This section introduces several relevant innovations in cardiovascular risk estimation. In line with other current guidelines, the use of the SCORE2 (ages 40-69 years) and SCORE2-OP (ages 70-89 years) algorithms is recommended to calculate the 10-year risk of fatal and nonfatal cardiovascular events in apparently healthy individuals (without prior cardiovascular disease, diabetes, chronic kidney disease, genetic or rare lipid disorders, or hypertension), with a class IB recommendation. This represents a significant change compared with the 2019 guidelines, which used the SCORE system. The SCORE2 and SCORE2-OP estimate both fatal and nonfatal cardiovascular events (whereas SCORE assessed only fatal events), using non-HDL cholesterol instead of total cholesterol, and extend the age range of application from 70 years in SCORE to 89 years in SCORE2-OP. In addition, SCORE2 and SCORE2-OP are recalibrated using contemporary population data (figure 1).

Figure 1.

CV, cardiovascular; HIV, human immunodeficiency virus; hs-CRP, high-sensitivity C-reactive protein; LDL-C, low-density lipoprotein cholesterol.

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The categories of cardiovascular risk (very high, high, moderate, and low) are maintained, although adjusted to SCORE2 and SCORE2-OP. As a new element, the very high cardiovascular risk category now includes chronic coronary syndromes, the presence of significant plaque (> 50% stenosis) detected by ultrasound in the femoral artery, and a markedly elevated calcium score (> 300) on coronary tomography.

The update emphasizes that cardiovascular risk is a continuum and that individual risk estimation should consider risk modifiers, which include clinical-demographic characteristics (such as hypertensive disorders of pregnancy and HIV infection) and biomarkers (persistent elevation of high-sensitivity C-reactive protein, elevated lipoprotein(a)). These risk modifiers may justify reclassifying an individual to a higher risk category, with stricter LDL-C targets.

Another section refers to individuals with moderate cardiovascular risk or who are at thresholds close to treatment decisions. In this group, a new recommendation (IIa B) indicates that risk modifiers should be included to improve risk stratification, and that the presence of subclinical coronary atherosclerosis detected by imaging should also be considered for cardiovascular risk adjustment (IIa B). There is also an upgrade in recommendation strength (from IIb B to IIa B) for the use of an elevated coronary calcium score by CT as a risk modifier.

With respect to LDL-C targets by cardiovascular risk category, there are no major changes compared with 2019, except for the introduction of an “extreme cardiovascular risk” category (patients with established cardiovascular disease [CVD] and new vascular events despite the maximum tolerated statin dose, or patients with polyvascular disease), in whom the LDL-C target should be<40mg/dL.

Finally, thresholds for initiating lipid-lowering therapy in primary prevention are reviewed, considering estimated risk and baseline LDL-C levels (untreated). A class IA recommendation is established for lipid-lowering pharmacological therapy in individuals with very high cardiovascular risk and LDL-C ≥ 70mg/dL, or in individuals with high cardiovascular risk and LDL-C ≥ 100mg/dL.

The new update incorporates additional agents, notably bempedoic acid and evinacumab, and recognizes inclisiran as a potential alternative pending the availability of outcome data.

Bempedoic acid, an ATP-citrate lyase inhibitor, has a class I recommendation for statin-intolerant patients, as demonstrated in the CLEAR Outcomes trial.2 It reduces LDL-C by 23% as monotherapy and up to 38% when combined with ezetimibe. In CLEAR Outcomes, bempedoic acid achieved a 13% reduction in major cardiovascular events (MACE), providing outcome-based evidence for its efficacy. It may also be considered as an add-on to maximally tolerated statin therapy, with or without ezetimibe, in patients at high or very high risk (class IIa). Evinacumab, a monoclonal antibody against ANGPTL3, is recommended in patients with homozygous familial hypercholesterolemia. It reduces LDL-C by 50%, even in refractory cases, thereby addressing a critical therapeutic gap (class IIa, level B). Inclisiran, a twice-yearly small interfering RNA (siRNA) that inhibits PCSK9 synthesis, achieves sustained LDL-C lowering of 50% with a favorable safety profile. Although outcome trials are still pending, the task force notes it could represent an alternative to PCSK9 monoclonal antibodies, particularly given its potential to improve adherence.

The guidelines advocate the early combined use of nonstatin therapies based on cardiovascular risk and the need to reduce LDL-C. This flexible approach contrasts with the stepwise strategy of 2019 and supports the “fire to target” strategy of initiating combination therapy upfront to quickly achieve LDL-C goals, particularly in patients at high and very high risk.

This section highlights the need for early, intensive lipid-lowering therapies after acute coronary syndrome, in line with the “the lower, the better” strategy, as the benefit of LDL-C reduction begins during hospitalization and is particularly relevant in the first year, the period of maximum vulnerability.

To achieve the recommended LDL-C levels in the shortest possible time, the guidelines emphasize the existing therapeutic lag, which can extend up to 12 weeks because of the step-by-step approach proposed in the 2019 guidelines. This strategy is considered suboptimal due to factors such as therapeutic inertia, adherence problems related to adverse effects, and the lack of adequate care circuits for the follow-up of patients with ischemic heart disease.

This update presents evidence of safety and early target achievement with PCSK9 inhibitors, based on current trials, showing that evolocumab and alirocumab, respectively, induced improvements in the composition and characteristics of atherosclerotic plaque. Observational studies also support this view by demonstrating that risk reduction is obtained even at very low LDL-C levels without J-curve phenomena, and that the time to reach these targets is also of vital importance.

A relevant change is introduced in the guideline, as it incorporates a paradigm shift from the “step-by-step” approach to the”strike early and strong” strategy, which was already advanced in the 2023 ACS3 guidelines. The document emphasizes that the response to lipid-lowering therapy, although variable, is relatively predictable, which could justify a personalized selection of dual or triple combinations from the outset.

As a new element, a comprehensive graph is presented with the available therapeutic options (statins, ezetimibe, bempedoic acid, and monoclonal antibodies against PCSK9) together with the percentage reduction of LDL-C achievable with each of them, both in monotherapy and in various combinations. This resource facilitates the selection of the most appropriate strategy based on baseline LDL-C levels, although it does not take into account any existing reduction if the patient is already receiving treatment.

The guidelines present a strong recommendation to initiate combination therapy with a statin and ezetimibe in all treatment-naïve patients during hospitalization. However, they do not explicitly address systematic intensification if this combination is insufficient to achieve targets, a scenario in which the early introduction of additional therapies should be considered. In patients already treated with lipid-lowering drugs before the vascular event, the need to adjust and optimize therapy during hospitalization is emphasized; although not specified, the adjustment should be based on baseline LDL-C levels and the theoretical reduction percentages of the available therapies presented. The analytical time intervals for follow-up are maintained, with lipid control at 4 to 6 weeks after the index event.

Finally, the guidelines highlight ongoing clinical trials (EVOLVE-MI [NCT05284747] and AMUNDSEN-real [NCT04951865]) evaluating the potential benefit of evolocumab initiation in the acute phase of acute coronary syndrome, which will provide further evidence in this setting.

All epidemiological and genetic studies strongly support a direct, continuous, and causal association between elevated plasma levels of lipoprotein (a) [Lp(a)] and an increased risk of atherosclerotic CVD. Lp(a) should be considered a risk factor when it is greater than 50mg/dL (recommendation IIa); nevertheless, the update notes that Lp(a) may also be considered a risk modifier.

The update recommends a lifetime determination of Lp(a), as well as screening in young patients with familial hypercholesterolemia, premature CVD without other identifiable risk factors, a family history of premature CVD or high Lp(a), or in individuals at moderate risk or close to therapeutic decision thresholds, to improve risk stratification. A new measurement could be considered only after menopause.

The update recognizes that important gaps remain in the evidence related to Lp(a) measurement, since variability between assays may be related to the structure of apolipoprotein [apo(a)] and the variability of Kringle-IV.

Therefore, this update introduces only the need for measurement and the consideration of Lp(a) as a risk modifier, a concept not included in the 2019 guidelines.4 It does not resolve many of the questions that arise in routine clinical practice regarding the management of patients with elevated Lp(a), because it has not yet been demonstrated whether reducing Lp(a) decreases the risk of CVD or slows CVD progression, nor is the degree of reduction required for clinical benefit known. In the absence of specific therapies to reduce Lp(a), early management of risk factors and a more intensive reduction of LDL-C is considered reasonable, taking into account both absolute cardiovascular risk and Lp(a) levels.

This section emphasizes that hypertriglyceridemia increases cardiovascular risk, regardless of LDL-C levels. In high-risk patients, statins are the drugs of choice for the treatment of hypertriglyceridemia to reduce cardiovascular risk.

With respect to fibrates, the available evidence for fenofibrate and bezafibrate is reviewed, showing no reduction in MACE or total mortality in their pivotal studies. The PROMINENT5 study with pemafibrate, which was stopped early due to futility in reducing MACE, is also reviewed. In this study, an increase in LDL-C and apolipoprotein B (ApoB) levels was observed in the active treatment arm. Triglyceride-lowering therapy with fibrates has not yet been shown to reduce the risk of developing atherosclerotic CVD. Therefore, a class IIb recommendation is maintained for fenofibrate and bezafibrate, and the use of fibrates to reduce total cholesterol or LDL-C is not recommended.

Regarding n-3 polyunsaturated fatty acids (PUFA) or omega-3 fatty acids, the guidelines incorporate data from the STRENGTH study,6 which did not demonstrate a reduction in MACE-5 with a combined preparation of eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA). This contrasts with the results previously obtained in the REDUCE-IT trial7 with high-dose icosapent ethyl, a highly purified ethyl ester of EPA, which showed a significant reduction in MACE-5. Therefore, the updated guidelines for PUFA explicitly recommend treatment with only high-dose icosapent ethyl (4g/d, administered as 2g twice daily) in patients at high or very high cardiovascular risk with elevated triglyceride levels (fasting triglyceride levels 135-499mg/dL or 1.52-5.63 mmol/L) despite statin treatment, to reduce cardiovascular events, while maintaining a class IIa recommendation.

A novel therapy introduced in this section is volanosersen, an antisense oligonucleotide that targets hepatic apolipoprotein C-III (ApoC-III) messenger RNA (mRNA). The updated guidelines recommend its use in patients with familial chylomicronemia syndrome and severe hypertriglyceridemia (> 750mg/dL or >8.5 mmol/L) with class IIa to reduce triglyceride levels and the risk of pancreatitis. Volanosersen reduces plasma concentrations of ApoC-III, triglycerides, and chylomicrons, which reduces the risk of pancreatitis; safety concerns include the risk of thrombocytopenia, which requires frequent monitoring and frequent injection sites.

Previous guidelines recommended considering lipid-lowering therapy, primarily statins, in people with HIV with dyslipidemia to achieve the LDL-C goal defined for high-risk patients (class IIa, level C).8 The recently published REPRIEVE trial led to an update in these recommendations. The REPRIEVE trial was a multicenter, randomized, double-blind, placebo-controlled study involving 7769 participants aged 40 to 75 years with HIV who were in primary prevention, had low-to-moderate atherosclerotic CVD risk, and were receiving ART. Participants were randomized to receive treatment or placebo. The trial was prematurely stopped due to the efficacy of pitavastatin (4mg once daily) after a median follow-up of 5.1 years. Results showed a 35% lower incidence of MACE in the pitavastatin group (HR, 0.65; 95%CI, 0.48-0.90; P=.002). Efficacy was similar in men and women, which is significant given women's higher risk of HIV-associated atherosclerotic CVD. Pitavastatin increased the rates of muscle-related symptoms (2.4% vs 1.3%) and new-onset diabetes (5.3% vs 4.0%), but the 5-year number needed to treat to prevent 1 MACE was 106. Pitavastatin 4mg daily showed no interactions with antiretroviral drugs. Consequently, this focused update now recommends statin therapy in people in primary prevention aged ≥ 40 years with HIV, regardless of estimated cardiovascular risk and LDL-C levels, to reduce the risk of CVD (class I, level B).

Regarding other lipid-lowering therapies, ezetimibe, either as monotherapy or in combination with statins, effectively reduces LDL-C in individuals receiving ART to a similar extent as in non-HIV individuals and is well tolerated. Evolocumab has also shown a significant reduction in LDL-C levels (56.9% compared with placebo) and good tolerability. However, no data are currently available on the efficacy and safety of bempedoic acid or icosapent ethyl in this clinical setting.

The update supports the results of 4 randomized clinical trials that demonstrated the benefit of statin treatment for the reduction of cardiac toxicity from anthracycline-based chemotherapy. Statins should be considered in adult patients at high or very high risk of developing chemotherapy-related cardiovascular toxicity to reduce the risk of anthracycline-induced cardiac dysfunction (IIa, B).

The role of heart-healthy nutrition accompanied by physical exercise remains a fundamental pillar of nonpharmacological treatment for controlling plasma lipid levels and, therefore, cardiovascular risk.9 A balanced diet and weight control remain the main targets for preventing cardiovascular disease.

The use of dietary supplements for therapeutic purposes to lower total cholesterol and LDL-C levels does not have sufficient scientific support to be included as a recommendation in nonpharmacological treatment for lipid control,10 specifically: a) red yeast rice preparations; although they have a lipid-lowering mechanism similar to statins, it has been confirmed that commercially available red yeast rice preparations contain varying concentrations of monacolin-K, a substance banned (if ≥ 3mg/d) by the European Parliament and Council since 2023; b) phytosterols, there is still no scientific evidence supporting their benefit in reducing cardiovascular risk; and c) n-3 fatty acids; EPA, DHA, and PUFA are healthy fats that are essential for health and must be obtained from the diet through the consumption of vegetable oils, nuts, and fish. There is no scientific evidence that PUFA supplementation lowers cholesterol and reduces cardiovascular risk. As an exception, the use of high doses of purified EPA reduces cardiovascular risk in the context of intermediate hypertriglyceridemia.7

In conclusion, the use of dietary supplements for lipid-lowering purposes can cause drug interactions and adverse effects; therefore, their use should be supervised by health care professionals.