Lipid-Lowering Drug Therapy: Critical Approach for Implementation in Clinical Practice

Maddalena Rossi; Enrico Fabris; Davide Barbisan; Laura Massa; Gianfranco Sinagra

Am J Cardiovasc Drugs. 2022;22(2):141-155.

Abstract and Introduction

Abstract

Increased levels of low-density lipoprotein cholesterol (LDL-C) are recognized as a primary risk factor for atherosclerotic cardiovascular disease, which remains the leading cause of death worldwide. Lowering LDL-C levels clearly reduces the risk of cardiovascular events, with benefits related to both absolute reduction and duration of treatment; however, a threshold below which low LDL-C levels can be dangerous has never been established. Since the discovery of statins, cardiovascular research has focused on developing new lipid-lowering agents. Ezetimibe and proprotein convertase subtilisin–kexin type 9 inhibitors have been found to further reduce LDL-C values and subsequent cardiovascular risk. Novel recently approved inclisiran and bempedoic acid, currently being tested in cardiovascular outcomes studies, are further expanding our pharmacological armamentarium, enabling the clinician to diminish residual risk related to LDL-C. Moreover, new agents are paving the way to successful treatment of homozygous familial hypercholesterolemia. This review summarizes the main characteristics of current and emerging lipid-lowering therapies to assist with comprehensive evidence-based decision making.

Introduction

Introduction: Why do we Need new Lipid-lowering Therapies?

Accounting for 30% of the world's total deaths, atherosclerotic cardiovascular disease (ASCVD) is considered the leading cause of morbidity and mortality all over the world.^[1] In Europe, it causes more than 4 million deaths annually, with an estimated global economic cost of €196 billion per year, in terms of direct healthcare costs, loss of work productivity, and informal family care.^[2]

It is well-known that low-density lipoprotein cholesterol (LDL-C) represents the key initiating event in atherogenesis as it enters the subendothelial space, accumulates in the arterial wall, and promotes a local inflammatory response.^[3] A consistent body of evidence from randomized controlled trials (RCTs) confirms that elevated LDL-C is associated with the highest odds ratio for ASCVD among all modifiable cardiovascular risk factors,^[4] with an "effect size" proportional to both LDL-C blood levels and the total time of exposure. Moreover the positive association between ASCVD and LDL-C extends to even very low levels of LDL-C,^[5] and lowering LDL-C and apolipoprotein B (apoB) reduces the risk of major atherosclerotic vascular events, with benefits directly and positively correlated with the incrementally achieved absolute LDL-C reduction and duration of treatment.^[6–8] Most importantly, a threshold below which LDL-C reduction is dangerous has never been detected, so there is no lower limit for achievable LDL-C values.^[7]

Given this, the 2019 European Society of Cardiology (ESC)/European Atherosclerosis Society (EAS) guidelines for the management of dyslipidemias have further lowered LDL-C goals for each cardiovascular risk class, thus paving the way for implementation of new pharmacological approaches.

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Next Section

Abstract and Introduction
Current Approach
New Emerging Therapies
Other Approaches to Low-density Lipoprotein Cholesterol Lowering
Drugs Under Development
Targeting the Optimal Patients: Who Could Benefit the Most?
Conclusions
References

Table 1. Results from the main randomized controlled trials evaluating ezetimibe, PCSK9i monoclonal antibodies, bempedoic acid, and inclisiran
Trial	Study population	Follow-up	Primary endpoints	Results	LDL-C reduction
EZETIMIBE
SEAS [16]^a (simvastatin 40 mg plus ezetimibe 10 mg daily vs. placebo)	1873 asymptomatic pts with mild-to-moderate aortic-valve stenosis	52.2 months	Death from CV causes, aortic-valve replacement, nonfatal MI, hospitalization for UA, HF, CABG, PCI, nonhemorrhagic stroke	Composite endpoint: HR 0.96 (95% CI 0.83–1.12; P = 0.59) Ischemic CV events: HR 0.78 (95% CI 0.63–0.97; P = 0.02)	53.8%
SHARP[17]^a (simvastatin 20 mg plus ezetimibe 10 mg daily vs. placebo)	9270 pts with CKD with no known history of MI or coronary revascularization	4.9 years	First major atherosclerotic event (nonfatal MI or coronary death, nonhemorrhagic stroke, or any arterial revascularization)	RR 0.83 (95% CI 0.74–0·94; P = 0.002)	55%
IMPROVE-IT [18]^a (simvastatin 40 mg plus ezetimibe 10 mg vs. simvastatin 40 mg plus placebo daily)	18,144 pts within 10 days of ACS with LDL-C 50–100 mg/dL on LLT or 50–125 mg/dL on no LLT	6 years	CV death, nonfatal MI, UA requiring hospitalization, coronary or nonfatal stroke	HR 0.936 (95% CI 0.89–0.99; P = 0.016)	24%
PCSK9 INHIBITOR MONOCLONAL ANTIBODIES
FOURIER [25]^a (evolocumab 140 mg every 2 wks or 420 mg monthly vs. placebo)	27,564 pts with ASCVD and LDL-C ≥ 70 mg/dL despite statin therapy	2.2 years	CV death, MI, stroke, hospitalization for UA, or coronary revascularization	HR 0.85 (95% CI 0.79–0.92; P < 0.001)	59%
ODYSSEY [26]^a (alirocumab 75 mg every 2 wks vs. placebo)	18,924 pts with ACS 1–12 months earlier and LDL-C ≥ 70 mg/dL or high non-HDL-C/apoB, despite statin therapy	2.8 years	Death from CHD, nonfatal MI, fatal or nonfatal ischemic stroke, or UA requiring hospitalization	HR 0.85 (95% CI 0.78–0.93; P < 0.001)	55%
BEMPEDOIC ACID
CLEAR Tranquillity [35] (ezetimibe 10 mg plus bempedoic acid 180 mg vs. ezetimibe 10 mg plus placebo daily)	269 pts with a history of statin intolerance and an LDL-C ≥ 100 mg/dL while on stable LLT	12 wks	LDL-C percent change from BL to wk 12	LDL-C reduction by 28.5% more than placebo (P < 0.001)	28%
CLEAR Harmony [37] (bempedoic acid 180 mg vs. placebo daily)	2230 pts with ASCVD and/or HeFH with LDL-C ≥ 70 mg/dL despite maximally tolerated statin therapy	52 wks	Incidence of AEs	Incidence of AEs: 78.5 vs. 78.7% (P = 0.91). Incidence of serious AEs: 14.5 vs. 14.0% (P = 0.8)	16.5%
CLEAR Wisdom [38] (bempedoic acid 180 mg vs. placebo daily)	779 pts with ASCVD and/or HeFH with LDL-C ≥ 70 mg/dL despite maximally tolerated statin therapy	52 wks	LDL-C percent change from BL to wk 12	LDL-C reduction by 17.4% more than placebo (95% CI 21.0–13.9; P < 0.001)	17.4%
CLEAR Serenity [36] (bempedoic acid 180 mg vs. placebo daily)	345 pts with hypercholesterolemia and a history of intolerance to at least two statins	24 wks	LDL-C percent change from BL to wk 12	LDL-C reduction by 21.4% more than placebo (95% CI 25.1−17.7; P < 0.001)	21.4%
INCLISIRAN
ORION-9 [44] (inclisiran 300 mg vs. placebo on days 1, 90, 270, and 450)	482 pts with HeFH and LDL-C ≥ 100 mg/dL despite maximally tolerated statin therapy	18 months	LDL-C percent change on day 510 and time-adjusted LDL-C percent change between day 90 and day 540	LDL-C percent change on day 510 by 47.9% (95% CI 53.5–42.3; P < 0.001). Time-averaged percent change in LDL-C between day 90 and 540 by 44.3% (95% CI 48.5–40.1; P < 0.001)	48%
ORION-10 [45] (inclisiran 300 mg vs. placebo on days 1, 90, 270, and 450)	1561 pts with ASCVD and LDL-C ≥ 70 mg/dL despite maximally tolerated statin therapy	18 months	LDL-C percent change on day 510 and time-adjusted LDL-C percent change between day 90 and day 540	LDL-C percent change on day 510 by 52.3% (95% CI 48.8–55.7; P < 0.001) Time-averaged percent change in LDL-C between day 90 and 540 by 53.8% (95% CI 51.3–56.2; P < 0.001)	52%
ORION-11 [45] (inclisiran 300 mg vs. placebo on days 1, 90, 270, and 450)	1617 pts with ASCVD and LDL-C ≥ 70 mg/dL or ASCVD risk equivalents and LDL-C ≥ 100 mg/dL despite maximally tolerated statin therapy	18 months	LDL-C percent change on day 510 and time-adjusted LDL-C percent change between day 90 and day 540	LDL-C percent change on day 510 by 49.9% (95% CI 46.6–53.1; P < 0.001) Time-averaged percent change in LDL-C between day 90 and 540 by 49.2% (95% CI 46.8–51.6; P < 0.001)	52%

ACS acute coronary syndrome, AE adverse event, apoB apolipoprotein B, ASCVD atherosclerotic cardiovascular disease, BL baseline, CABG coronary artery bypass graft, CHD coronary heart disease, CI confidence interval, CKD chronic kidney disease, CV cardiovascular, HDL-C high-density lipoprotein cholesterol, HeFH heterozygous familial hypercholesterolemia, HF heart failure, HR hazard ratio, LDL-C low-density lipoprotein cholesterol, LLT lipid-lowering therapy, mAbs monoclonal antibodies, MI myocardial infarction, PCI percutaneous coronary intervention, PCSK9 proprotein convertase subtilisin-kexin type 9, pts patients, RR rate ratio, UA unstable angina, wk(s) week(s)
^aCardiovascular outcomes trials

Table 2. Randomized controlled trials of ORION development program for inclisiran
Trial	Description	Patients (n)	Follow-up
ORION-1	Phase II dose finding trial	501	360 days
ORION-2	Pilot study enrolling patients with HoFH	4	300 days
ORION-3	Open-label extension study of ORION-1, compared with evolocumab	374	4 years
ORION-4	Cardiovascular outcomes phase III trial	15,000	Event-driven (median duration ≥ 5 years)
ORION-5	Phase III trial enrolling patients with HoFH	45	2 years
ORION-6	Supporting single-dose, open-label, parallel-group study, designed to assess inclisiran pharmacology in subjects with mild or moderate hepatic impairment compared with subjects with normal liver function	24	180 days
ORION-7	Supporting single-dose, open-label, parallel-group study designed to evaluate inclisiran pharmacology in subjects with renal impairment	31	180 days
ORION-8	Phase III extension study of ORION-9, 10, and 11	3600	3 years
ORION-9	Phase III trial designed to assess efficacy and safety of inclisiran in patients with HeFH	482	540 days
ORION-10	Phase III trial designed to assess efficacy and safety of inclisiran in patients with ASCVD (USA)	1561	540 days
ORION-11	Phase III trial designed to assess efficacy and safety of inclisiran in patients with ASCVD or ASCVD equivalents (Europe–South Africa)	1617	540 days

ASCVD atherosclerotic cardiovascular disease, HeFH heterozygous familial hypercholesterolemia, HoFH homozygous familial hypercholesterolemia

Table 3. Ongoing phase III trials of lerodalcibep (LIB003) [69]
Trial	Description	Study population	Pts (N)	Primary endpoints	Secondary endpoints	Estimated primary completion date
LIBerate-H2H (NCT04790513)	Open-label, randomized 2:2:1 with active comparators Three arms: LIB003 300 mg monthly vs. evolocumab 420 mg monthly vs. alirocumab 300 mg monthly	Pts with CVD or a high risk of CVD based on 2019 ESC/EAS guidelines, with LDL-C ≥ 90 mg/dL while on stable diet and oral LLT	≈220	LDL-C percent change from BL to wk 12	(1) Percent of pts achieving ESC/EAS 2019 LDL-C target (2) Injection-site reactions	30 September 2021
LIBerate-FH (NCT04797104)	Double-blind, placebo-controlled, randomized 2:1 to receive LIB003 300 mg monthly or placebo	Pts with HeFH and LDL-C ≥ 70 mg/dL (if very high risk for CVD) or ≥ 100 mg/dL (if high risk for CVD) while on stable oral LLT	≈600	LDL-C percent change from BL to wk 24	(1) Incidence of AEs (2) Change in serum free PCSK9	28 February 2022
NCT04034485	Randomized, open-label, cross-over with active comparator Two arms: LIB003 300 mg monthly vs. evolocumab 420 mg monthly	Pts with verified HoFH on stable and continuing doses of oral LLT	≈70	LDL-C percent change from BL to wk 24	(1) Incidence of AEs (2) Percent change in serum Lp(a) at wk 24 (3) Change in serum apoB at wk 24 (4) Presence of anti-LIB003 antibodies	30 May 2022
LIBerate-CVD (NCT04797247)	Double-blind, placebo-controlled, randomized 2:1 to receive LIB003 300 mg monthly or placebo. Only USA involved	Pts with history of ASCVD or very high risk of ASCVD as defined in 2019 ESC/EAS guidelines with LDL-C ≥ 70 mg/dL while on stable diet and oral LLT	≈900	(1) LDL-C percent change from BL to wk 52 (2) Mean LDL-C change at wk 50 and 52	(1) Incidence of AEs (2) Free PCSK9 change (3) Percentage of pts at 2019 ESC/EAS LDL-C goals	31 October 2022
LIBerate-HR (NCT04806893)	Double-blind, placebo-controlled, randomized 2:1 to receive LIB003 300 mg monthly or placebo	Pts with history of ASCVD or very high risk of ASCVD as defined in 2019 ESC/EAS guidelines with LDL-C ≥ 70 mg/dL while on stable diet and oral LLT	≈900	(1) LDL-C percent change from BL to wk 52 (2) Mean LDL-C change at wks 50 and 52	(1) Incidence of AEs (2) Free PCSK9 change (3) Percentage of pts at 2019 ESC/EAS LDL-C goals	31 October 2022
LIBerate-OLE (NCT04798430)	Open-label extension trial	Pts who successfully completed LIB003-003, LIB003-004, LIB003-005, LIB003-006, LIB003-008, or LIB003-011	≈2000	(1) Incidence of AEs after 48 and 72 wks	(1) Incidence of antidrug antibodies 2) Percent decrease in LDL-C from BL of original study	30 December 2023

AEs adverse events, apoB apolipoprotein B, ASCVD atherosclerotic cardiovascular disease, BL baseline, CVD cardiovascular disease, EAS European Atherosclerosis Society, ESC European Society of Cardiology, HeFH heterozygous familial hypercholesterolemia, HoFH homozygous familial hypercholesterolemia, LDL-C low-density lipoprotein cholesterol, LLT lipid-lowering therapy, Lp(a) lipoprotein(a), PCSK9 proprotein convertase subtilisin-kexin type 9, pts patients, wk(s) week(s)

Table 4. Main characteristics of ezetimibe, PCSK9i monoclonal antibodies, bempedoic acid, and inclisiran
Drug	Route, dose, and frequency of administration	Most common adverse reactions	Mean LDL-C reduction
Ezetimibe	Oral, 10 mg daily	Abdominal pain, flatulence, diarrhea, muscle-related symptoms if given plus statins	24%
Evolocumab	Subcutaneous injection, 140 mg every 2 weeks or 420 mg monthly	Injection-site reactions, back pain, arthralgia, upper respiratory symptoms	59%
Alirocumab	Subcutaneous injection, 75/150 mg every 2 weeks or 300 mg monthly	Injection-site reactions, upper respiratory symptoms, itching	55%
Bempedoic acid	Oral, 180 mg daily	Hyperuricemia and gout, anemia, arm and leg pain	20%
Inclisiran	Subcutaneous injection, 300 mg at time 0, after 3 months and then every 6 months	Injection-site reactions	52%