiKSaneeiPHajhashemyZEsmaillzadehA. Adherence to the Mediterranean diet, five-year weight change, and risk of overweight and obesity: a systematic review and dose–response meta-analysis of prospective cohort studies. Adv Nutr. (2021) 13(1):152–66. 10.1093/advances/nmab092

  • CrossRef
  • Google Scholar
  • View reference in article

• 21.

  LiyanageTNinomiyaTWangANealBJunMWongMGet alEffects of the Mediterranean diet on cardiovascular outcomes—a systematic review and meta-analysis. PLoS One. (2016) 11(8):e0159252. 10.1371/journal.pone.0159252

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 22.

  Organization WH. Sodium Reduction. World Health Organization (2025). Available online at:https://www.who.int/news-room/fact-sheets/detail/sodium-reduction#:∼:text=For%20adults%2C%20WHO%20recommends%20less,based%20on%20their%20energy%20requirements(Accessed October 27, 2025).

  • Google Scholar
  • View reference in article

• 23.

  YafeiGMeilingLYueqinH. Association of dietary fiber intake with all-cause and cardiovascular mortality in U.S. adults with metabolic syndrome: NHANES 1999–2018. Front Nutr. (2025) 12. 10.3389/fnut.2025.1659000

  • CrossRef
  • Google Scholar
  • View reference in article

• 24.

  MozaffarianDMichaRWallaceS. Effects on coronary heart disease of increasing polyunsaturated fat in place of saturated fat: a systematic review and meta-analysis of randomized controlled trials. PLoS Med. (2010) 7(3):e1000252. 10.1371/journal.pmed.1000252

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 25.

  Makarewicz-WujecMDworakowskaAKozłowska-WojciechowskaM. Replacement of saturated and trans-fatty acids in the diet v. CVD risk in the light of the most recent studies. Public Health Nutr. (2018) 21(12):2291–300. 10.1017/S1368980018000782

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 26.

  MendozaKSmith-WarnerSARossatoSLKhandpurNMansonJEQiLet alUltra-processed foods and cardiovascular disease: analysis of three large US prospective cohorts and a systematic review and meta-analysis of prospective cohort studies. Lancet Reg Health Am. (2024) 37:100859. 10.1016/j.lana.2024.100859

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 27.

  WangYZhaoRWangBZhaoCZhuBTianX. The dose-response associations of sugar-sweetened beverage intake with the risk of stroke, depression, cancer, and cause-specific mortality: a systematic review and meta-analysis of prospective studies. Nutrients. (2022) 14(4). 10.3390/nu14040777

  • CrossRef
  • Google Scholar
  • View reference in article

• 28.

  VisserenFLJMachFSmuldersYMCarballoDKoskinasKCBäckMet al2021 ESC guidelines on cardiovascular disease prevention in clinical practice: developed by the task force for cardiovascular disease prevention in clinical practice with representatives of the European Society of Cardiology and 12 medical societies with the special contribution of the European association of preventive cardiology (EAPC). Eur Heart J. (2021) 42(34):3227–337. 10.1093/eurheartj/ehab484

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 29.

  Saz-LaraAMartínez-VizcaínoVSequí-DomínguezIÁlvarez-BuenoCNotario-PachecoBCavero-RedondoI. The effect of smoking and smoking cessation on arterial stiffness: a systematic review and meta-analysis. Eur J Cardiovasc Nurs. (2021) 21(4):297–306. 10.1093/eurjcn/zvab102

  • CrossRef
  • Google Scholar
  • View reference in article

• 30.

  DuncanMSFreibergMSGreevyRAKunduSVasanRSTindleHA. Association of smoking cessation with subsequent risk of cardiovascular disease. JAMA. (2019) 322(7):642–50. 10.1001/jama.2019.10298

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 31.

  MonsUMüezzinlerAGellertCSchöttkerBAbnetCCBobakMet alImpact of smoking and smoking cessation on cardiovascular events and mortality among older adults: meta-analysis of individual participant data from prospective cohort studies of the CHANCES consortium. Br Med J. (2015) 350:h1551. 10.1136/bmj.h1551

  • CrossRef
  • Google Scholar
  • View reference in article

• 32.

  BanksEJoshyGKordaRJStavreskiBSogaKEggerSet alTobacco smoking and risk of 36 cardiovascular disease subtypes: fatal and non-fatal outcomes in a large prospective Australian study. BMC Med. (2019) 17(1):128. 10.1186/s12916-019-1351-4

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 33.

  ChenCHuoCMattey-MoraPPBidulescuAParkerMA. Assessing the association between e-cigarette use and cardiovascular disease: a meta-analysis of exclusive and dual use with combustible cigarettes. Addict Behav. (2024) 157:108086. 10.1016/j.addbeh.2024.108086

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 34.

  JeffersAMGlantzSByersALKeyhaniS. Association of cannabis use with cardiovascular outcomes among US adults. J Am Heart Assoc. (2024) 13(5):e030178. 10.1161/JAHA.123.030178

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 35.

  GrässlerBThielmannBBöckelmannIHökelmannA. Effects of different training interventions on heart rate variability and cardiovascular health and risk factors in young and middle-aged adults: a systematic review. Front Physiol. (2021) 12. 10.3389/fphys.2021.657274

  • CrossRef
  • Google Scholar
  • View reference in article

• 36.

  MommaHKawakamiRHondaTSawadaSS. Muscle-strengthening activities are associated with lower risk and mortality in major non-communicable diseases: a systematic review and meta-analysis of cohort studies. Br J Sports Med. (2022) 56(13):755–63. 10.1136/bjsports-2021-105061

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 37.

  AuneDSchlesingerSLeitzmannMFTonstadSNoratTRiboliEet alPhysical activity and the risk of heart failure: a systematic review and dose–response meta-analysis of prospective studies. Eur J Epidemiol. (2021) 36(4):367–81. 10.1007/s10654-020-00693-6

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 38.

  Organization WH. WHO Guidelines on Physical Activity and Sedentary Behaviour: At a Glance. World Health Organization (2020).

  • Google Scholar
  • View reference in article

• 39.

  Powell-WileyTMPoirierPBurkeLEDesprésJ-PGordon-LarsenPLavieCJet alObesity and cardiovascular disease: a scientific statement from the American Heart Association. Circulation. (2021) 143(21):e984–e1010. 10.1161/CIR.0000000000000973

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 40.

  RiazHKhanMSSiddiqiTJUsmanMSShahNGoyalAet alAssociation between obesity and cardiovascular outcomes: a systematic review and meta-analysis of Mendelian randomization studies. JAMA Netw Open. (2018) 1(7):e183788. 10.1001/jamanetworkopen.2018.3788

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 41.

  QiuZLiuZZhangNFanFWengHZhangLet alAssociation between early age body mass index and the risk of adulthood cardiovascular diseases: a systematic review and meta-analysis. Int J Obes. (2025) 49(5):766–75. 10.1038/s41366-024-01710-4

  • CrossRef
  • Google Scholar
  • View reference in article

• 42.

  ChenXZhangXXiangXFangXWeiFFengS. Effects of weight control interventions on cardiovascular outcomes: an umbrella review of systematic reviews and meta-analyses. Int J Obes. (2025) 49:1911–20. 10.1038/s41366-025-01860-z

  • CrossRef
  • Google Scholar
  • View reference in article

• 43.

  JonasDEReddySMiddletonJCBarclayCGreenJBakerCet alScreening for cardiovascular disease risk with resting or exercise electrocardiography: evidence report and systematic review for the US preventive services task force. JAMA. (2018) 319(22):2315–28. 10.1001/jama.2018.6897

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 44.

  BloetzerCBovetPSurisJCSimeoniUParadisGChioleroA. Screening for cardiovascular disease risk factors beginning in childhood. Public Health Rev. (2015) 36:9. 10.1186/s40985-015-0011-2

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 45.

  RobertsR. Genetic risk score enables a vaccine for early primary prevention of CAD. Methodist Debakey Cardiovasc J. (2025) 21(4):101–12. 10.14797/mdcvj.1617

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 46.

  NikorowitschJOjedaFLacknerKJSchnabelRBBlankenbergSZellerTet alHead-to-head comparison of the incremental predictive value of the three established risk markers, hs-troponin I, C-reactive protein, and NT-proBNP, in coronary artery disease. Biomolecules. (2020) 10(3). 10.3390/biom10030394

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 47.

  EverettBMZellerTGlynnRJRidkerPMBlankenbergS. High-sensitivity cardiac troponin I and B-type natriuretic peptide as predictors of vascular events in primary prevention. Circulation. (2015) 131(21):1851–60. 10.1161/CIRCULATIONAHA.114.014522

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 48.

  LeeHSLeeJ-H. Early elevation of high-sensitivity C-reactive protein as a predictor for cardiovascular disease incidence and all-cause mortality: a landmark analysis. Sci Rep. (2023) 13(1):14118. 10.1038/s41598-023-41081-w

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 49.

  SinghMKumarAKhannaNNLairdJRNicolaidesAFaaGet alArtificial intelligence for cardiovascular disease risk assessment in personalised framework: a scoping review. eClinicalMedicine. (2024) 73. 10.1016/j.eclinm.2024.102660

  • CrossRef
  • Google Scholar
  • View reference in article

• 50.

  CaiYCaiY-QTangL-YWangY-HGongMJingT-Cet alArtificial intelligence in the risk prediction models of cardiovascular disease and development of an independent validation screening tool: a systematic review. BMC Med. (2024) 22(1):56. 10.1186/s12916-024-03273-7

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 51.

  KheraROikonomou EvangelosKNadkarni GirishNMorley JessicaRWiensJButte AtulJet alTransforming cardiovascular care with artificial intelligence: from discovery to practice. JACC. (2024) 84(1):97–114. 10.1016/j.jacc.2024.05.003

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 52.

  LiuTKrentzALuLCurcinV. Machine learning based prediction models for cardiovascular disease risk using electronic health records data: systematic review and meta-analysis. Eur Heart J Digit Health. (2024) 6(1):7–22. 10.1093/ehjdh/ztae080

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 53.

  MihanAPandeyAVan SpallHGC. Artificial intelligence bias in the prediction and detection of cardiovascular disease. npj Cardiovasc Health. (2024) 1(1):31. 10.1038/s44325-024-00031-9

  • CrossRef
  • Google Scholar
  • View reference in article

• 54.

  ElwoodPCCochraneALBurrMLSweetnamPMWilliamsGWelsbyEet alA randomized controlled trial of acetyl salicylic acid in the secondary prevention of mortality from myocardial infarction. Br Med J. (1974) 1(5905):436–40. 10.1136/bmj.1.5905.436

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 55.

  BaigentCBlackwellLCollinsREmbersonJGodwinJPetoRet alAspirin in the primary and secondary prevention of vascular disease: collaborative meta-analysis of individual participant data from randomised trials. Lancet. (2009) 373(9678):1849–60. 10.1016/S0140-6736(09)60503-1

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 56.

  GroupTASC. Effects of aspirin for primary prevention in persons with diabetes mellitus. N Engl J Med. (2018) 379(16):1529–39. 10.1056/NEJMoa1804988

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 57.

  HerringtonWGEmbersonJMihaylovaBBlackwellLReithCSolbuMDet alImpact of renal function on the effects of LDL cholesterol lowering with statin-based regimens: a meta-analysis of individual participant data from 28 randomised trials. Lancet Diabetes Endocrinol. (2016) 4(10):829–39. 10.1016/S2213-8587(16)30156-5

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 58.

  SultanSKhanSUHoldenKHendiAASaeedSAbbasAet alReducing the threshold of primary prevention of cardiovascular disease to 10% over 10 years: the implications of altered intensity “statin” therapy guidance. Curr Probl Cardiol. (2023) 48(2):101486. -. 10.1016/j.cpcardiol.2022.101486

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 59.

  CannonCPBlazingMAGiuglianoRPMcCaggAWhiteJATherouxPet alEzetimibe added to statin therapy after acute coronary syndromes. N Engl J Med. (2015) 372(25):2387–97. 10.1056/NEJMoa1410489

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 60.

  SabatineMSGiuglianoRPKeechACHonarpourNWiviottSDMurphySAet alEvolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. (2017) 376(18):1713–22. 10.1056/NEJMoa1615664

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 61.

  NHS. Side Effects of Ezetimibe. National Health Services (2023). Available online at:https://www.nhs.uk/medicines/ezetimibe/side-effects-of-ezetimibe/(Accessed September 3, 2024).

  • Google Scholar
  • View reference in article

• 62.

  GürgözeMTMuller-HansmaAHGSchreuderMMGalema-BoersAMHBoersmaERoeters van LennepJE. Adverse events associated with PCSK9 inhibitors: a real-world experience. Clin Pharmacol Ther. (2019) 105(2):496–504. 10.1002/cpt.1193

  • CrossRef
  • Google Scholar
  • View reference in article

• 63.

  FatimaEQureshiZKhanzadaMSafiARehmanOUAltafF. The efficacy of tafolecimab in Chinese patients with hypercholesterolemia: a systematic review and meta-analysis. Am J Cardiovasc Drugs. (2024) 24(5):641–50. 10.1007/s40256-024-00654-4

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 64.

  WichaiyoSSupharattanasitthiW. Bempedoic acid: a new non-statin drug for the treatment of dyslipidemia. Clin Drug Investig. (2021) 41(10):843–51. 10.1007/s40261-021-01075-w

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 65.

  MarxNHusainMLehrkeMVermaSSattarN. GLP-1 receptor agonists for the reduction of atherosclerotic cardiovascular risk in patients with type 2 diabetes. Circulation. (2022) 146(24):1882–94. 10.1161/CIRCULATIONAHA.122.059595

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 66.

  WangWChenLYWalkerRFChowLSNorbyFLAlonsoAet alSGLT2 inhibitors are associated with reduced cardiovascular disease in patients with type 2 diabetes: an analysis of real-world data. Mayo Clin Proc. (2023) 98(7):985–96. 10.1016/j.mayocp.2023.01.023

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 67.

  Usman MuhammadSSiddiqi TariqJAnker StefanDBakris GeorgeLBhatt DeepakLFilippatosGet alEffect of SGLT2 inhibitors on cardiovascular outcomes across various patient populations. JACC. (2023) 81(25):2377–87. 10.1016/j.jacc.2023.04.034

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 68.

  RiveraFBCruzLLAMagalongJVRuyerasJMMJApareceJPBantayanNRBet alCardiovascular and renal outcomes of glucagon-like peptide 1 receptor agonists among patients with and without type 2 diabetes mellitus: a meta-analysis of randomized placebo-controlled trials. Am J Prev Cardiol. (2024) 18:100679. 10.1016/j.ajpc.2024.100679

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 69.

  HtooPTBuseJCavenderMWangTPateVEdwardsJet alCardiovascular effectiveness of sodium-glucose cotransporter 2 inhibitors and glucagon-like peptide-1 receptor agonists in older patients in routine clinical care with or without history of atherosclerotic cardiovascular diseases or heart failure. J Am Heart Assoc. (2022) 11(4):e022376. 10.1161/JAHA.121.022376

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 70.

  McEvoyJWMcCarthyCPBrunoRMBrouwersSCanavanMDCeconiCet al2024 ESC guidelines for the management of elevated blood pressure and hypertension. Eur Heart J. (2024) 45(38):3912–4018. 10.1093/eurheartj/ehae178

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 71.

  WheltonPKCareyRMAronowWSCaseyDECollinsKJDennison HimmelfarbCet al2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ASPC/NMA/PCNA guideline for the prevention, detection, evaluation, and management of high blood pressure in adults: executive summary: a report of the American College of Cardiology/American Heart Association task force on clinical practice guidelines. Circulation. (2018) 138(17):e426–e83. 10.1161/CIR.0000000000000597

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 72.

  YusufSJosephPDansAGaoPTeoKXavierDet alPolypill with or without aspirin in persons without cardiovascular disease. N Engl J Med. (2021) 384(3):216–28. 10.1056/NEJMoa2028220

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 73.

  GuptaRYusufS. Challenges in management and prevention of ischemic heart disease in low socioeconomic status people in LLMICs. BMC Med. (2019) 17(1):209. 10.1186/s12916-019-1454-y

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 74.

  Cohen RodriguesTRde BuisonjéDRKeesmanMReijndersTvan der GeerJEJanssenVRet alFacilitators of and barriers to lifestyle support and eHealth solutions: interview study among health care professionals working in cardiac care. J Med Internet Res. (2021) 23(10):e25646. 10.2196/25646

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 75.

  NiakoueiATehraniMFultonL. Health disparities and cardiovascular disease. Healthcare (Basel). (2020) 8(1). 10.3390/healthcare8010065

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 76.

  WidmerRJCollinsNMCollinsCSWestCPLermanLOLermanA. Digital health interventions for the prevention of cardiovascular disease: a systematic review and meta-analysis. Mayo Clin Proc. (2015) 90(4):469–80. 10.1016/j.mayocp.2014.12.026

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 77.

  MuellerSDingesSMTGassFFegers-WustrowITreitschkeJvon KornPet alTelemedicine-supported lifestyle intervention for glycemic control in patients with CHD and T2DM: multicenter, randomized controlled trial. Nat Med. (2025) 31(4):1203–13. 10.1038/s41591-025-03498-w

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 78.

  JiangXMingWKYouJH. The cost-effectiveness of digital health interventions on the management of cardiovascular diseases: systematic review. J Med Internet Res. (2019) 21(6):e13166. 10.2196/13166

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 79.

  IkedaNYamashitaHHattoriJKatoHNishiN. Economic effects of dietary salt reduction policies for cardiovascular disease prevention in Japan: a simulation study of hypothetical scenarios. Front Nutr. (2023) 10:1227303. 10.3389/fnut.2023.1227303

  • Pubmed Abstract
  • CrossRef
  • Google Scholar

• 80.

  QureshiNQMufarrihSHBloomfieldGSTariqWAlmasAMokdadAHet alDisparities in cardiovascular research output and disease outcomes among high-, middle- and low-income countries—an analysis of global cardiovascular publications over the last decade (2008–2017). Glob Heart. (2021) 16. 10.5334/gh.815

  • CrossRef
  • Google Scholar
  • View reference in article

• 81.

  InamMSamadZVaughanEMAlmasAHanifBMinhasAMet alGlobal cardiovascular research: gaps and opportunities. Curr Cardiol Rep. (2023) 25(12):1831–8. 10.1007/s11886-023-01996-2

  • Pubmed Abstract
  • CrossRef
  • Google Scholar
  • View reference in article

• 82.

  MendisSGrahamI. Prevention and control of cardiovascular disease in “real-world” settings: sustainable implementation of effective policies. Front Cardiovasc Med. (2024) 11:2024. 10.3389/fcvm.2024.1380809

  • CrossRef
  • Google Scholar
  • View reference in article