Trends in Hyperlipidemia Treatments: Summary of Recommendations for Statin and Non-Statin Options

  

    
Medication Class
    
Mechanism of Action
    
Agents Available in US
    
LDL- C Relative Reduction
    
Side Effects
    
NNT
    
NNTH
    
Cost
    
Strength of Recommendation
  
  

    
Statins
    
Inhibition of the    rate limiting step in the endogenous pathway in cholesterol synthesis
    
Atorvastatin

      Fluvastatin

      Lovastatin

      Pitavastatin

      Pravastatin

      Rosuvastatin
    
10-60% reduction
    
myalgia, Rare    Rhabdomyolysis, Headache, dizziness, digestive changes
    
83-154a
    
10-50a
    
$
    
SORT A, Level 1
  
  

    
Fibrates
    
Stimulates    peroxisome proliferator activated receptor alpha (PPARa), increasing    lipolysis, activating lipoprotein lipase, and reducing apoprotein C-III
    
Gemfibrozil,    fenofibrate, fenofibric acid
    
11-20% reduction,    Greatest impact on Triglycerides
    
Abdomnial pain,    Nausea and vomiting, change in taste, decreased appetite
    
47-100b
    
132b
    
$
    
SORT B, Level 2
  
  

    
Bile Acid    Sequestrant
    
bind bile acids in    the intestine, interrupt enterohepatic recirculation of bile acids and impede    their reabsorption. Decrease bile acid pooling in liver, increase conversion    of cholesterol to bile acids
    
Cholestyramine,    Colestipol, Colesevelam
    
15-30% reduction
    
GI side effects,    Triglyceridemia if Triglycerides>300mg/dl
    
-
    
-
    
$$
    
SORT B, Level 2
  
  

    
Cholesterol    Absorption Inhibitor
    
inhibits    cholesterol absorption from small intestine
    
Ezetimibe
    
+statin= 23-24%
    
Diarrhea, abdominal    pain, Headache, dizziness, 

    
    
59-166c
    
100c
    
$$$
    
SORT B, Level 1
  
  

    
PCSK9 Inhibitors
    
Monoclonal    Antibodies that bind PCSK9 enzyme, avoiding the degradation of LDLRs in the    liver, increasing absorption of LDL-C and decreasing serum LDL-C levels
    
evolocumab and    alirocumab
    
54% to 74%    reduction
    
injection site    reaction, 

    
    
67-250c, d
    
99-101c, d
    
$$$
    
SORT B, Level 1
  
  

    
Microsomal    Triglyceride Transfer Protein
    
Act via the CYP3A4    pathway to reduce plasma levels of Apo-B lipoproteins thereby decreasing very    low-density lipoprotein (VLDL)
    
Lomitapide,    Mipomersen
    
40% reduction
    
Both agents require    hepatic monitoring. injection site reaction, flu like illness, flatulence,    diarrhea, nausea, and vomiting
    
62.5
    
71
    
$$$$
    
Orphan drugs,

      SORT C Level 2
  
  

    
Adenosine    Triphosphate-Citrate Lyase (ACL) inhibitors
    
Prodrug will reduce    the production of LDL in the liver and increasing LDL receptors
    
Bempedoic acid
    
15.1 -21.4%    reduction
    
injection cite    reaction, gout flares, tendon rupture, nasopharyngitis, and urinary tract    infections
    
62-76e
    
100e
    
$$
    
Orphan drugs,

      SORT C Level 2
  
  

    
Angiopoietin-Like 3    (ANGPTL3) inhibitors
    
inhibits hydrolysis    of triglycerides and phospholipids exclusively in the liver thereby    regulating plasma lipid levels
    
Evinacumab
    
56% reduction
    
Allergic reaction    and Pregnancy category not assigned
    
67
    
100.5
    
$$$$
    
Orphan drugs,

      SORT C Level 2
  
  

    
Niacin
    
modulation of liver    triglyceride synthesis leading to increased intracellular apo B degradation    and modulating triglyceride lipolysis in adipose tissue
    

    
15 - 23% reduction
    
niacin-induced    flushing
    
250f
    
100f
    
$
    
SORT C, level 2
  
  

    
Omega-3 Fatty Acids
    
mechanism of this    claim is thought to be the blood pressure lowering effects
    
Vascepa and Lovaza
    
OM3-FA had no    significant effect on LDL-C
    
Pruritis. dental    hyperesthesia,
    
86g
    
0g
    
$
    
SORT C, level 2
  
  

    
Curcumin
    
downregulate    factors in lipogenesis and stimulates lipid excretion and mobilization from    adipose tissue
    

    
7.33% reduction
    
constipation, hot    flashes, and nausea patient.
    
-
    
-
    
$
    
SORT C, level 3
  
  

    
Fiber
    
inhibits absorption    of cholesterol by trapping cholesterol and bile acids in the small intestine
    

    

    
elevated liver    enzymes, abdominal pain, leg cramps, cholelithiasis, elevated CPK and venous    thromboembolus
    
-
    
-
    
$
    
SORT C, level 3
  

Table 1: Summary of Lipid Lowering Agents.

Statins,

Statins achieve marked reductions in LDL cholesterol via the inhibition of the rate limiting step in the endogenous pathway in cholesterol synthesis. LDL reductions from 10-60% can be achieved. To a lesser degree, triglycerides are also reduced along with a modest increase in HDL [1]. Statin medications have been shown through extensive clinical research to reduce overall cardiac morbidity and mortality [2,3]. Statins not only reduce LDL cholesterol but also reduce the local inflammatory reaction found at coronary plaques. This anti-inflammatory mechanism is associated with plaque stabilization and thought to play a role in reduction of myocardial infarction (4). Statin medications continue to be the go-to agent for primary and secondary risk reduction in patients with an elevated risk for Coronary Artery Disease (CAD).

The ACC/AHA guidelines for treatment of blood cholesterol recommended moderate to high intensity statin in four groups of patients:

1. Known Atherosclerotic Cardiovascular Disease (ASCVD)

2. Diabetics

3. LDL-C =190 mg/dl (= 4.9mmol/L)

4. ASCVD 10-year risk = 7.5%

Several studies have shown that muscle related symptoms attributed to statin therapy are not true statin associated muscle symptoms (SAMS). Efforts to confirm the origin of symptoms and optimize statin use are important as an increase in MACE (Major Adverse Cardiac Events) is observed in patients with an intolerance who go off statin therapy [5,6]. For the small percentage of patients with clinically presumed SAMS empiric use of either Vitamin D and/or co-enzyme Q10 have been postulated as potential treatment options to circumvent muscle symptoms. A known association exists between muscle related symptoms and vitamin D deficiency. This can benefit from supplementation. But no studies have shown that Vitamin D directly blunts or reverses SAMS. Like vitamin D, there is no clear clinical evidence to support use of co-enzyme Q10 to alleviate SAMS.

For patients with potential SAMS a reasonable first approach following the initiation of a statin is patient education and select lab testing. Informing the patient that the muscle symptoms are frequently not associated with the medication is a key initial step. Blood testing to consider can include: a serum creatinine kinase level to rule out a rare episode of rhabdomyolysis, a 25-hydroxy vitamin D level, and an inflammatory marker, ESR or CRP, to screen for polymyalgia rheumatica. Once select initial blood testing is reassuring, the patient can have statin treatment discontinued (i.e., a drug holiday). If the symptoms dissipate and the lab results are not concerning the next step would be to restart the statin under careful monitoring. If symptoms return both the clinician and patient would reasonably consider SAMS. However, a patient who has seen resolution of muscle symptoms after statin discontinuation may be reluctant to do a second trial on the medication. Overall, statins are well tolerated with the risk for a serious myositis or rhabdomyolysis being rare (<0.01%). Hepatic side effects are even less likely at <0.01%.

Fibrates,

The fibrate class provides a more significant reduction of triglycerides than LDL cholesterol [1]. Thus, they are not considered a class that is utilized for LDL-C reduction. In those with severe hypertriglyceridemia, fibrates decrease triglycerides but may increase LDL-C. Among the class, gemfibrozil improves some CV outcomes but concurrent use with a statin can increase risk of severe myopathy. Although fenofibrate is the safer add on option to decrease the risk of severe myopathy, there is no evidence for it improving CV outcomes [7]. There is some moderate evidence for fibrates providing a reduction in CAD risk [8]. Fibrates are used most often for the adjunctive reduction of triglycerides when statins alone are insufficient to bring triglycerides below target levels particularly in patients with Type 2 Diabetes Mellitus [7].

Bile Acid Sequestrants,

A meta-analysis reviewed effects of additional LDL-C reduction from combining bile acid sequestrants to statin therapy. Although a thorough literature search was done, only seven articles met the final criteria of inclusion. The analysis concluded that combination of statin and bile acid sequestrant resulted in an additional 16.2-point reduction in LDL-C when compared to statins alone, this was more pronounced for patients taking maximum strength bile acid sequestrant and was not affected in a major way by type of bile acid sequestrant. The study was not powered to assess morbidity and mortality effects and found it difficult to assess adverse events, compliance, medication interaction and side effects [9].

Cholesterol Absorption Inhibitors,

Cholesterol Absorption inhibitors, specifically ezetimibe, have been on the US market since 2002. These are no longer considered appropriate firstline agents in management of hyperlipidemia, quite a few studies have demonstrated their effectiveness as add-on medications to statins. The IMPROVE-IT [10] trial was published in 2015 and is a landmark trial in the category affecting the ACC/AHA 2018 guidelines [11] on management of blood cholesterol. Other trials such as HIJ-PROPER [12] and RACING [13] have investigated other statin/ezetimibe combinations as well and their effects on LDL-C reduction and Acute Coronary Syndrome (ACS) outcomes. PRECISE-IVUS [14] was unique in that it looked at association between statin/ezetimibe combination therapy and percentage change in atheroma volume of plaque rather than LDL-C. The role between LDL-C and coronary plaque regression, has already been evaluated previously.

Overall, most trials have suggested that combination of a statin and ezetimibe decreases LDL-C to goal for higher risk patients, MACE, total atheroma volume and some decrease in secondary instances of cardiovascular events. These effects were present with prolonged use and observed in diabetics and age >75 years. It was also suggested that combination therapy with ezetimibe should be considered prior to statin dose maximization in those at risk for intolerance to statins at higher doses. Although HIJ-PROPER did not demonstrate a difference in MACE between combination statin-ezetimibe therapy versus statin therapy alone, it was thought to be related to the small number of overall ACS events in the study.

PCSK9 Inhibitors,

PCSK9 inhibitors increase absorption of LDL-C by the liver and decrease serum LDL-C levels [15]. Network meta-analyses have shown that the PCSK9 inhibitors evolocumab and alirocumab were associated with reductions in LDL-C of 54% to 74% versus placebo and 26% to 46% versus ezetimibe in patients not adequately controlled by statins alone [16].

The FOURIER study [17] demonstrated an absolute risk reduction in patients with ASCVD for both primary endpoints of 1.5% and the NNT was 67. Additionally, those patients with a greater risk profile benefited the most from PCSK9 inhibitor use, with a NNT of 27-30 in the high-risk group.

Wang, et al, conducted a meta-analysis of PCSK9 inhibitors vs placebo and standard of care therapy in patients with ASCVD and the effects on all-cause mortality and MACE. The effects on all-cause mortality and cardiovascular mortality were not significant. However, the effect on MI was statistically significant (RR 0.78, 95% CI 0.70-0.88), NNT of 84. The effects on stroke (RR 0.78, 95% CI 0.68-0.90) with NNT of 294 and coronary revascularization (RR 0.83, 95% CI, 0.78-0.88) and NNT of 81 were also found to be significant [18].

ANGPTL3 Inhibitors/ ACL Inhibitors/ MTP Inhibitors,

Homozygous Familial Hypercholesterolemia (HoFH) is a rare genetic condition characterized by markedly elevated LDL cholesterol causing premature cardiovascular disease. Starting in 2012 there have been several new treatments of different classes and modalities to get FDA approval. None of the medications to treat HoFH have been studied in human pregnancy studies and many are contraindicated based on animal studies. Evinacumab is a monthly intravenous infusion human monoclonal antibody against angiopoietin-like protein 3 (ANGPTL3) which was FDA approved in 2021 for ages twelve and older [1]. The Adenosine Triphosphate-Citrate Lyase (ACL) inhibitor Bempedoic acid (FDA approved 2020) is the only drug in this class and is intended to be used in conjunction with lifestyle modification and statin therapy or ezetimibe, and recently received FDA approval for treatment resistant ASCVD [19-21]. Recent data shows bempedoic acid alone reduces MACE in statin intolerant patients [22]. Microsomal Triglyceride transfer Protein (MTP) inhibitors Lomitapide and Mipomersen are another class approved by the FDA to treat HoFH. Lomitapide is an oral agent (FDA approved 2012) for ages eighteen and older. Mipomersen (FDA approved 2013) administered subcutaneously is for ages twelve and older but is contraindicated in liver or severe renal disease. Both agents are metabolized in the liver and require hepatic monitoring. These medications have shown promising results and further study may expand their indications for treatment [1,23,24].

Niacin,

Studies demonstrated no advantageous outcomes in MACE in patients with known atherosclerosis and well-controlled LDL-C levels on statin therapy when niacin was added [25,26]. Niacin may be beneficial in specific cases of severe hypertriglyceridemia at doses of 1000-2000 mg; however, a 2017 Cochrane Systematic Review concluded with moderate to high evidence that niacin did not reduce the number of deaths, heart attacks, or stroke [27,28].

Supplements,

The addition of omega-3 fatty acids (OM3-FAs) to statin therapy in patients with residual hypertriglyceridemia has been shown to be effective in lowering triglycerides to target goal, however if there is concern for LDL-C levels, high-purity EPA products such as Icosapent Ethyl (IPE) are more beneficial than those containing DHA [29-31]. The effect of OM3-FAs on MACE is unclear. The REDUCE-IT trial studied patients with a history of coronary artery bypass grafting and found that IPE was associated with an absolute risk reduction of 6.2% in first ischemic events, with a number needed to treat of 16 [32]. In the STRENGTH trial, patients with high cardiovascular risk who were already on statin therapy were administered a carboxylic acid formulation of EPA and DHA. When compared with corn oil, there was no significant difference in MACE [33].

Phytosterols are also believed to reduce cholesterol and the FDA claims that 1.3g of plant sterol esters and 3.4g of plant stanol esters consumed daily with a diet low in saturated fat and cholesterol may reduce the risk of heart disease [34]. The NATCOL study examined the effectiveness of a combined nutraceutical of phytosterols, red yeast rice, niacin and policosanols which demonstrated statistically significant reduction in LDL-C, TC, non-HDL-C and apoB [35].

Curcumin was shown to be superior compared to either coenzyme Q10 or curcumin + coenzyme Q10 [36]. At 1000 mg/day and 2100 mg/day Curcumin was shown to improve the lipid profile in patients with metabolic syndrome and T2DM, however data is lacking in the role of curcumin in ASCVD risk reduction [37,38].

Fiber is encouraged by the FDA as part of diet low in saturated fat and cholesterol to reduce the risk of heart disease, however no trials have demonstrated the effect of fiber on cardiovascular morbidity and mortality [39] (Table 2).

  

    
Drug Class
    
Major Trials
    
Study Overview
    
CV Outcomes
    
LDL-C outcomes
  
  

    
Statins,

      Cholesterol absorption inhibitors
    
IMPROVE-IT [10]
    
Multicenter RCT
    
Combination therapy decreased:
    
LDL- C    at the time of index event- 93.8 mg/dl
  
  

    
18,000 patients, followed for 6 years
    
- LDL- C additional 24%
  
  

    
- first    CV events
    
mean    LDL- C in combination group- 53.7 mg/dl versus 69.5 mg/ dl in statin alone.
  
  

    
9545 total events (1st and subsequent)
    
No    mortality benefit, reduction in other MACE events
  
  

    
Patients with ACS: simvastatin 40 mg vs simvastatin 40 mg +    ezetimibe 10 mg
    
Subgroup    analysis showed combination therapy benefits in diabetics, those older than    age 75
    
Greater    percentage in combination therapy achieved LDL-C < 70 and High sensitivity    CRP < 2
  
  

    
HIJ-    PROPER [47]
    
Multicenter RCT in Japan:2010- 2013. 
    
No    difference in all-cause mortality, non- fatal MI, and non-fatal stroke in the    two groups
    
Combination therapy + aggressive revascularization lowered    LDL-C < 70 mg/ dl but no difference in CV events in both groups
  
  

    
- 19    hospitals
  
  

    
- 1733    patients
  
  

    
- 2003    events
  
  

    
-    Followed for 3 years
  
  

    
Patients with ACS + dyslipidemia:
  
  

    
pitavastatin 2mg vs pitavastatin 2mg + ezetimibe    10mg
  
  

    
RACING [13]
    
Multicenter RCT in South Korea from 2017- 2018 
    
Combination    therapy non inferior to monotherapy in MACE occurrence
    
Combination    therapy group 

      ( sustained over 3 years)
  
  

    
- 25    centers
    
- 70%    of patients achieved LDL-C < 70
  
  

    
- 3779    patients
    
- 40%    patients with LDL-C< 55
  
  

    
- 2    year follow up
    
Monotherapy
  
  

    
Patients    with CVD
    
- 55%    of patients achieved LDL-C < 70
  
  

    
Rosuvastatin    20 mg vs Rosuvastatin 10 mg + ezetimibe 10 mg
    
- 25%    patients with LDL-C< 55
  
  

    
PRECISE-IVUS [14]
    
RCT
    
Combination therapy showed greater percent atheroma volume    regression (78% vs 55%)
    
Combination therapy- greater percentage reduction in LDL-C
  
  

    
Patients with CAD post cath./ PCI
    
No change in CRP, cholesterol absorption markers
  
  

    
Atorvastatin titrated to LDL-C< 70 vs atorvastatin +    ezetimibe 10 mg
  
  

    
Fibrates
    
ACCORD [7,48]
    
RCT

      Patients treated with statin or    statin+fibrate
    
No difference in MACE with    combination therapy
    
 
  
  

    
PCSK9    Inhibitors
    
FOURIER [17] 
    
Patients with ACSVD and LDL>= 70    on statin + evolocumab 
    
15% reduction in primary endpoint    (AMI, stroke, coronary revascularization, hospitalization for unstable angina    and CV mortality) 
    
LDL reduction by 60% 
  
  

    
ODYSSEY [49] 
    
alirocumab + statin vs statin    monotherapy 
    
15% reduction in all-cause    mortality 
    
LDL reduction by 54.7% 
  
  

    
Microsomal    Triglyceride Transfer Protein
    
Pivotal Phase 3 trial
    
Lomitapide was treated in a multicenter, 78-weeks single arm    open label study on 29 adults
    
Unable to assess due to limited number of participants
    
More than 50% achieved >50% reduction in LDL-c levels.
  
  

    
FOCUS
    
Mipomersen phase 3 trial with double blinded then open label    treatment of 309 adults
    
Unable to assess due to limited number of participants
    
LDL-C reduction of 28-36%
  
  

    
Adenosine    Triphosphate-Citrate Lyase (ACL) inhibitors
    
CLEAR [22]
    
Phase 3 Randomized control, double blinded, placebo controlled    multisite study for 24 weeks.
    

    
Significant reduction in LDL-c from baseline within 12 weeks.
  
  

    
All patients had a history of statin intolerance
    

    
Most common side effect of Myalgia was more common in placebo    than treatment group.
  

Table 2: Summary of Major Lipid Management Trials.

  

    
Guideline Organization
    
LDL Goals for high CV risk
    
Recommendations
    
Strength of Recommendation (SOR) & Level of    Evidence (LOE)
  
  

    
2019 ESC/EAS Guidelines    for the Management of Dyslipidemia [50]
    
55 mg/dl (1.4    mmol/L)
    
For patients at    very high risk (ESC/EAS criteria):
    
Primary prevention: 

      SOR- IIb,

      LOE- C
  
  

    
LDL-C remains =1.4    mmol/L (=55 mg/dL) on maximally tolerated statin, first add ezetimibe
  
  

    
LDL-C remains =1.4    mmol/L (=55 mg/dL), a combination with a PCSK9 inhibitor is recommended
    
Secondary    prevention: 

      SOR- I,

      LOE- A
  
  

    
2018 AHA/ACC    Multi-Society Cholesterol Guideline [25]
    
70 mg/ dl    (1.8mmol/L)
    
For patients at    very high risk (AHA/ACC criteria):
    
SOR- I to IIA,

      LOE- A to B- NR
  
  

    
LDL-C remains =70    mg/dL on maximum tolerated statin: consider adding ezetimibe
  
  

    
LDL-C remains =70    mg/dL (or non–HDL-C =100 mg/dL), consider adding PCSK9 inhibitor
  
  

    
>75 years of age    with ASCVD, potential benefits versus adverse effects of statin therapy    should be considered before initiation of statin therapy
  
  

    
Canadian CV Society Guidelines    for Management of Dyslipidemia for Prevention of CV disease in Adult in 2021
    
70 mg/ dl    (1.8mmol/L)
    
For all secondary    prevention Patients with CV disease in whom LDL-C =70 mg/dl (1.8mmol/L) on    maximally tolerated statin, Intensify therapy with ezetimibe and/or PCSK9    Inhibitor
    
SOR: "High    quality evidence"
  
  

    
If ezetimibe is    used initially and LDL-C remains =70 mg/dl (1.8mmol/L), PCSK9 inhibitor is    recommended
  
  

    
National Lipid    Association
    
LDL-C >70 or    non-HDL-C > 100 mg/dL
    
HoFH despite ASCVD    status. LDL-C >70 treat with maximized statin +/- ezetimibe
    

  
  

    
Baseline LDL-C >    190 mg/dL and 

      LDL-C > 100 mg/dL or non-HDL-C > 130 mg/dL.
    
HeFH age 18-39 with    uncontrolled ASCVD, or age 40-79 with controlled ASCVD:

      Treat with    maximized statin +/- ezetimibe
    

  
  

    
Baseline LDL-C >    190 mg/dL and 

      LDL-C > 70 mg/dL or non-HDL-C > 100 mg/dL.
    
HeFH age 40-79 with    uncontrolled ASCVD:

      Treat with    maximized statin +/- ezetimibe
    

  
  

    
American Geriatric    Society [43]
    

    
Discussion with    patient of risk-benefit and life expectancy
    
LOE- C
  
  

    
USPSTF [40]
    
No LDL-C goal
    
Only apply to those    >40 years who do not have CVD or symptoms of CVD and have an LDL-C <190    mg/dL. Does not apply to those with FH
      
=40-75 with 1 or    more CVD risk factors and an estimated 10-year CVD risk of =10%: Initiate    statin
      
=40-75 with 1 or    more CVD risk factors and an estimated 10-year CVD risk of 7.5%-10%:

        Selectively offer    statin
    
 
      
 
      
Grade B
      
 
      
Grade C
  

Table 3: Summary of Major Guidelines for Lipid Screening, Targets, and Medication Therapy.

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Citation:Schultz PA, Chaudhri P, Szymanski K, Landis E, Snyder J. Trends in Hyperlipidemia Treatments: Summary of Recommendations for Statin and Non-Statin Options. J Fam Med. 2023; 10(5): 1343.

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