Clinical Feature: Non-Lipid Lowering Therapies Impacting Cardiovascular Disease Risk

Atherosclerosis is the leading cause of death and disability globally, with the highest burden continuing to have dominant impact in the developing world.(1) Lipids play a major role in the development of atherosclerosis, but contemporary models demonstrate they are not the sole determinant of disease. Other factors including inflammatory processes and creation of a prothrombotic environment in the vascular tree, suggest that a multi-faceted understanding of pathophysiology should be incorporated in an inclusive treatment model. Patients with atherosclerotic cardiovascular disease (ASCVD) have many associated co-morbidities and treatment primarily directed towards those disease states has an impact on cardiovascular risk reduction.

Previously considered a cholesterol storage disease, atherogenesis is currently understood as a complex interaction of risk factors.(2) Coronary artery disease (CAD) progresses by two mechanisms - gradual progressive lipid accumulation causing coronary artery stenosis or sudden plaque rupture associated with localized inflammation and thrombosis that partially or completely blocks the artery. (3) An increased concentration of lowdensity lipoprotein cholesterol (LDL-C) can be sufficient to cause atherosclerosis in certain conditions such as familial hypercholesterolemia. However, more often, the disease develops at lower LDL-C levels in the presence of other risk factors, including smoking, hypertension, diabetes mellitus (DM), male sex, family history, and complex genetic susceptibility.(1) Therefore, CAD is a multifactorial disease. Oxidative stressors and inflammation cause changes in the vascular endothelium which permits access of atherogenic lipoproteins such as LDL-c into the subendothelial space, followed by further oxidation and scavenging incited by the monocytemacrophage system. The release of growth factors, cytokines, and upregulation of adhesion molecules attracts further monocytes. Foam cells (arising from lipidladen macrophages) accumulate, and smooth muscle cells proliferate, resulting in plaque progression. Inflammatory cell infiltration, smooth muscle cell death through apoptosis, and matrix degradation through proteolysis generate a vulnerable plaque with a thin fibrous cap and a lipidrich necrotic core.(4)

Link Between LDL, Non-HDL, and Cardiovascular Disease Outcomes
The link between LDL-C, non-high-density lipoprotein cholesterol (non-HDL-C) and cardiovascular disease (CVD) is well established. Non-HDL-C represents cholesterol carried by all of the atherogenic apoB-containing particles. In the study Effect of Potentially Modifiable Risk Factors Associated with Myocardial Infarction in 52 Countries (INTERHEART Study), 15,152 cases and 14,820 controls were enrolled, and nine easily measured risk factors were identified that account for over 90% of the risks of acute myocardial infarction (MI).(5,6) Elevated ratios of Apolipoprotein B/ Apolipoprotein A1 proved to be one of the most important indicators of risk (population attributable risk 49.2%). Protective factors included lifestyle changes, including diet, regular physical activity, alcohol consumption, and smoking cessation. These factors are the same among almost every geographic region and every ethnic group worldwide and consistent among both men and women.(6)

In the Multinational Cardiovascular Risk Consortium, Brunner et al investigated the relevance of blood lipid concentration to the long-term incidence of CVD and the relevance of lipid-lowering therapy for CVD outcomes.(5) This study concluded that non-HDL-C concentrations in blood are strongly associated with long-term risk of atherosclerotic CVD. A 50% reduction of non-HDL-C concentrations was associated with a reduced risk of a CVD event by the age of 75 years. Early and sustained reduction of cholesterol concentrations were associated with more pronounced reduction in risk.(5)

Lifestyle: Foundation of CVD Prevention
Lifestyle modifications, such as physical activity and a heart-healthy diet, have major impacts on reducing adverse cardiovascular (CV) outcomes. The Prospective Urban Rural Epidemiology (PURE) study, which included 130,843 participants, aged 35-70 years, from urban
and rural areas in 17 countries, found that 150 minutes of physical activity per week could prevent 1 in 20 CV deaths with greater benefits seen with higher activity levels (750 min/week).(7) Physical activity has also been associated with a longer life expectancy. In a large,
pooled cohort analysis of 6 studies from the National Cancer Institute Cohort Consortium comprising 654,827 individuals, 21-90 years of age, a physical activity level of 0.1-3.74 Metabolic Equivalents per hour per week (equivalent to 75 min/week) (MET-hour/week) was
associated with a gain of 1.8 year (95% confidence interval [CI], 1.6 to 2.0) in life expectancy relative to no leisure time activity. Higher levels of physical activity were associated with greater gains in life expectancy, with a gain of 4.5 years at the highest level (equivalent to walking 450 min/week). These gains were observed across body-mass index groups.(8)

The Mediterranean diet has been shown to benefit heart health and reduce CVD risk. It focuses on minimally processed plant-based foods, rich in monounsaturated fat from olive oil but low in saturated fat, meats and dairy products.(9) Several studies have examined the benefits of the Mediterranean diet and CVD. The World Health Organization compared CV mortality rates between northern and southern European populations, which varied between 2-10% in southern European countries and 10-18% in northern European countries.(10) These differences were attributed to nutritional habits, particularly higher consumption of saturated fats in northern countries. The Lyon Diet Heart Study examined 605 secondary prevention patients and found that patients who had a previous MI and followed a Mediterranean diet had a 50-70% lower risk of a recurrent MI compared with patients who did not adhere to the same diet.(11) Several other studies have associated the Mediterranean diet with a decrease in coronary heart disease, development of hypertension, and improvements in the lipid profile, specifically reduction in the LDL cholesterol and triglycerides.(12)

Non-Lipid Lowering Therapies impacting CVD Risk Reduction
The role of cholesterol in atherosclerosis development is evident, as are therapies that lower LDL cholesterol and thereby reduce CVD risk, such as statins. The remainder of this review will focus on nonlipid- lowering therapies that reduce CV events and on promising future therapies.

Inflammation:
Inflammation plays a major role in all stages of atherogenesis.(2) In the Justification for the Use of Statins in Prevention: An Intervention Trial Evaluating Rosuvastatin (JUPITER) trial, healthy individuals without hyperlipidemia but with elevated highsensitivity C-reactive protein (hs-CRP) were randomized to receive rosuvastatin 20mg daily or placebo for a median follow-up of 1.9 years.(13) In this study, rosuvastatin reduced hs-CRP levels by 37% and significantly reduced the incidence of major CV events (hazard ratio [HR]: 0.56, 95% CI, 0.46 to 0.69; p<0.00001). The reduction in HR in this trial with enrollment based on elevated hs-CRP was almost twice the magnitude and revealed a greater relative benefit than that found in prior statin trials.

Researchers have also examined antiinflammatory agents to assess the impact of inflammation on CV outcomes independent of lipid-lowering. In the Canakinumab Anti Inflammatory Thrombosis Outcome Study (CANTOS), canakinumab (a monoclonal antibody targeting IL-1β) 150mg every 3 months led to a significantly lower rate of recurrent CV events than placebo, independent of lipid-lowering (HR: 0.85, 95% CI, 0.74 to 0.98; p=0.021).(14) The median reduction in baseline hs-CRP with 150mg canakinumab was 37% at 48 months (p<0.001). In a post hoc analysis of Studies of PCSK9 Inhibition and the Reduction of Vascular Events (SPIRE) trials with statin and bococizumab (a monoclonal antibody targeting PCSK9), residual inflammatory risk at 14 weeks was evaluated based on on-treatment
levels of hs-CRP, LDL-C, and incidence of future CV events.(15) In this study, statin-treated patients who additionally received bococizumab had a significant decrease in LDL-C (p<0.001), but there was no change in hs-CRP (p=0.09). After adjustment for traditional CV risk
factors and LDL-C, higher hs-CRP levels were associated with a higher incidence of future CV events (hs-CRP <1,1-3 and >3mg/L corresponded to multivariateadjusted HR of 1.0, 1.1, and 1.62 with p trend=0.001). This demonstrates that despite optimization of LDL-C, residual inflammation has deleterious CV effects.

In Colchicine CV Outcomes Trial (COLCOT) involving 4,745 patients recruited within 30 days after MI, lowdose colchicine (an oral anti-inflammatory agent) led to a significantly lower risk of ischemic CV events than placebo over a median of 22.6 months (HR: 0.77, 95%
CI, 0.61 to 0.96, p=0.02).(16) Hs-CRP was measured in a small subgroup of 207 patients at the time of randomization and after 6 months, which limited its interpretability (placebo-adjusted geometric mean percent change was -10.1 percentage points in the colchicine group, 95% CI, -28.6 to 13.4). In the second Low Dose Colchicine (LoDoCo2) trial, the use of colchicine in patients with chronic CAD led to a significantly lower risk of CV events than placebo over a median of 28.6 months (HR: 0.69; 95% CI, 0.57 to 0.83; P<0.001) [17]. A sub-study of LoDoCo2 targeting proteomic analysis of the patient’s serum sample before and after 30 days of colchicine revealed a decrease in inflammatory markers.(18)

Novel diabetes pharmacologic agents and cardiovascular outcomes:
Type 2 Diabetes Mellitus and associated insulin resistance show direct and indirect effects leading to residual CVD risk.(19) The recent inclusion of sodium-glucose cotransporter-2 (SGLT2) inhibitors and glucagon-like peptide-1 receptor agonists (GLP1RA) as therapeutic options for type 2 DM has expanded the potential for CVD risk reduction. In the UKPDS-34 (UK Prospective Diabetes Study), the use of metformin in overweight newly-diagnosed type 2 DM patients was associated with a significant decrease in DM-related endpoints (p=0.002), DMrelated death (p=0.017), and all-cause mortality (p=0.011) compared to the conventional group.(20) In the Liraglutide Effect and Action in Diabetes: Evaluation of CV Outcome Results (LEADER) trial, liraglutide (a GLP1RA agent) was associated with a significantly lower rate of the first occurrence of death from CV causes, nonfatal MI, or non-fatal stroke among patients with type 2 DM (HR, 0.87; 95% CI, 0.78 to 0.97, p=0.01 for superiority).(21) A meta-analysis of randomized control trials assessing GLP1RAs revealed a class effect for the composite CV benefits of longacting GLP1RAs.(22) In the Empagliflozin CV Outcome Event Trial in Type 2 DM Patients (EMPA-REG OUTCOME trial), the addition of 10mg or 25mg of empagliflozin (a SGLT2 inhibitor) to standard care was associated with a significantly lower rate of the primary composite CV outcome and of death from any cause (HR, 0.86; 95% CI, 0.74 to 0.99; P=0.04 for superiority).(23) In the Dapagliflozin in Patients with Heart Failure and Reduced Ejection Fraction (DAPA-HF) trial, the risk of worsening heart failure or death from CV causes was significantly lower among those patients who received 10mg dapagliflozin daily (a SGLT2 inhibitor) compared to placebo, regardless of DM status (HR, 0.74; 95% CI, 0.65 to 0.85; P<0.001).(24) The convergence of evidence from randomized control trials assessing SGLT2 inhibitors showed inconsistency in major adverse CV event reduction, but a class effect was evident for reducing heart failure hospitalization and diabetic kidney disease progression.(25)

Investigational agents for lowering lipoprotein(a)
Lipoprotein(a) (Lp(a)) is an LDL particle with a unique apolipoprotein (a) covalently bound to apolipoprotein B-100 by a disulfide bond. Researchers have shown that high Lp(a) is an independent CVD risk factor with a predisposition to both CVD and calcific aortic stenosis.(26) A study assessed two phase 2 trials evaluating the efficacy, safety, and tolerability of two antisense oligonucleotides targeting apolipoprotein(a).(27) In the first trial (NCT02160899) involving two cohorts of 64 participants, at day 85/99 IONISAPO(a)Rx had a mean Lp(a) reduction of 66.8% in cohort A and 71.6% in cohort B (both p<0.0001 vs. pooled placebo). In the second trial (NCT02414594) involving 58 healthy participants with Lp(a) >75 nmol/L, at day 36, IONIS-APO(a)-LRx showed a significant mean reduction in Lp(a) ranging from 66-92% (p=0.0007 for all vs. placebo). A phase 3 trial (NCT04023552 HORIZON) evaluating the impact of Lp(a) lowering on major adverse CV events in patients with elevated Lp(a) ≥ 70 mg/dL is underway. Another molecule, AMG-890, is a small interfering RNA that is currently in phase 2 trials (NCT04270760) to investigate the effects of Lp(a) lowering.

Anticoagulation risks and benefits:
Anticoagulants have also been postulated to help lower CV events due to the disruption of thrombus formation in acute coronary syndrome. In the CV Outcomes for People Using Anticoagulation Strategies (COMPASS) trial, 27,395 participants with the stable atherosclerotic vascular disease were randomized to receive rivaroxaban (2.5mg twice daily) plus aspirin (100mg once daily), rivaroxaban (5mg twice daily), or aspirin (100mg once daily).(28) The primary outcome was a composite of CV death, stroke, or MI. The primary
outcome occurred in fewer patients in the rivaroxaban-plus-aspirin group than in the aspirin-alone group (379 patients [4.1%] vs. 496 patients [5.4%]; HR, 0.76; 95% CI, 0.66 to 0.86; P<0.001), but major bleeding events occurred in more patients in the rivaroxaban-plus-aspirin group (288 patients [3.1%] vs. 170 patients [1.9%]; HR: 1.70; 95% CI, 1.40 to 2.05; P<0.001). There was no significant difference in intracranial or fatal bleeding between these two groups. There were 313 deaths (3.4%) in the rivaroxaban-plus-aspirin group as compared with 378 (4.1%) in the aspirin-alone group (HR, 0.82; 95% CI, 0.71 to 0.96; P=0.01). This study concluded that rivaroxaban 2.5mg twice daily plus aspirin resulted in a better CV outcome in patients with stable disease. However, there were more bleeding events
in the rivaroxaban plus aspirin group than aspirin alone. Higher doses of rivaroxaban (5mg twice daily) were not associated with better CV outcomes and were associated with more major bleeding.(28)

Conclusion
The link between lipids and CVD is very well established. In addition to multipronged pharmacotherapy advances, healthy dietary patterns and regular physical exercise have also been shown to reduce CV risk.(8,12) Addressing CVD as a multifactorial process with lifestyle and diverse pharmacotherapy has great promise to show substantial CVD reduction.

Disclosure statement:
Dr. Minga has no financial disclosures to report. Dr. Pulipati has no financial disclosures to report. Dr. Davidson has received honoraria from Amgen, Regeneron, Amryt, and Esperion.

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