Prevention of ASCVD in Women Through Lipid Management in the New Era

The American Heart Association’s cardiovascular disease mortality statistics show that CV events were rising in women during the late 1980s and 1990s in the United States.¹ This increase in women continued until 1999 when the first women-specific cardiovascular prevention guidelines were released, followed shortly thereafter by the launch of the Go Red for Women campaign. Since that time, there has been a steep decline in cardiovascular disease mortality. Now there is a slight uptick in cardiovascular mortality in both men and women, likely due to the epidemic of obesity, diabetes, and cardiometabolic disease. A larger rise of 7% can be seen in middle-aged women between 45 and 64.^1,2

Traditional cardiovascular risk factors such as diabetes and smoking confer greater risk in women than they do in men, but there are also unique risk factors that women experience related to menarche, menopause, hormones, and pregnancy. It is important to discuss these factors with women because these can be red flags that may identify a woman who is at a higher cardiovascular risk.³ It is also important to discuss these factors at any age because excess cardiovascular risk from hypertensive disorders in pregnancy, such as preeclampsia and preterm delivery, can extend more than 10 years out from the adverse pregnancy.⁴ Putting together pooled data from many cohorts shows that preeclampsia is associated with a 4-fold increased risk of heart failure and a 2-fold increased risk of coronary disease, stroke, and cardiovascular death; preterm delivery is associated with a 2-fold increased risk of cardiovascular disease, especially if it occurred before 32 weeks.⁵ Cohort data from France showed that even after adjustment, a history of gestational diabetes was associated with a 25% increased risk of a subsequent cardiovascular disease event.⁶ The UK Biobank data found that premature menopause before the age of 40 is associated with a 36% increased risk of a subsequent cardiovascular event even after accounting for traditional cardiovascular risk factors.⁷

To lower cardiovascular risk, the reduction of LDL-C is very important, but all traditional risk factors should be assessed because prevention is a multifaceted approach. The most important way to prevent cardiovascular disease is to emphasize a healthy lifestyle throughout one’s life.⁸ While there are many healthy dietary patterns, a Mediterranean-style diet is associated with the most evidence for a reduction of myocardial infarction.

In addition to diet, it is important to underscore the importance of physical activity. The guidelines recommend physical activity of moderate to vigorous intensity for 150 minutes a week, which averages 30 minutes a day for 5 days a week.⁸ Most of the cardiometabolic benefits occur with a moderate-level intensity activity like a brisk walk, and all patients should be encouraged to make time to exercise.

The AHA/ACC guidelines still emphasize statins as the first-line treatment. While statins are also indicated for first-line use in secondary prevention, they should be used for primary prevention of cardiovascular disease in patients with elevated LDL-C above 190 mg/dL.⁸ These patients should be given a high-intensity statin to lower their LDL-C by more than 50% regardless of their 10-year risk score. Similarly, patients with diabetes who are between 40 and 75 years old should be recommended for a moderate-intensity statin regardless of their 10-year risk score, as should other patients in primary prevention who are deemed to be of sufficient atherosclerotic cardiovascular disease (ASCVD) risk after a clinician-patient risk discussion.

The guidelines recommend beginning the treatment decision-making process by using the Pooled Cohort Equation to determine a 10-year risk score for individuals 40-75 years old who do not have diabetes and who have an LDL-C 70-189 mg/dL. These patients would automatically be indicated for statins above that range.⁸ The 10-year risk score sorts patients into 4 groups. Patients with a 10-year risk of less than 5% are low-risk individuals, and in general, lifestyle modifications are enough for prevention. Those with a 10-year risk score of more than 20% are in the high-risk category where statins are recommended in addition to lifestyle changes with the goal of reducing LDL-C by more than 50%. In between these extremes are the borderline risk group with scores ranging from 5%-7.5% and the intermediate risk group, with scores from 7.5%-20%. Statins are generally recommended for patients with a 10-year risk score above 7.5%, but this is not a mandated statin prescription. Rather, this is the start of a shared decision conversation with your patient.

The guidelines acknowledge that even after the 10-year risk is estimated, there can still be risk uncertainty, so it is recommended that risk-enhancing factors be reviewed with the patient. These are factors that are already known about the patient clinically, such as traditional ASCVD risk factors and diabetes-specific risk enhancers, such as duration of diabetes, albuminuria, CKD, retinopathy, neuropathy, or a low ankle-brachial index. For borderline- or intermediate-risk individuals, these additional factors would strengthen the decision to start a statin or intensify the statin if one is already being taken.

The guidelines further recognize that there can still be clinical indecision about the benefits of preventive pharmacotherapy even after 10-year risk is estimated and risk-enhancing factors are considered. In these cases, the guidelines state that it may be reasonable to determine a coronary artery calcium score to refine risk up or down to guide shared decision-making.^8,9 A score of 0 puts a patient into a much lower risk category. On the other hand, if the score is greater than 0, atherosclerosis is present, and a statin would generally be recommended. A score of 100 or higher, which is the 75^th percentile or above, puts patients into a higher-risk category where they would likely derive benefit from statins for primary prevention.

Statins are safe, efficacious, and well tolerated, and in clinical trials there really is no difference in myalgias between statin-treated and placebo patients. In clinical practice, however, up to 20%-30% of patients report statin-associated muscle symptoms, which may be a nocebo effect.^10-11 Accordingly, it is important to educate patients about how effective statins are at reducing events, both for primary and secondary prevention, across all LDL-C levels. The risk of serious adverse events is very low. For instance, the risk of a serious muscle injury, including rhabdomyolysis, is less than 0.1%, and the risk of serious hepatotoxicity is ~0.001%.¹¹ There is a very modest increased risk of newly diagnosed diabetes mellitus, but this is in patients who were already glucose intolerant and prediabetic; statins do still provide this group with the benefit of reduced vascular events. Unfortunately, a large proportion of patients stop their statins within 1 to 2 years after initiation, and this is associated with increased cardiovascular risk. If patients cannot use the recommended intensity or cannot tolerate it, the maximum-tolerated statin dose should be used.

Triglycerides (TGs) also must be added into the treatment equation because even a small elevation of TGs despite appropriate statin therapy can substantially elevate ASCVD risk. The most recent data and guidelines now support managing elevated TGs as a biomarker and therapeutic target to reduce ASCVD events. The optimal TG level is less than 100 mg/dL.¹² In the 100-200 mg/dL range, the risk of ASCVD events begins to increase, and there is a considerable increase when the level reaches 200-500 mg/dL. Lab tests for nonfasting TG levels are sufficient, but the measurement is slightly more precise when fasting.

Management of elevated TG levels has been challenging, and fibrate and niacin trials have not shown a statistically significant benefit in reducing ASCVD events. The data for ASCVD reduction with these 2 drug classes added to a statin is not very robust and is not recommended by current guidelines.⁸

Notable trials of omega-3 fatty acids to lower TGs include ASCEND and VITAL, each of which used 1 gram a day of EPA (eicosapentaenoic acid) plus DHA (docosahexaenoic acid) and failed to meet their primary endpoint.^13,14 These trials used a combination of EPA plus DHA at low doses, which was more of a dietary supplement dose and not a prescription dose of 4 grams a day.

The first major indication of omega-3 benefit as an adjunct to statin therapy was the JELIS trial.¹⁵ JELIS recruited patients with high LDL-C and treated everybody with a statin according to Japanese guidelines. Patients were then randomly assigned to receive 1.8 grams of pure EPA or control. There was a 19% relative risk reduction in the patients receiving EPA and an even higher relative risk reduction of 53% in the subgroup of patients with high TGs and low HDL-C levels.¹⁶

More recently, the REDUCE-IT trial used a full dose of 4 grams a day of a virtually identical pure EPA ethyl ester called icosapent ethyl in patients who were already on a statin.¹⁷ The study population (N=8,179) was selected for elevated TGs of 135-500 mg/dL, and subjects were followed for up to 5 years. The results were very dramatic, showing a 25% relative risk reduction of the primary endpoints (nonfatal MI, stroke, CV death, coronary revascularization, hospitalization for unstable angina) and a very similar reduction with key secondary hard endpoints (nonfatal MI, stroke, CV death).¹⁷ Further analysis of the REDUCE-IT data showed a reduction in total mortality and impressive ASCVD recurrent event reductions that were achieved by simply treating patients with 4 grams a day of icosapent ethyl for 5 years.¹⁸ This translates into preventing hundreds of thousands of events by just implementing icosapent ethyl in patients who already have their LDL-C controlled on a statin but have a slightly elevated TG level.

On-treatment TG levels in REDUCE-IT decreased less than 20%, and the relative risk reduction was similar if the patients’ levels got below 150 mg/dL compared to those whose levels were ≥150 mg/dL. There was a comparable benefit across the entire spectrum of baseline TGs.¹⁹

REDUCE-IT also showed interesting data on the relationship of plasma EPA and ASCVD benefit. The higher the achieved EPA level during the trial, the greater the relative risk reduction.²⁰

There are stark differences between prescription-only icosapent ethyl (IPE) and over-the-counter dietary supplement omega-3s, which are not regulated by the FDA. Studies show that up to 36% of the content in supplements may be saturated fat, the EPA and DHA content may often be overstated, oxidation of the omega-3 fatty acid content tends to be high, and contamination risks exist.^21-24 While the supplements may not be harmful taken in small doses, fish oil supplements are not recommended to treat disease, especially ASCVD.²⁵

As a result of the REDUCE-IT study, icosapent ethyl is now indicated by the FDA for ASCVD reduction.²⁶ There are also many professional societies that have recommended its use as an adjunct to statin therapy for high-risk patients with TG levels 135-500 mg/dL.^27-31 They recommend using 4 grams of IPE a day on top of appropriate statin therapy for patients with TGs either >135 mg/dL fasting or >150 mg/dL nonfasting. The recommendation is to get the LDL-C to the goal level with a statin and then add IPE if the TGs remain slightly elevated in the 135-500 mg/dL or 150-500 mg/dL range, depending on fasting or nonfasting levels. ^32-33 The first step is to optimize statin therapy. If further LDL lowering is needed, ezetimibe can be prescribed, followed by the PCSK9 inhibitors or newly approved bempedoic acid. If a patient’s LDL-C is controlled on the statin therapy, the LDL cholesterol may not need to be further reduced, but icosapent ethyl is indicated if the TGs are elevated.

A final point is a reminder not to give up on statins. The data from REDUCE-IT was from patients who were on statins. Patients who initially cannot tolerate statins often can when rechallenged. Ezetimibe or other LDL-C adjuncts can be used as needed, and icosapent ethyl should be used to treat elevated TG.

References

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