1. Introduction

2. Methods

3. HMG-CoA Reductase Inhibitors

3.1. Primary Prevention

In the primary prevention setting, any intervention aimed at reducing difficult outcomes such as mortality or myocardial infarction (MI) must involve large and/or long trials with sufficient power to detect differences in the inherently low event rate when compared to secondary prevention trials. Furthermore, the highest degree of scrutiny and critical reasoning is necessary before indicating an intervention to asymptomatic individuals, since its benefits tend to occur in the long term, while unaccounted adverse effects may derive from any kind of intervention.

One of the first and most relevant trials that rose to this challenge was the West of Scotland Coronary Prevention Study Group (WOSCOPS) trial [4]. In this study, pravastatin 40 mg was tested against placebo in patients with elevated LDL-C levels and no documented coronary artery disease (CAD). Over the 4.9 years of follow-up, LDL-C levels were reduced by an average of 26% and patients in the pravastatin group had lower rates of MI and coronary heart disease-related death.

Subsequently, the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS) evaluated the effect of cholesterol lowering with lovastatin in patients with moderately elevated lipid levels without clinically evident atherosclerotic cardiovascular disease (ASCVD) [5]. Lovastatin reduced the risk of the primary outcome of MI, unstable angina (UA), or sudden cardiac death (SCD). However, due to the low cardiovascular (CV) risk of the enrolled patients, the absolute risk reduction (ARR) of 0.2% per year was much smaller than demonstrated in previous trials (Number Needed to Treat [NNT] of 86). Furthermore, the study was stopped early for efficacy. Statistical simulations, however, suggest that truncated studies overestimate the magnitude of benefit of the treatment being evaluated by up to 29% [6].

Two other important studies that showed the CV benefits of statins in patients without documented ASCVD were ASCOT-LLA and MEGA.

The Anglo-Scandinavian Cardiac Outcomes Trial - Lipid Lowering Arm (ASCOT-LLA) trial showed that among patients with hypertension and relatively low cholesterol, treatment with atorvastatin was associated with a reduction in the primary endpoint of MI or coronary death at 3-year follow-up [7].

The Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese (MEGA) trial showed that treatment with pravastatin in addition to diet modification was associated with a reduction in coronary heart disease events compared with diet modification alone at a mean 5.3-year follow-up [8].

Despite the evidence provided by the WOSCOPS study, concerns have arisen regarding patients with lower LDL-C levels but with an estimated risk of ASCVD. Thus, markers capable of detecting patients who may benefit from statin therapy for primary prevention have been investigated. The Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial compared rosuvastatin versus placebo in patients with LDL-C <130 mg/dL, no known ASCVD and high-sensitivity C-reactive protein (hsCRP) levels of 2.0 mg per liter or higher [9]. The study showed a reduction in the primary composite endpoint (MI, stroke, arterial revascularization, hospitalization for UA, or CV death) [HR 0.56, 95% CI 0.46 to 0.69, ARR of 0.59% per year for the primary endpoint, NNT 169]. For coronary events, including fatal or non-fatal myocardial infarction, 500 persons need to be treated for one year to prevent one event. In addition to the low effect estimate demonstrated by rosuvastatin in the JUPITER study, methodological concerns have limited the widespread application of the results of this trial. First, the trial was truncated, which is known to overestimate the benefits of the intervention [6]. A 5-year follow-up was planned, but a median of only 1.9 years of follow-up was achieved. Regarding the use of hsCRP, it was not possible to determine whether patients benefited from rosuvastatin because they had high levels of hsCRP, since all patients had similar levels, and the study was not designed to test the strategy of using hsCRP as a marker for statin initiation versus standard care nor multivariate models to evaluate the impact of hsCRP were reported. The benefit found may have derived, for example, from the reduction of LDL-C in patients with high CV risk related to uncontrolled hypertension (the upper quartile of blood pressure was 145/87 mmHg).

Subsequently, the Heart Outcomes Prevention Evaluation (HOPE)-3 trial was published, shedding a little more light into this scenario. Patients of intermediate risk (estimated annual rate of major adverse cardiovascular events [MACE] ~1%) were randomly assigned to either rosuvastatin 10 mg or placebo, in a 2 x 2 factorial design with blood pressure lowering agents (candesartan and hydrochlorothiazide) [10]. There was not a specific LDL-C threshold for eligibility. The rosuvastatin group had a reduction in the composite coprimary endpoint of CV death, MI or stroke (HR 0.76, 95% CI 0.64 to 0.91, NNT of 91).

Despite the cardiovascular benefits suggested by the aforementioned trials, it is important not to let go of clinical reasoning and recognize the magnitude of the findings. Due to the inherent low incidence of events in the primary prevention population, it is important to acknowledge that the clinical benefit is marginal in the follow-up period of the trials, with high NNTs. Also, older patients comprise most of these study populations. The long-term benefit is probably greater than found in the aforementioned trials, and lifelong LDL-C lowering therapies might have an impact when considering younger patients with high LDL-C levels or higher than average CV risk factors.

Table 1. Primary prevention trials. Legend: CAD: coronary artery disease; CV: cardiovascular; hsCRP: high sensitivity C-reactive protein; MI: myocardial infarction; UA: unstable angina; TC: total cholesterol.

Table 1. Primary prevention trials. Legend: CAD: coronary artery disease; CV: cardiovascular; hsCRP: high sensitivity C-reactive protein; MI: myocardial infarction; UA: unstable angina; TC: total cholesterol.

Study	Sample size	Characteristics of patients	Comparison groups	Follow-up	LDL effect	CV effects
WOSCOPS (1995) [4]	6,595	TC > 252 mg/dL	Pravastatin 40 mg vs. placebo	4.9 years	26%	MI or coronary death (HR 0.69, 95% CI 0.57 to 0.83, NNT 111)
AFCAPS / TexCAPS (1998) [5]	6,605	LDL-C 130-180 mg/dL	Lovastatin 20-40 mg vs. placebo	5.3 years	25%	major coronary events (HR 0.63, 95% CI 0.50 to 0.79, NNT 86)
ASCOT-LLA (2003) [7]	10,305	Hypertension and CV risk factors	Atorvastatin 10 mg vs. placebo	3.3 years	35%	MI or coronary death (HR 0.64, 95% CI 0.50 to 0.83, NNT 83)
MEGA (2006) [8]	7,832	TC 220-270 mg/dL	Pravastatin 10 mg vs. placebo	5.3 years	18%	CAD (HR 0.67, 95% CI 0.49 to 0.91, NNT 119)
JUPITER (2008) [9]	17,802	LDL-C <130 mg/dL + hsCRP ≥2 mg/L	Rosuvastatin 20 mg vs. placebo	1.9 years	50%	CV death, MI, stroke, arterial revascularization, or UA hospitalization (HR 0.56, 95% CI 0.46 to 0.69, NNT 169)
HOPE-3 (2016) [10]	12,705	Intermediate CV risk (CV event rate 1%/year)	Rosuvastatin 10 mg vs. placebo	5.6 years	26.5%	CV death, MI and stroke (HR 0.76, 95% CI 0.64 to 91, NNT 91)

3.2. Secondary Prevention

The consistent relative risk reduction (RRR) of MACE points towards a solid relationship between statin use and lower ratio of events. However, the clinical significance of such reduction will depend on the absolute rate of events, with more evident benefit seen in patients at the highest risk of MACE. This is found in secondary prevention clinical studies.

The Scandinavian Simvastatin Survival Study (4S) trial randomized 4,444 patients with coronary artery disease (CAD), defined by prior MI or angina, to simvastatin or placebo [11]. The trial was stopped early due to an ARR of 3.3% in all-cause mortality with simvastatin (11.5% vs. 8.2%; p=0.0003; NNT 30). In addition to being a truncated study, the low rate of aspirin use among the 4S trial population (~37%) draws attention. Possibly the magnitude of the benefit would be attenuated with widespread aspirin use. Also, the rate of patients with previous MI was high (79%), which configures a higher risk secondary prevention population, and benefits can be attenuated in a CAD population with no prior history of MI.

The Cholesterol and Recurrent Events (CARE) trial confirmed reduction of coronary events in patients with previous MI, even in a group with lower total cholesterol levels (<240 mg/dL, mean LDL-C of 139) [12] Similarly, the Long-term Intervention with Pravastatin in Ischaemic Disease (LIPID) trial showed a reduction in coronary death in patients with previous MI or hospitalization for UA (NNT of 53) [13]. The Heart Protection Study (HPS) showed a reduction in all-cause mortality, driven by vascular causes (7.6% vs. 9.1%, HR 0.83, 95% CI 0.75 to 0.91, NNT 67) in high-risk patients - 65% with previous CAD [13]. On the other hand, the FLuvastatin On RIsk Diminishing after Acute myocardial infarction (FLORIDA) trial showed that fluvastatin did not reduce coronary events in post-MI patients [15]. However, the trial was underpowered and a post hoc analysis revealed a trend towards a reduction in the primary endpoint in patients with pronounced ischaemia at trial onset [16].

So far, the relationship between intervention and outcome seems to be established, naturally with greater benefits seen in patients at higher baseline risk. However, new questions arose - What is the best statin regimen for reducing cardiovascular outcomes?

The Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 (PROVE IT-TIMI 22) trial tested different intensity regimens in patients in the acute phase of a MI [17]. Among those up to 10 days after an acute event, atorvastatin 80 mg reduced a composite of death from any cause, MI, documented UA requiring rehospitalization, revascularization after 30 days of randomization or stroke when compared to pravastatin 40 mg (22.4% vs 26.3%, HR 0.84, 95% CI 0.74 to 0.95). However, it is important to note that this endpoint is very broad and includes more fragile outcomes such as unstable angina and need for revascularization. Moreover, reductions in LDL-C levels in the pravastatin group were strikingly low (baseline LDL-C 106 mg/dL and LDL-C achieved at follow-up 95 mg/dL), which surely favors the atorvastatin group, which achieved LDL-C of 62 mg/dL on follow-up (41% reduction). This low LDL-C reduction in LDL-C is in part explained by the 25% of participants that were already on statin therapy and did not have their LDL-C levels changed by pravastatin use and had an additional 32% reduction with atorvastatin. In the 75% of patients who were not already on a statin, atorvastatin reduced LDL-C by 51% in 30 days and pravastatin reduced LDL-C by 22%.

The Incremental Decrease in Endpoints Through Aggressive Lipid Lowering (IDEAL) trial tested atorvastatin 80 mg versus simvastatin 20 mg and found no difference in the primary endpoint of coronary death, non-fatal MI or cardiac arrest with resuscitation (HR 0.89, 95% CI 0.78 to 1.01) [18]. One limitation of this trial was the smaller than expected reductions in LDL-C levels, which were around 34% with atorvastatin 80 mg and 17.7% in the simvastatin 20 mg group, possibly blunting an eventual difference in effects, but this is merely speculatory.

The Treating to New Targets (TNT) trial tested different regimens of atorvastatin (80 mg versus 10 mg, a high versus a moderate intensity regimen) in patients with stable CAD [19]. This trial found a reduction in coronary death, nonfatal non-procedural MI, resuscitation after cardiac arrest or stroke (8.7% vs 10.9%, NNT of 46). The primary endpoint was mainly driven by MI and stroke.

Finally, the Study of the Effectiveness of Additional Reductions in Cholesterol and Homocysteine (SEARCH) trial tested different simvastatin doses (20 mg versus 80 mg) and found no difference in efficacy outcomes, yet with a higher incidence of myopathy [20]. Thus, simvastatin 80 mg should not be used.

Based on findings from randomized clinical trials (RCTs), it appears that high intensity regimens lead to a modest benefit in patients with CAD, even with “normal” LDL-C levels, mainly driven by reduction in cardiac events but without clear mortality benefits.

Table 2. Secondary prevention trials. * Included both primary and secondary prevention patients. Legend: ACS: acute coronary syndrome; CA: cardiac arrest; CAD: coronary artery disease; HTN: hypertension; MI: myocardial infarction; TC: total cholesterol; UA: unstable angina.

Table 2. Secondary prevention trials. * Included both primary and secondary prevention patients. Legend: ACS: acute coronary syndrome; CA: cardiac arrest; CAD: coronary artery disease; HTN: hypertension; MI: myocardial infarction; TC: total cholesterol; UA: unstable angina.

Study	Sample size	Characteristics of patients	Comparison groups	Follow-up	LDL effect	CV effects
4S (1994) [11]	4,444	Angina or previous MI	Simvastatin 20-40 mg vs. placebo	5.4 years	35%	mortality (HR 0.70, 95% CI 0.58 to 0.85, NNT 30)
CARE (1996) [12]	4,159	Previous MI TC < 240 mg/dL LDL-C 115-174 mg/dL	Pravastatin 40 mg vs. placebo	5 years	28%	coronary death or MI (10.2% vs. 13.2%, NNT 34)
LIPID (1998) [13]	9,014	Previous MI or UA TC 155-271 mg/dL	Pravastatin 40 mg vs. placebo	6.1 years	25%	coronary death (6.4% vs. 8.3%, NNT 53)
FLORIDA (2000) [15]	540	MI	Fluvastatin 80 mg vs. placebo	1 year	21%	No significant difference in the incidence of major coronary event
HPS* (2002) [14]	20,536	TC > 135 mg/dL + CAD or other arterial disease or diabetes or > 65y male w/ HTN	Simvastatin 40 mg vs. placebo	5 years	35%	all-cause mortality (12.9% vs. 14,7%, NNT 56)
PROVE-IT (2004) [17]	4,162	ACS < 10 days	Atorvastatin 80 mg vs. pravastatin 40 mg	24 months	31%	all-cause mortality, MI, UA hospitalization, revascularization in 30 days, or stroke (HR 0.84, 95% CI 0.74 to 0.95, NNT 53)
IDEAL (2005) [18]	8,888	Previous MI	Atorvastatin 80 mg vs. simvastatin 20 mg	4.8 years	20%	No significant difference in the incidence of major coronary event
TNT (2005) [19]	10,001	CAD	Atorvastatin 80 mg vs. atorvastatin 10 mg	4.9 years	24%	CV death, MI, CA, or stroke (HR 0.78, 95% CI 0.69 to 0.89, NNT 45)
SEARCH (2010) [20]	12,064	Previous MI LDL-C >135 mg/dL (statin use) or LDL-C >193 mg/dL (no statin)	Simvastatin 20 mg vs. simvastatin 80 mg	6.7 years	14%	No significant difference in the incidence of CV events

3.3. Special groups

Despite growing evidence solidifying statins as the cornerstone in LDL-C lowering therapy, the possibility has been raised that specific groups could have clinical benefits from statins.

The Collaborative Atorvastatin Diabetes Study (CARDS) trial tested atorvastatin 10 mg versus placebo for primary prevention in patients with diabetes and at least one additional risk factor (retinopathy, albuminuria, current smoking or hypertension), with LDL-C <160 mg/dL [21]. Although truncated (terminated 2 years earlier due to prespecified efficacy criteria), this trial showed a reduction in CV events (9.0% vs. 3.2%, NNT 32).

The Atorvastatin Study for Prevention of Coronary Heart Disease Endpoints in Non-Insulin-Dependent Diabetes Mellitus (ASPEN) trial randomized patients with diabetes in primary (79%) and secondary prevention (21%) to receive atorvastatin 10 mg or placebo and found no difference in the primary endpoint of CV death, MI, stroke, revascularization, worsening UA requiring hospitalization or resuscitated cardiac arrest [22]. These results can be explained by important steering disturbances during the trial. A widespread recognition of the importance of CV prevention in diabetes patients led to a recommendation to stop the study medications and allocate all secondary prevention patients and previously primary prevention patients that now met an endpoint to receive usual care. This led to a very low completion rate, and only 67% of the intervention and 58% of the placebo group were receiving the study medication at the end of the double-blind follow-up. This reduces the power to detect differences and hinders the evaluation of the results; care should be taken when using these findings.

Subanalyses of the HPS and ASCOT-LLA trials with diabetic patients showed that statin reduces CV events [23,24].

In patients with chronic kidney disease (CKD), several trials have evaluated the CV effects of statins. The Assessment of Lescol in Renal Transplantation (ALERT) trial showed that among renal transplant patients, treatment with fluvastatin was not associated with a reduction in the primary composite endpoint of cardiac death, MI, or coronary intervention procedure during 5.1 years of follow-up [25].

The Die Deutsche Diabetes Dialyse Study (4D) also showed no reduction in the composite primary endpoint of death from cardiac causes, MI or stroke with atorvastatin treatment in patients with type 2 diabetes undergoing routine hemodialysis [26]. Similarly, the Study to Evaluate the Use of Rosuvastatin in Subjects on Regular Hemodialysis: An Assessment of Survival and Cardiovascular Events (AURORA) trial found no benefit in 2,776 CKD patients on dialysis who were randomized to rosuvastatin 10 mg or placebo [27].

On the other hand, the Study of Heart and Renal Protection (SHARP) showed that ezetimibe/simvastatin compared to placebo reduces LDL-C and atherosclerotic and major vascular events in patients with CAD, but no overt CAD (11.3% versus 13.4%, HR 0.83, 95% CI 0.74 to 0.94) [28].

Thus, CKD patients not on dialysis might benefit from statins, with a modest impact, while CKD patients on dialysis do not seem to benefit from this therapy.

Patients with heart failure (HF) are another group of interest, and have been frequently excluded from statin trials. The Controlled Rosuvastatin Multinational Trial in Heart Failure (CORONA) trial showed that therapy with rosuvastatin was not associated with a reduction in the primary endpoint of CV death, MI, or stroke at a median follow-up of 32.8 months compared with placebo [29]. Additionally, the Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico-Heart Failure (GISSI-HF) trial showed that rosuvastatin 10 mg daily is not beneficial in reducing cardiac outcomes among patients with chronic symptomatic HF [30].

The elderly population was exclusively studied in the Prospective Study of Pravastatin in the Elderly at Risk (PROSPER) trial [31]. This study showed a reduction in the composite primary outcome of coronary death, MI and stroke (14.1% versus 16.2%, HR 0.85, 95% CI 0.74 to 0.97, NNT 48) in the statin group.

Persons with HIV infection, a group with increased cardiovascular risk, were also analyzed in a recent phase 3 trial. In the Randomized Trial to Prevent Vascular Events in HIV (REPRIEVE) study, 7,769 participants with HIV infection were randomized to daily pitavastatin at a dose of 4 mg or placebo. After a median follow-up of 5.1 years, the study was interrupted due to efficacy. The rate of MACE was 4.81 and 7.32 per 1000 person-years in the pitavastatin and placebo groups, respectively (HR 0.65, 95% CI 0.48 to 0.90, p=0.002). Muscle-related symptoms and incident diabetes were more common in the pitavastatin group [32].

Finally, a meta-analysis of data from 170,000 patients, evaluated statin versus placebo and different statin regimens and reported a 10% reduction in all-cause mortality per 38 mg/dL LDL-C reduction (HR 0.90, 95% CI 0.87 to 0.93) [33]. In an unweighted analysis of the 21 placebo-controlled trials included, any major vascular event occurred in 3.6% in the placebo groups versus 2.8% in the statin groups. translating into a 0.8% ARR and a 22% RRR. Regarding higher versus lower intensity regimens, higher intensity regimens led to reductions in major vascular events (RRR 15%, 95% CI 11 to 18), especially when weighted for LDL-C reductions (RRR per 1 mmol/L reduction in LDL-C), suggesting that greater reductions in LDL-C accompany greater reductions in MACE.

The evidence presented so far establishes the relationship between intervention and effect, and statins reduce CV events. The magnitude of benefits should however always permeate clinical reasoning, and NNTs ranging from 30 to a lot higher numbers have been found. The higher the baseline risk, the greater benefit that should be expected from statins. There is a logical chain binding CV risk factors. CV disease and death. Treating one will probably affect the other, but with progressively smaller magnitude. On the other hand, benefits in the above discussed trials seem to increase over time, which is expected since risk factors may be lifelong cumulative. Trials tend to follow patients over the course of a few years. and potential long-term benefits should be taken into account. The concepts proven with the studies above should be used as tools to individualized decision-making in clinical practice.

Table 3. Statins in special groups. Legend: ACS: acute coronary syndrome; CHD: coronary heart disease; CKD: chronic kidney disease; CV: cardiovascular; LVEF: left ventricular ejection fraction; MACE: major cardiovascular events; MI: myocardial infarction; NYHA: New York Heart Association; TG: triglycerides.

Table 3. Statins in special groups. Legend: ACS: acute coronary syndrome; CHD: coronary heart disease; CKD: chronic kidney disease; CV: cardiovascular; LVEF: left ventricular ejection fraction; MACE: major cardiovascular events; MI: myocardial infarction; NYHA: New York Heart Association; TG: triglycerides.

Study	Sample size	Characteristics of patients	Comparison groups	Follow-up	LDL effect	CV effects
CARDS (2004) [21]	2,838	Diabetes (40-75y) + LDL-C <160 mg/dL + TG <600 mg/dL + additional risk factor	Atorvastatin 10 mg vs. placebo	3.9 years	40%	ACS, additional revascularization, or stroke (HR 0.63, 95% CI 0.48 to 0.83, NNT 31)
ASPEN (2006) [22]	2,410	Diabetes (40-75y) + LDL <160 mg/dL or <140 mg/dL (prior MI or revascularization)	Atorvastatin 10 mg vs. placebo	4 years	29%	No significant difference in the incidence of CV events
ALERT (2003) [25]	2,102	Renal or combined renal and pancreas transplants >6 months	Fluvastatin 40 mg vs. placebo	5.1 years	25%	No significant difference in the incidence of CV events
4D (2005) [26]	1,255	Diabetes + CKD on dialysis	Atorvastatin 20 mg vs. placebo	4 years	42%	No significant difference in the incidence of CV events
AURORA (2009) [27]	2,773	CKD on dialysis	Rosuvastatin 10 mg vs. placebo	3.8 years	43%	No significant difference in the incidence of CV events
SHARP (2011) [28]	9,270	CKD	Simvastatin 20 mg + ezetimibe 10 mg vs. placebo	4.9 years	31%	coronary death, MI, stroke, or revascularization (HR 0.83, 95% CI 0.74 to 0.94, NNT 53)
CORONA (2007) [29]	5,011	LVEF < 40% + NYHA II-IV	Rosuvastatin 10 mg vs. placebo	2.7 years	45%	No significant difference in the incidence of CV events
GISSI-HF (2008) [30]	6,975	Heart failure NYHA II-IV	Rosuvastatin 10 mg vs. placebo	3.9 years	16%	No significant difference in the incidence of CV events
PROSPER (2002) [31]	5,804	Elderly (70-82 years) + high CV risk	Pravastatin 40 mg vs. placebo	3.2 years	34%	coronary death, MI, or stroke (HR 0.85. 95% CI 0.74 to 0.97. NNT 48)
REPRIEVE (2023) [32]	7,769	HIV	Pitavastatin 4 mg vs. placebo	5.1 years	30%	MACE (HR 0.65, 95% CI 0.48 to 0.90)

4. PCSK9 inhibitors

Table 4. Main PCSK9 Inhibitors trials. Legend: ACS: acute coronary syndrome; ApoB: apolipoprotein B; CV: cardiovascular; MI: myocardial infarction; UA: unstable angina.

5. Ezetimibe

Table 5. Major clinical trials of ezetimibe. Legend: CAD: coronary artery disease; CABG: coronary artery bypass graft; CV: cardiovascular; DM: diabetes mellitus; ER-niacin: extended-release-niacin; HF: familial hypercholesterolemia; MI: myocardial infarction; NA: not evaluated; PAD: peripheral artery disease; PCI: percutaneous coronary intervention; SCD: sudden cardiac death; TC: total cholesterol; TG: triglycerides.

6. Bempedoic acid

7. Lp(a)-Targeted Therapies

8. Bile Acid–Binding Resins

9. Nicotinic Acid

Table 6. Major clinical trials of niacin. Legend: ACS: acute coronary syndrome; CAD: coronary artery disease; CABG: coronary artery bypass graft; CV: cardiovascular; DM: diabetes mellitus; ER-niacin: extended-release-niacin; MI: myocardial infarction; PAD: peripheral artery disease; TC: total cholesterol; TG: triglycerides; TIA: transient ischemic attack.

10. Fibric Acid Derivatives

Table 7. Major clinical trials and epidemiological studies of fibrates. Legend: CAD: coronary artery disease; CV: cardiovascular; MI: myocardial infarction; NE: not evaluated; PAD: peripheral artery disease; TG: triglycerides; T2DM: type 2 diabetes mellitus.

11. Omega-3 fatty acids

Table 8. Characteristics of the main published trials involving omega-3 fatty acids. Legend: ACS: acute coronary syndrome; CV: cardiovascular; MI: myocardial infarction; NA: not evaluated; SCD: sudden cardiac death; TC: total cholesterol.

12. Cholesteryl ester transfer protein (CETP) inhibitors

Table 9. Characteristics of the main published trials involving CETP inhibitors. Legend: ACS: acute coronary syndrome; CAD: coronary artery disease; CV: cardiovascular; HeFH: heterozygous familial hypercholesterolemia; MI: myocardial infarction; NE: not evaluated.

13. Gene Therapy

13.1. siRNA

Small interfering RNAs (siRNAs) are short regulatory RNA molecules that suppress genes that are overexpressed in a given disease through post-transcriptional silencing.

Effective pharmacological use of siRNA requires 'carriers' that can deliver the siRNA to its intended site of action, such as viral and non-viral vectors (polymeric or lipid nanoparticles, polyplexes, lipoplexes, liposomes, or multifunctional nanocarriers).

In the cytoplasm, siRNA is processed from double-stranded RNA, which comes from endogenous transcription of DNA or from exogenous sources such as a virus. This double-stranded RNA is then cleaved by the ATP-dependent RNA endonuclease, Dicer, into fragments 21-23 nucleotides long with two nucleotide overhangs at both ends. This siRNA is then loaded into another protein, Argonaute. Argonaute has four different domains – N-terminal, PAZ, Mid, and PIWI. Its PIWI domain has RNase activity that allows Argonaute to cleave target mRNA. The Argonaute-siRNA complex then binds with a helicase and other proteins to form the RNA-induced silencing complex (RISC). In RISC, the sense strand is separated from the antisense, or guide strand, which is thought to be catalyzed by the helicase. The sense strand is degraded in the cytoplasm, and the guide strand directs the RISC to a complementary target mRNA.

The fate of the target mRNA is determined by whether the guide mRNA exhibits optimal or sub-optimal base pairing with the target mRNA. If the guide strand shows ideal base pairing with the target mRNA, the target mRNA is cleaved by Argonaute. Then the RISC complex is reused again to target another mRNA. In contrast, if the guide strand exhibits suboptimal base pairing with the target mRNA strand, Argonaute will not cleave the mRNA. Instead, it will lead to translation arrest, as the RISC complex will obstruct ribosome binding and translocation. These mRNAs are then guided to processing bodies (P-bodies) where they are gradually degraded. In the nucleus, siRNA can silence transposable DNA elements and thus prevent their unwanted and dangerous random insertions into the genome.

There are, however, some challenges to the administration of siRNAs [114], as shown in Table 9.

Table 9. Challenges for administering siRNAs.

Table 9. Challenges for administering siRNAs.

Physicochemical characteristics of the siRNA molecule	Hydrophilic macromolecule
	High molecular weight (~13 kDa)
	Negative charge
	Low stability in biological fluids
Barriers inherent to the route of administration	Tissue penetration
	Interstitial nucleases
	Internalization by target cells
	Activation of the immune response

13.1.1. Lepodisiran

Lepodisiran is a short interfering RNA directed at hepatic production of apolipoprotein(a). In a phase 1 study of 48 participants with elevated Lp(a) levels and without cardiovascular disease, lepodisiran reduced Lp(a) levels by 94% at 48 weeks [115].

13.1.2. Inclisiran

Since the discovery of the interaction of PCSK9 with LDL-C metabolism, several studies have sought alternative therapies for LDL-C reduction, targeting PCSK9. The initial results of monoclonal antibodies (alirocumab and evolocumab) were highlighted in the scientific world due to the significant decrease in LDL-C levels and reduction in cardiovascular death, MI, stroke and hospitalization for angina in an average follow-up of 2.5 years [116,117]. However, there are still doubts about potential adverse immunological effects of these medications in the long-term, as the studies are recent. Furthermore, the current dosage (biweekly application) of these medications can make it difficult for patients to adhere to them. Due to these concerns, an alternative to monoclonal antibody treatment was sought, but still involving PCSK9 as a target.

Inclisiran is a small interfering RNA (siRNA), small synthetic molecule that binds to PCSK9 mRNA, promoting its degradation and consequent inhibition of PCSK9 synthesis [118]. These molecules called siRNA are about 25 nucleotides of RNA, which have recently become known as important regulators of the expression and function of the human genome. Long double-stranded RNA, like that present in some types of viruses, induces an immunological response via interferon, which, in turn, causes a generalized interruption of protein synthesis. Due to this characteristic, long double-stranded RNA cannot be used to silence specific genes. On the other hand, siRNAs can escape the response radar via interferon and, therefore, promote the effective silencing of specific genes through complementary nucleotide sequences that affect post-transcriptional mRNA degradation, thus preventing the translation process [119]. Inclisiran is composed of these long-acting synthetic siRNA molecules, which bind intracellularly to the RISC, cleaving mRNA that would specifically participate in the translation of PCSK9 and consequently its synthesis in the liver, allowing the reduction of circulating levels of PCSK9 by up to 70% in phase 1 study [120].

The characteristics of the main trials published on inclisiran are available in Table X. The first phase 2 study was published in 2017 [121]. The ORION-1 trial included patients with ASCVD and elevated LDL-C (>70 mg/dL) despite maximum tolerated statin therapy and patients without ASCVD but with high cardiovascular risk conditions such as diabetes and FH in whom LDL-C was >100 mg/dL despite maximally tolerated statin therapy. Patients using PCSK9 inhibitors were excluded. Patients were randomized into eight treatment groups: a single dose regimen of 200, 300 or 500 mg inclisiran, or placebo; or a two-dose regimen of 100, 200 or 300 mg inclisiran, or placebo. The primary endpoint of LDL-C reduction at 180 days was reduced by 27.9-41.9% with one subcutaneous injection and by 35.5-52.6% with two injections (p <0.001). At 240 days, the reductions in PCSK9 and LDL-C remained significantly lower than baseline with all the studied doses of inclisiran. Two injections of the 300 mg dose of inclisiran produced the greatest reduction in LDL-C, with 48% of patients receiving this dose achieving an LDL-C level <50 mg/dL.

The ORION-3 trial, an open-label extension of the phase II ORION-1 trial, assessed whether LDL-C level reduction was sustained over a four-year follow-up [122]. Patients treated with inclisiran achieved an average 47.5% reduction in LDL-C from baseline (day 1 of ORION-1) to day 210 (95% Cl -50.7 to -44.3) and a time-averaged reduction in LDL-C of 44.2% over the 4 years through twice-yearly dosing. Another result of this study is the evaluation of the efficacy and safety of switching from a monoclonal antibody (evolocumab) to inclisiran 24 days after the last dose of evolocumab (staggered change) or on the same day of the last application (concurrent change). The researchers allocated patients into two groups: “inclisiran-only”, which was the extension of the duration of use of those patients who were originally already receiving inclisiran (in the ORION-1 study) and a second group called “switching arm”, formed by patients who had received placebo in the ORION-1 trial and started receiving evolocumab for one year and a pre-established switch to inclisiran for the next 3 years. There was a greater mean percentage reduction in LDL-C in patients using evolocumab - 61.0% (95% CI 64.5 to 57.4) than after switching to inclisiran - time-averaged 3-year LDL-C reduction of 45.3% (95% CI 49.7 to 40.9). However, it was not a study designed to compare the effectiveness of inclisiran versus evolocumab, but rather, the ease, safety and effectiveness of switching from one medication to the other at different times and in a single arm – formally, to compare the effectiveness of the two medications, ideally randomization should take place into three arms: inclisiran, evolocumab and a placebo group. Interestingly, the placebo group showed a very small average variation in LDL-C levels (less than 10% compared to baseline levels), even with more than 70% of the population using statins. Absolute LDL-C levels in both groups (“inclisiran-only” and “switching arm”) were similar at the time of switching from one medication to the other. There was no placebo group in this study: 92 patients out of the 127 originally belonging to the placebo group of the ORION-1 trial started receiving evolocumab before the scheduled switch to inclisiran (on day 336 or 360, as mentioned above) while 290 of 370 patients were allocated to drug continued into the inclisiran-only arm.

On the other hand, the phase 3 ORION-5 trial showed that inclisiran treatment did not reduce LDL-C levels in patients with homozygous familial hypercholesterolemia (HoFH) despite substantial lowering of PCSK9 levels [123]

Subsequently, the ORION-9 trial evaluated the safety and efficacy of inclisiran in lowering LDL-C among patients with HeFH [124]. There was a 50% observed LDL-C lowering at Day 510 with a 45% time-adjusted LDL-C lowering between days 90 and 540 indicating that inclisiran is superior to placebo in reducing LDL-C among patients with HeFH who are already on statins and ezetimibe. Almost all patients in both groups used statins (90%), however, 76.4% of the group that received inclisiran used high-potency statins versus 71.2% of the placebo group and 55.8% of the inclisiran group used ezetimibe versus 50.0% of the placebo group. These differences in lipid-lowering treatment between the groups do not seem to have considerably affected the result, but the increase of 8.2% in LDL-C levels on day 510 when compared to baseline levels in the placebo group is noteworthy, even when receiving a high-potency statin in a large proportion and half of the population using ezetimibe.

A pooled analysis of two phase 3 trials (ORION-10 and -11 trials) evaluated the individual responses of patients on LDL-C reduction with inclisiran [125]. This analysis showed a highly consistent effect, with a safety and tolerability profile similar to placebo, on a twice-yearly dosing schedule after an initial dose and one 3 months later, across individual patients with ASCVD or risk equivalents over 17 months of treatment. At day 510, inclisiran reduced LDL-C levels by 52.3% (95% CI 48.8 to 55.7) in the ORION-10 trial and by 49.9% (95% CI 46.6 to 53.1) in the ORION-11 trial.

In a post hoc analysis of the ORION-9, -10 and -11 trials showed that inclisiran was well-tolerated and effective in LDL-C reduction in both patients with and without polyvascular disease (PVD) [126]. The mean placebo-corrected LDL-C % change from baseline to day 510 was -48.9% (95% CI -55.6 to -42.2) in patients with PVD and -51.5% (95% CI -53.9 to -49.1) in patients without PVD.

Recently, a patient-level, pooled analysis of ORION-9, -10 and -11 trials showed a placebo-corrected percentage reduction in LDL-C with inclisiran (50.6% at day 90) [127]. Furthermore, inclisiran reduced composite MACE (non-adjudicated CV death, cardiac arrest, MI, and stroke) [OR 0.74, 95% CI 0.58 to 0.94], but not fatal and non-fatal MIs [OR 0.80, 95% CI 0.50 to 1.27] or fatal and non-fatal stroke [OR 0.86, 95% CI 0.41 to 1.81] over 18 months, suggesting a potential benefit of inclisiran for MACE.

The ongoing ORION-4 trial recruited more than 16,000 patients from 2018 to evaluate the reduction of clinical outcomes in patients at high risk for atherosclerotic disease [128].

Table 10. Characteristics of the main published trials involving inclisiran. Legend: CV: cardiovascular; NE: not evaluated.

Table 10. Characteristics of the main published trials involving inclisiran. Legend: CV: cardiovascular; NE: not evaluated.

Study	Sample size	Characteristics of patients	Comparison groups	Follow-up	Lipids effect	CV effects
ORION-1 (2017) [121]	501	Patients at high risk for CV disease and elevated LDL-C	Different doses of inclisiran vs. placebo	180 days	LDL-C 27.9% (200mg inclisiran); LDL-C 38.4% (300mg inclisiran); LDL-C 41.9% (500mg inclisiran); LDL-C 35.5% (double dose 100mg inclisiran); LDL-C 44.9% (double dose 200mg inclisiran); LDL-C 52.6% (double dose 300mg inclisiran)	NE
ORION-3 (2023) [122]	382	Patients at high risk for CV disease and elevated LDL-C	Inclisiran-only (patients who already received inclisiran continued to receive it) vs. switching-arm (patients who received placebo started receiving evolocumab for 1 year and then switched to inclisiran)	4 years	LDL-C 44.2%	NE
ORION-5 (2023) [123]	56	HoFH	Inclisiran 300 mg vs. placebo	150 days	LDL-C 1.68% PCSK9 60.6%	NE
ORION-9 (2020) [124]	482	HeFH	Inclisiran 300 mg vs. placebo	510 days	LDL-C 39.7%	NE
ORION-10 and ORION-11(2020) [125]	1,561 (ORION-10) and 1,617 (ORION-11)	Patients with atherosclerotic CV disease (ORION-10 trial) and patients with atherosclerotic CV disease or an atherosclerotic CV disease risk equivalent (ORION-11 trial) and elevated LDL-C despite receiving statin therapy at the maximum tolerated dose	Inclisiran 284 mg vs. placebo	510 days	LDL-C 52.3% (ORION-10) LDL-C 49.9% (ORION-11)	NE

14. Lomitapide

15. Vaccines against PCSK9

16. Plasmapheresis

17. Conclusion

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