TC and LDL-C were the first lipids identified as responsible for atherosclerotic CVD (ASCVD). Initially, TC and LDL-C were not widely accepted as a risk factor, but statin studies that reduced TC and LDL-C levels supported the lipid theory of atherosclerosis (Supplementary Table S1). Today, LDL-C remains the primary therapeutic target for ASCVD management and prevention, but should not be the only one. Statins are LDL-C lowering drugs that inhibit hepatic cholesterol synthesis through inhibition of hydroxymethylglutaryl-CoA (HMG-CoA) reductase (6). In the statin-treated patient the LDL-C targets should be met. The significant residual CVD risk observed in ≈70% of patients under optimal statin therapy warrants the exploration and testing of alternative risk factors and specific drugs (2). In addition to statins, ezetimibe a cholesterol absorption blocker, monoclonal antibodies alirocumab and evolocumab, which are proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, and inclisiran, a small interfering RNA (siRNA) therapeutic agent that inhibits synthesis of PCSK9, have been reported to effectively lower LDL-C.

One of the secondary targets for intervention in individuals treated with statins was HDL-C, as low HDL-C was reported to be a characteristic for atherogenic dyslipidemia. Many studies were devoted to therapies that reduced residual CVD risk by increasing HDL-C. In dyslipidemic patients with CVD and in patients with dyslipidemia HDL-C levels are generally low, most often in combination with elevated TG levels. Worldwide, much effort has been paid to treat patients, already on statins, with HDL-raising medication. In the ARBITER 2 trial, among patients with CHD and mean levels of HDL-C and TG of 1.03 mmol/L and 1.84 mmol/L, respectively, therapy with nicotinic acid was associated with increase of HDL-C, decrease of TG, and lack of progression of carotid intima-media thickness (IMT), whereas in controls carotid IMT increased over time (23). A cholesterol-ester transport protein (CETP) inhibitor, torcetrapib, added to atorvastatin therapy, produced a dose-dependent increase in HDL-C, as well as an additional decrease in LDL-C (24). Torcetrapib was withdrawn from clinical testing because of serious adverse effects (25, 26). Besides CETP inhibitors, apoA-I mimetics, recombinant HDL, liver X receptor (LXR) agonists and peroxisome proliferator-activated receptors (PPAR) agonists were advocated as HDL-C raising drugs to reduce CVD risk (27). Pöss et al. presented the warning that an increase of HDL-C does not necessarily imply an improvement of the functional properties of HDL (28). Indeed, the JUPITER trial demonstrated that in statin-treated patients with CVD who had low LDL-C levels, low HDL-C was not predictive of residual CVD risk (29). An important conclusion of the ACCORD trial was that extension of statin therapy with fenofibrate yielded no significant ASCVD risk reduction (30). The ILLUMINATE trial found no improvement of torcetrapib on residual CVD risk, which questions the benefit of HDL-raising therapy (31). The AIM-HIGH trial showed no incremental benefit of niacin with statin therapy after 36-months follow-up (32). As the same was true for CETP inhibitors and fibrates, it was suggested that instead of targeting HDL-C levels, the quality of HDL in terms of particle number, shape, size, and composition e.g., apolipoprotein, triglyceride and cholesterol content and HDL’s functionality should be taken into consideration (33–35). HDL is considered atheroprotective, is involved in reverse cholesterol transport, and has anti-inflammatory, anti-thrombotic, anti-oxidative, anti-infectious, and vasodilatory activities (36). High levels of dysfunctional HDL are associated with increased risk of CVD, whereas high levels of functional HDL, enriched in ApoA-I are associated with decreased risk of CVD (35, 37). Besides ApoA-I, other HDL components, such as HDL-associated hydrolases (e.g., paraoxonase-1), certain (lyso)phospholipids, nutrition, smoking, air pollution, and plastic-associated chemicals influence HDL’s functionality (38). In individuals with very low HDL-C, due to rare monogenic dyslipidemia (e.g., Tangier disease, LCAT deficiency, familial hypoalphalipoproteinemia) or due to secondary dyslipidemias, the very low HDL-C levels are associated with (1) increased risk of CVD, (2) comorbidities, such as T2DM, and (3) elevated levels of sdLDL (39).

In statin-treated individuals residual CVD risk may be due to persistent atherogenic dyslipidemia, which can be defined by high fasting TG levels (≥2.31 mmol/L) and low HDL-C levels (≤1.0 and ≤1.29 mmol/L in men and women, respectively), sdLDL particles, remnant lipoproteins, and postprandial hyperlipidemia. HTG results from hepatic oversecretion and/or hypocatabolism of TGRLs, being VLDL particles and their remnants (43). Atherogenic dyslipidemia is a characteristic often seen in individuals and patients with obesity, T2DM, and MetS (44, 45), and is associated with an increased (by 58%) risk of CVD (46). Often TG elevations are secondary to several conditions, but are primary to syndromes like familial combined hyperlipidemia, type III hyperlipidemia in combination with the apoɛ2/ɛ2 genotype, and familial chylomicronemia syndrome (FCS) (47). In the FMD-J study serum TG levels >100 mg/dl (1.13 mmol/L) in patients undergoing PCI had increased risk of new events compared with those having TG levels <100 mg/dl (1.13 mmol/L) (48). In primary prevention, individuals with TG levels ≥150 mg/dl (1.69 mmol/L) were at lower (by 9%) adjusted risk of death and higher (by 14%) risk of MACE. In secondary prevention patients with TG levels ≥150 mg/dl (1.69 mmol/L) were at lower adjusted risk of death (by 5%), higher (by 4%) risk of MACE, and higher (3%) risk of all-cause hospitalization (49). Mason et al. considered “TG levels as a potential biomarker of CV risk, but found no evidence that TG lowering itself is an effective strategy for reducing such risk” (50). Individuals with HTG having low to moderate risk of CVD suffered from subclinical atherosclerosis and vascular inflammation, even in the absence of hypercholesterolemia (51).

In statin-treated individuals, the incidence rate of CV events is reduced by ≈30%. This means that remaining residual risk is effectuated by factors other than LDL-C, the most frequent being TGRLs and Lp(a). Particularly the accumulation of the relatively cholesterol-enriched, incompletely catabolized remnants of CMs and VLDL has become a new target to reduce residual CVD risk (76, 77). Of the VLDL subclasses identified, the smallest remnant subclass was associated with the highest residual risk (78). In literature there are multiple definitions used for “remnants” in relation to lipoprotein particles and their composition. Usually, remnants of TGRLs are referred to as remnant lipoproteins and the cholesterol content of those remnants are reported as remnant cholesterol (RC). However, there is no consensus on the definition of RC as the ways RC are calculated and measured differ widely among studies. Varbo and Nordestgaard referred to RC as non-HDL-C minus LDL-C, which can be referred to as calculated RC (79). This means that it includes the cholesterol content of unmetabolized VLDL, intermediate density lipoprotein (IDL) and CMs (non-fasting) and not just their remnants. Unless specified otherwise, we will be referring to calculated RC when discussing RC.

Remnant lipoproteins are formed through lipolysis of VLDL and CM, resulting in enrichment of cholesterol (both free and esterified) and depletion of TG content. Efficient lipolysis of TG in VLDL particles by LPL results in a rapid conversion to regular-sized LDL, with limited formation of remnants. However, when lipolysis is retarded, more remnants are formed and can accumulate, leading to a prolonged residence time in circulation. On top of that, slower lipolysis leads to the formation of sdLDL. Remnant lipoproteins are either cleared directly via hepatic uptake or converted to IDL and LDL. Multiple factors can impair lipolysis such as VLDL accumulation, elevated apoC-III levels, and lower LPL activity due to mutations.

In 2013, Varbo et al. found that elevated levels of RC is a causal factor for both increased risk for ischemic heart disease (IHD) and low-grade inflammation in the general Danish population (80). In 2016, Jepsen et al. showed in the Copenhagen Ischemic Heart Disease Study that RC in IHD patients was associated with increased risk and all-cause mortality (81). Measured RC was also associated with this increased risk, although less strongly than the calculated RC, including VLDL and IDL cholesterol. Interestingly, this increased risk was not associated with elevated levels of measured LDL-C, suggesting a role for RC in addressing residual all-cause mortality risk for patients with IHD. The authors concluded that 8%–18% of residual risk of all-cause mortality in IHD patients can be attributed to elevated levels of RC (81). In the NHANES study population, Zhang et al. demonstrated that elevated levels of RC were associated with increased risk of CV mortality, independent of HDL-C and LDL-C (82). The authors concluded that the time has come to address residual CVD risk by targeting RC. Fasting plasma apoB48 levels are correlated with severity of CAD (83). Patients with high levels of chylomicron remnants should be managed with anti-diabetes therapy, complemented with a low-fat diet.

Lp(a) is a lipoprotein containing a plasminogen-like glycoprotein apo(a) covalently bound to an apoB100-containing LDL-like particle. Unlike most other types of lipoproteins, Lp(a) levels are largely determined by genetics and are not significantly affected by lifestyle characteristics such as nutrition and exercise. The precise mechanism by which Lp(a) operates is uncertain, but Lp(a) is thought to contribute to ASCVD via pro-atherogenic, pro-inflammatory, and/or pro-thrombotic pathways. In 2011, Mangalmurti et al. mentioned assessment of Lp(a) level, apoB level and LDL particle number as lipid biomarkers that “potentially have clinical utility” (15). The AIM-HIGH trial with patients with previous ASCVD on statin treatment in combination with niacin, showed that Lp(a) was a risk factor for recurrent ASCVD in the group with combination therapy and in the control group (only statins), whereas apoB and apoA-I (corresponding to all atherogenic lipoprotein particles and corresponding to HDL particle number, respectively) were only predictive for recurrent ASCVD in the control group, suggesting an independent role for Lp(a) in relation to ASCVD (91, 92). Indeed, compelling pieces of evidence from clinical trials, such as AIM-HIGH and JUPITER, and meta-analyses have now consistently shown that Lp(a) is a risk factor for atherosclerosis and CVD independent of LDL-C levels (93, 94). Elevated levels of Lp(a) are an independent risk factor for aortic valve stenosis (95). This has been supported by Mendelian randomization studies that suggest a causal relationship between elevated levels of Lp(a) and the occurrence of both ASCVD and aortic stenosis (96). Already in 2016, Tsimikas discussed the role of Lp(a) in primary and secondary prevention of CVD and concluded that one measurement of Lp(a) can reclassify 40% of the patients in intermediate risk score categories in primary care (92). Averna and Stroes together with the Expert Working Group on Lipid Alterations Beyond LDL conducted a thorough evaluation of clinical data resulting in recommendations addressing residual CVD risk with biomarkers beyond LDL-C, such as non-HDL-C, apoB, RC and Lp(a). The authors state that Lp(a) is a strong, genetic, independent, and causal risk factor for CVD and should be considered measuring in patients with premature CVD, FH, and family history of CVD (97). The recent identification of a correlation between Lp(a) level and CVD risk has resulted in updated guidelines that suggest Lp(a) measurement in specific clinical situations. In 2020, Tsimikas et al. conducted a meta-analysis including twelve statin trials and concluded that statins significantly increase Lp(a) from baseline up to 24.2% and stressed the importance of investigating the Lp(a)-attributable residual CVD risk after statin treatment (98).

High sensitivity C-reactive protein (hsCRP) provides the most substantial evidence as a useful prognostic inflammatory marker for residual inflammatory risk in patients at target levels of LDL-C. Despite hsCRP being a valuable marker for increased risk (102), research on the association between genetic variants in the CRP gene and CHD risk suggest that CRP is not likely a causal factor in CHD (103). Instead, a number of Mendelian randomization studies found causal relations between the IL-6 receptor gene and the risk for CHD (104). The JUPITER trial was the first significant clinical study that examined whether CRP could be used as novel biomarker to identify patients who could benefit from statin therapy, but who were on target LDL-C levels and therefore not eligible for lipid-lowering according to guidelines (105). This trial showed that patients with LDL-C levels <130 mg/dl (3.36 mmol/L) and CRP levels of ≥2 mg/L had a higher risk of CV events compared to patients with low LDL-C and CRP <2 mg/L. Moreover, CRP was found to be a stronger predictor of these events than LDL-C (106, 107). Assessing both LDL-C and CRP levels together provided superior prognostic information than testing for either measure alone (120). This was supported by other clinical trials (SATURN, PROVE-IT, AFCAPS/TexCAPS, REVERSAL, and IMPROVE-IT) (108–110).

CANTOS was the first clinical trial that directly investigated the relationship between atherothrombosis and inflammation regardless of lipid levels. Canakinumab, an IL-1β antagonist, directly inhibits IL-1-to-IL-6-to-CRP signaling pathway. In 2017, CANTOS showed a 26% reduction of MACE for patients with on-treatment hsCRP <2 mg/L after canakinumab administration, independent of LDL-C lowering, compared to the placebo group (111). In addition, in this subgroup CV mortality and all-cause mortality were significantly reduced by 31%. However, canakinumabs’ clinical applicability is hampered due to high prevalence (over 10%) of adverse events including neutropenia, cellulitis, pseudomembranous colitis, fatal infection, and sepsis, as well as expensive treatment costs (112).

In parallel with CANTOS, the CIRT with methotrexate was conducted. Initially, methotrexate was a chemotherapeutic drug acting as a folic acid antagonist, and it is commonly used to treat rheumatoid arthritis and psoriasis. A cross-sectional study involving rheumatoid arthritis patients revealed that methotrexate was associated with a 15% reduction in CV events, indicating its potential as a promising new therapeutic approach for CVD (113, 114). However, when tested in a CV context, methotrexate did not reduce levels of IL-1β, IL-6 or CRP among patients with stable atherosclerosis, nor did it lead to a reduction in CV events compared to placebo (115).

Colchicine, another anti-inflammatory agent, inhibits NLRP3 inflammasome activation and the downstream activation of IL-1, IL-18, and IL-6. The COLCOT trial showed a 23% risk reduction in MACE with colchicine administration after MI (116). In the LoDoCo2 trial, colchicine administration to stable CAD patients resulted in a 30% reduction in CV events compared to placebo. However, it can cause myalgia, gastrointestinal distress, and drug interactions with commonly prescribed medications, including antibiotics and statins (117).

Bempedoic acid is a therapeutic agent that inhibits ATP citrate lysase, just upstream from HMG-CoA reductase, lowers LDL-C, and reduces hsCRP. The CLEAR Outcomes trial assessed its effects in patients with ASCVD or heFH on statin therapy with residual inflammatory risk (hsCRP ≥2 mg/L). Results show that bempedoic acid lowers lipid levels (LDL-C, TC, and apoB) and inflammation (IL-6 and hsCRP) independently, making it a promising candidate for residual cholesterol-related and inflammatory risk. However, it has no impact on Lp(a) levels (118).

Recently, ziltivekimab, an IL-6 inhibitor, has shown to effectively reduce hsCRP up to 92% in individuals with elevated hsCRP and CKD (119). Currently, the ZEUS trial is investigating its impact on reducing hsCRP and MACE.

PLA2 is a family of enzymes that is responsible for the hydrolysis of oxidized phospholipids on LDL particles, resulting in the production of two highly inflammatory mediators, lysophosphatidylcholine and oxidized FAs, which can be linked to atherosclerotic plaque formation and plaque inflammation (120).

In 2005, Lp-PLA2 was a novel inflammatory marker of CV risk that was being considered as a potential therapeutic target (121, 122). Lp-PLA2 is primarily bound to LDL, but also to HDL, Lp(a) and TGRLs. Multiple studies have shown that elevated levels of Lp-PLA2 are associated with increased risk of CHD and stroke, independently of hsCRP and after adjusting for traditional risk factors (105). Lp-PLA2 seemed to be an interesting target as it is a cross-over between lipid metabolism and inflammation, both involved in CVD risk. In 2008, a phase II trial was conducted with darapladib, an Lp-PLA2 inhibitor, in patients with CHD. Darapladib reduced interleukin-6 (IL-6) and hsCRP levels and prevented necrotic core expansion in coronary atherosclerotic lesions (123). However, in two trials darapladib administration in patients with recent ACS and in patients with stable CHD did not lead to a reduction in MACE (SOLID-TIMI 52 and STABILITY). This implies that Lp-PLA2 may be a biomarker for vascular inflammation instead of being a direct cause of CVD. In addition, darapladib administration led to adverse side effects such as diarrhea and malodorous feces, urine, and skin (123). Notably, patients in both trials had low levels of LDL-C and the majority was taking statins, which inhibits PLA2 activity. These findings suggest that targeted PLA2 inhibition on top of statin treatment does not offer any additional benefit (124).

Endothelial dysfunction is a general term that describes the site that attracts, binds, and internalizes monocytes that may develop into foam cells and subsequent plaque formation. Besides, dysfunctional endothelium produces less nitric oxide (NO), a vasodilator, due to depressed eNOS (NOS3) activity. Instead, in dysfunctional endothelium inducible NOS (iNOS or NOS2) is formed, ultimately leading to massive quantities of peroxynitrite, a molecule with detrimental effects on tissues, such as hypertrophy, dilatation, fibrosis, and dysfunction. Factors that contribute to endothelial dysfunction include dyslipidemia, oxidative stress, and inflammation (125). Statins have been reported to improve endothelial dysfunction (126). HTG was recognized as a therapeutic target in the treatment of endothelial dysfunction and ω3-fatty acids administration was recommended as therapy to improve endothelial function (61, 127). When patients with CAD and impaired vascular function underwent optimal medical treatment for 24 weeks, the improvements of flow-mediated vascular dilatation, a marker of vascular endothelial function, predicted the lowest probability of future MACE (128).

Clonal hematopoiesis of indeterminate potential (CHIP), a collection of somatic mutations, is an age-associated risk factor for MI, stroke, heart failure events, and survival following percutaneous aortic valve intervention (129, 130). It is suggested that CHIP activates the inflammasome pathway and contributes to thrombosis, leading to CVD. Although the association between CHIP and CVD is still being studied, early evidence indicates that CHIP may serve as a useful biomarker for identifying those at increased risk of CVD (129, 130). There are no specific therapies yet.

The platelet P2Y12 receptor has a key role in thrombus formation during ACS. Dual antiplatelet therapy, combining aspirin and a P2Y12 inhibitor, was used to decrease residual thrombotic risk, at the expense of a bleeding risk. The PEGASUS-TIMI 54 trial with ACS patients with stable CAD demonstrated that treatment with P2Y12 inhibitor, ticagrelor, on top of aspirin administration resulted in a 16% reduction in MACE (132, 133). Particularly after invasive procedures, dual antiplatelet therapy proved to be highly effective in preventing thrombotic events. Also, in diabetics anti-thrombotic strategies in acute and chronic CAD remain an unmet clinical need (134).

A relatively novel approach to address this residual thrombotic risk is dual pathway inhibition (DPI). DPI involves targeting both platelet activation and coagulation cascade by combining antiplatelet and anticoagulant agents. The COMPASS trial with patients with stable ASCVD showed that the combination of rivaroxaban (a Factor Xa inhibitor) and aspirin was superior in preventing recurrent MACE compared to aspirin alone, but at the expense of significant bleeding risk (135). Low-dose rivaroxaban in combination with aspirin has been implemented in European guidelines for patients with diabetes and peripheral artery disease at low bleeding risk (136). The combination of rivaroxaban on top of clopidogrel has been examined in patients with ACS, resulting in significant reduction of ischemic events and CV mortality, again at the expense of increased risk of bleeding (137, 138).

DM is one of the comorbidities associated with considerable residual risk of CVD. Already in 2001, diabetes, smoking, hypercholesterolemia, and hypertension were mentioned as correctable risk factors that should be addressed by physicians “before cardiovascular and renal damage become manifest” (139). In patients with T2DM, hyperglycemia and dyslipidemia were found to be associated with inflammatory risk, thrombotic risk, and risk of endothelial dysfunction (140). In the following years, many papers reported on new therapies to treat diabetic dyslipidemia, characterized by elevated levels of TG, reduced levels of HDL-C, elevated levels of remnant lipoproteins, and presence of sdLDL. The addition of fibrates to anti-diabetic therapy improved lipid abnormalities, reduced progression of atherosclerosis, and reduced risk of CAD in T2DM patients (44). Fibrates, being agonists of PPAR, can treat insulin resistance and HTG when combined with improvement of diet and physical activity (141). Particularly PPAR-γ activators, such as the thiazolidinediones, have, in combination with statins, complementary effects on CVD risk reduction in patients with T2DM (142). Fenofibrate was shown to offer macrovascular and microvascular benefits in patients with T2DM on statin therapy (143–145). However, the FIELD study demonstrated that fenofibrate did not reduce MACE in patients with T2DM, although fenofibrate was shown to have favorable impact on a number of nonlipid residual risk factors (146). Around 2010 it became evident that the ACCORD trial has demonstrated that in patients with T2DM with atherogenic dyslipidemia the combination therapy of statin and fibrate resulted in risk reduction, although in the absence of atherogenic dyslipidemia this favorable effect was absent (147–149). In patients with diabetes or MetS who achieved their desirable LDL-C levels, non-HDL-C levels may remain too high, and deserved specific therapy to reduce residual CVD risk (150). In the year 2012, it became clear that atherogenic dyslipidemia in patients with T2DM or MetS should not be treated with fenofibrate, torcetrapib or niacin in combination with statin to reduce residual risk. Instead, several authors recommended that correction of hyperglycemia should be combined with statin and lifestyle changes (151, 152). Around 2012 several reports proposed that therapy with ω3-fatty acids may treat HTG and may reduce residual risk in T2DM patients and patients with MetS (152, 153). By using lifestyle changes, anti-glycemic agents, and lipid-regulating therapies in patients with T2DM, endothelial function improved as well (125). Recently it was found that statins could slightly increase the risk of T2DM, but T2DM patients clearly benefit from statin therapy (154). In the REDUCE-IT trial icosapent ethyl markedly lowered residual risk of MACE in patients with ASCVD and with T2DM (155). Xiao et al. pointed out that the central abnormality of the atherogenic dyslipidemia in diabetics is the presence of TGRLs (remnants) that are primarily responsible for high residual risk (156). From 2019 on, several groups stated that HTG in diabetics is a serious risk factor that deserves therapy (157–161). As diabetes is a leading cause of CKD, new therapies with glucagon-like peptide-1 receptor agonists (GLP-1-RA) and sodium/glucose cotransporter 2 inhibitors (SGLT2i) showed antihyperglycemic effect, and reduced all-cause mortality and CV mortality. GLP-1-RA had favorable effects on diabetic nephropathy (162). SGLT2i have, besides glucose-lowering action, renoprotective effects in diabetics, thereby reducing the rates of end-stage kidney disease and acute kidney injury (AKI) (163–165), and promoting cardioprotection in diabetics (165, 166).

MetS is a complex condition with metabolic risk factors, like abdominal obesity, atherogenic dyslipidemia, high blood pressure, high plasma glucose, and a combination of prothrombotic and proinflammatory factors. Patients with MetS have high risk of ASCVD and predominant risk factors are abdominal obesity and diabetes. Therapy includes a combination of treatments for high LDL-C, high blood pressure, and diabetes, and includes improvement of lifestyle (167). Treatment of the atherogenic dyslipidemia in patients with MetS reduces residual CVD risk that remains with a statin. The authors advocated the use of fenofibrate that showed a 27% relative risk reduction for CV events (168). To prevent CV and renal events in patients with MetS the newer glucose-lowering medications, SGLT2i and GLP-1-RA, were recommended (169).

Anti-hypertensive therapy, even if blood pressure is at target, has its own contribution in CVD risk, as hypertensives on treatment had a higher risk of stroke than untreated individuals with normal blood pressure (170). But how low should the blood pressure be in treated hypertensive patients? Yannoutsos et al. stated that “the concept of ‘the lower the better’ tends to be abandoned”. But in 2010, the “J-curve concept” was still the subject of many studies and controversies (171). In a subanalysis of the PRIME trial, which involved patients treated with anti-hypertensive agents or lipid-lowering agents, anti-hypertensive therapy at baseline was significantly associated with risk of CV events, after adjusting for classic risk factors. It was concluded that patients who were treated for hypertension had “sizable residual cardiovascular risk”, and deserved more efficient risk reduction (172–174). The range of success of anti-hypertensive therapy, studied in a multi-country survey, was 32.1–47.5%, suggesting that “efficient risk reduction” is an effort to work on (5). Apparently, treatment of hypertension cannot completely reverse the sustained vascular damage (e.g., arterial stiffness) as well as other CV morbid conditions (e.g., left ventricular hypertrophy). This extra high residual CVD risk is best predicted by BNP and its inactive fragment NT-proBNP. (175) Even in treated hypertensive patients roughly 30% suffer from left ventricular hypertrophy (29%), diastolic (21%) or systolic (6%) ventricular dysfunction, left atrial expansion (15%), and silent myocardial ischemia (6%). In 13% of this group three or more of these abnormalities occur in combination (176). Apparently, anti-hypertensive therapy does not alter all components of the underlying mechanisms of hypertension that confer CV risk independent of blood pressure (176). Current guidelines therefore advise lifestyle changes, lipid-lowering therapy, antiplatelet therapy and fasting glucose management depending on the risk profile of the patient (177).

There are several mechanisms by which obesity can increase the risk of CVD as it is associated with an increased risk of hypertension, dyslipidemia, insulin resistance, T2DM, inflammation, and oxidative stress (178, 179). Already in 2007, Ryan et al. suggested the use of waist circumference (WC) as a measure of abdominal obesity, instead of BMI (180). Indeed, Dhaliwal et al. showed in a cohort study with subjects with no previous diabetes, heart attack, or stroke that WC and waist-to-hip ratio (WHR) both independently predicted CV deaths, whereas BMI did not have any predictive value (181). CRP, marker of inflammation, did not differ between the group that experienced CVD and the group without CVD, suggesting that WC is independently associated with CVD regardless of inflammation (182). However, abdominal obesity was associated with inflammation since adipose tissue was considered to generate inflammatory cytokines leading to a higher inflammatory profile in obese individuals (183). The case-control INTERHEART study demonstrated that the population attributable risk (PAR) of acute MI was greater for abdominal obesity than for diabetes or hypertension (183). Currently, bariatric surgery is one of the most effective interventions to reduce obesity. New drugs to treat obesity and reduce risk of MACE are semaglutide and tirzepatide (184–186).

Individuals with CKD have a greater risk of CVD compared with the general population but have largely been excluded from clinical trials. CKD patients on dialysis show little to no CV benefit from lipid-lowering therapy and thus have exaggerated residual CVD risk. Probably some of the residual risk in CKD patients is explained by changes in the level, composition, and functionality of HDL, which may contribute to the excess risk of CVD (187). Thus, therapy should be aimed at improving HDL function, possibly by targeting specific moieties within the HDL particle (188). In patients with CKD elevated levels of VLDL-C and apoB, and low levels of HDL-C and apoA-I, are associated with increased risk of ASCVD (189). In patients with combined CKD and atherosclerosis, inflammation is a major predictor of residual CVD risk. Interestingly, in this CKD group elevated levels of LDL-C were not associated with MACE and all-cause mortality (190).

Chronic overnutrition and consequential visceral obesity is associated with a cluster of risk factors for CVD and T2DM (191). The PREDIMED study has demonstrated a 30% reduction in the risk of onset of CVD in patients allocated to a Mediterranean diet as compared to patients with a low-fat diet. Amar et al. suggested that the impact of the probiotic Mediterranean diet on the microbiome causes the beneficial effects on CVD risk and should be considered in prevention of CVD (192, 193). The effect of diet on the microbiome in relationship to CVD has gained more interest over the years. Future research on microbially produced metabolites may lead to new ways to improve CV health (194). Intermittent fasting and variations of it, such as the fasting-mimicking diet, have been linked to improvements in CVD risk markers, including BMI, blood pressure, cholesterol, TG, and CRP (193).

Although the beneficial effects of physical activity on primary and secondary prevention of CVD have been well known for decades, exercise recommendations by clinicians are generally not followed at all or only followed for a brief time. Physical activity has been shown to significantly increase HDL concentration and HDL particle size as well as decrease sdLDL, LDL-C, VLDL and TG (193, 195). In addition, physical activity correlates with lower incidence of CVD up to 50% (195). Furthermore, an inverse relationship between the frequency and intensity of physical activity and all-cause mortality has been observed (195). Combination between caloric restrictive diet and physical exercise demonstrated an independent role for physical exercise in lowering LDL particle number and increasing LDL particle size and HDL particle size (196).

In the INTERHEART study, a case-control study that examined the contribution of various cardiometabolic risk factors to the risk of AMI, showed that the PAR of AMI was greatest for dyslipidemia and smoking (183). Another study that estimated the benefit of meeting guideline-recommended targets showed that smoking cessation in a group of 55 patients with acute ischemic stroke led to an absolute 10-year risk reduction of 14% with a median increase of 3.4 CVD-free life years (197).

Women have often been neglected in medical research and have not received adequate representation, recognition, diagnosis, or treatment in various fields, including cardiology.

Berry et al. conducted a meta-analysis using data from eighteen cohort studies involving black and white men and women whose risk factors for CVD were measured at the ages of 45, 55, 65, and 75 years. They observed marked differences in the lifetime risks of CVD across risk factor strata, and whatever the risk factor the risk of each group was evidently dependent of age (202).

The risk of developing CVD varies among different ethnicities, with the highest risk being found in individuals of sub-Saharan African, Chinese, and Southeast Asian descent (203). Well-established risk factors mostly reflect this increased risk in these populations, such as lower HDL-C levels and higher TG levels in South Asians. In contrast, the levels of LDL-C and apoB are similar across different ethnic groups. However, OxPL-apoB is more prevalent in African Americans than in Caucasians or Hispanics (12). Lp(a) shows the greatest variability between ethnic groups, with African descendants having twice the levels of Lp(a) compared to Caucasians. Interestingly, elevated levels of Lp(a) are not associated with subclinical calcific aortic valve disease in Hispanics, or Chinese individuals, while this association is seen in individuals of European and African descents (203).