Conditions

Treatment options for

Lipid lowering to prevent cardiovascular disease

Statins are the most effective drugs for preventing cardiovascular events.

Other drug classes have limited roles.

 

Treatment options:

Statins for the primary prevention of cardiovascular disease

Risk reduction for an individual depends on their baseline cardiovascular risk.

NICE recommends assessing this using the QRISK3 tool.

The figures below relate to the use of atorvastatin 20mg, a “high intensity” statin.

Here, “combined cardiovascular events” means: fatal and non-fatal angina, MI, TIA and stroke.

No treatment
With treatment
ARR -- Absolute Risk Reduction
NNT -- Number Needed to Treat
RRR -- Relative Risk Reduction
No treatment
5 people have a cardiovascular event over 10 years
With treatment
3.2 people have a cardiovascular event over 10 years
ARR 1.9% Absolute Risk Reduction
NNT 54 Number Needed to Treat
RRR 37% Relative Risk Reduction

If 100 people with a baseline 10-year risk of cardiovascular disease of 5% take a statin for 10 years, 1.9 will avoid a cardiovascular event compared with if they hadn't taken a statin

No treatment
10 people have a cardiovascular event over 10 years
With treatment
6 people have a cardiovascular event over 10 years
ARR 4% Absolute Risk Reduction
NNT 25 Number Needed to Treat
RRR 37% Relative Risk Reduction

If 100 people with a baseline 10-year risk of cardiovascular disease of 10% take a statin for 10 years, 4 will avoid a cardiovascular event compared with if they hadn't taken a statin

No treatment
15 people have a cardiovascular event over 10 years
With treatment
9 people have a cardiovascular event over 10 years
ARR 6% Absolute Risk Reduction
NNT 17 Number Needed to Treat
RRR 37% Relative Risk Reduction

If 100 people with a baseline 10-year risk of cardiovascular disease of 15% take a statin for 10 years, 6 will avoid a cardiovascular event compared with if they hadn't taken a statin

No treatment
20 people have a cardiovascular event over 10 years
With treatment
13 people have a cardiovascular event over 10 years
ARR 7% Absolute Risk Reduction
NNT 14 Number Needed to Treat
RRR 37% Relative Risk Reduction

If 100 people with a baseline 10-year risk of cardiovascular disease of 20% take a statin for 10 years, 7 will avoid a cardiovascular event compared with if they hadn't taken a statin

No treatment
25 people have a cardiovascular event over 10 years
With treatment
16 people have a cardiovascular event over 10 years
ARR 9% Absolute Risk Reduction
NNT 11 Number Needed to Treat
RRR 37% Relative Risk Reduction

If 100 people with a baseline 10-year risk of cardiovascular disease of 25% take a statin for 10 years, 9 will avoid a cardiovascular event compared with if they hadn't taken a statin

No treatment
30 people have a cardiovascular event over 10 years
With treatment
19 people have a cardiovascular event over 10 years
ARR 11% Absolute Risk Reduction
NNT 9 Number Needed to Treat
RRR 37% Relative Risk Reduction

If 100 people with a baseline 10-year risk of cardiovascular disease of 30% take a statin for 10 years, 11 will avoid a cardiovascular event compared with if they hadn't taken a statin

No treatment
35 people have a cardiovascular event over 10 years
With treatment
22 people have a cardiovascular event over 10 years
ARR 13% Absolute Risk Reduction
NNT 8 Number Needed to Treat
RRR 37% Relative Risk Reduction

If 100 people with a baseline 10-year risk of cardiovascular disease of 35% take a statin for 10 years, 13 will avoid a cardiovascular event compared with if they hadn't taken a statin

No treatment
40 people have a cardiovascular event over 10 years
With treatment
25 people have a cardiovascular event over 10 years
ARR 15% Absolute Risk Reduction
NNT 7 Number Needed to Treat
RRR 37% Relative Risk Reduction

If 100 people with a baseline 10-year risk of cardiovascular disease of 40% take a statin for 10 years, 15 will avoid a cardiovascular event compared with if they hadn't taken a statin

Myalgia and non-specific side effects

Muscle pains and general malaise are sometimes reported with statin use. Most of this (roughly 90%) is due to a nocebo* effect.

* an adverse effect experienced because the patient expects it, rather than as a result of the treatment itself

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This has been controversial over the years with some arguing that they are not genuine side effects because:

  • high quality RCTs have not shown an overall difference between statins and placebo in these common symptoms
  • evidence of side effects which comes from observational evidence is lower quality (subject to greater bias and confounders)6

Others argued that7:

  • RCTs are not designed to properly test for side effects like these
  • observational evidence is imperfect but valid, for example:
    • 22% of patients taking statins self-reported muscular pain in the last 30 days compared to 16.7% of those not taking a statin (US national health survey8)
    • 73% of people taking statins had a code for a musculoskeletal problem on their records over a 5-year period compared to 71% not taking a statin (US health database9)

The question has perhaps been resolved by 2 trials set in the UK, involving patients who had previously reported muscle aches or other side effects with statins10,11. They were given statins, placebo or no tablets for periods of 1-2 months in random order and asked to record their symptoms.

Both trials, which were fully blinded and well conducted, showed that muscle symptoms and other “side effects” (even ones severe enough to stop taking the tablets) were almost as common with placebo tablets. Half to two-thirds of patients were able to restart their statins after receiving feedback.

Myositis and rhabdomyolysis

2-22 excess cases per 10,000 person years for both combined3.

more

The NICE systematic review of RCTs did not find evidence of an increase in these side effects1.

However, RCTs can fail to pick up rare harms. Observational research (LOW quality evidence) has shown the following risks:

Myositis (muscle pain plus elevated CK x 10)

  • 5 excess cases per 10,000 people over 5 years6

Rhabdomyolysis (severe myopathy with extremely elevated CK, myoglobinaemia and renal impairment)

  • 2-3 excess cases per 100,000 people per year6

Elevated liver enzymes

4 in every 1000 people will develop raised transaminases (ALT >3 x normal) due to taking a statin.

Statin-related raised transaminases up to 3 x the upper limit of normal are thought to be harmless and do not require statin therapy to be stopped if stable1.

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This approximate figure is found by both the NICE systematic review of RCTs (who rated it MODERATE quality evidence)1 and a Cochrane review of observational studies2.

Serious liver disease

Acute hepatitis and liver failure associated with statins are so rare it is uncertain whether there is a causal effect.

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RCT data has not shown an increase in these harms compared to placebo. A 2007 review paper5 said:

‘Although hepatitis and liver failure have been reported spontaneously and from trials of statins, it is not clear whether they are causally related or that the risk is over and above the background risk of sporadic liver failure.’

New onset type 2 diabetes

1 excess case per 200 people over a 5-year period due to taking a statin.

However, the cardiovascular benefits of statins outweigh risks associated with glycaemic changes5.

Statins do not need to be stopped in response to increases in blood glucose or HbA1c1.

more

This number comes from the NICE evidence review of RCTs and was rated as HIGH quality evidence1. A similar figure was produced in another large systematic review of RCTs2.

Larger risks  have been reported in observational studies (up to 2% per annum), though this was described as weak evidence by the Cochrane review group undertaking the analysis3.

Larger risks (up to a few percent over 5 years) have been shown in RCTs using atorvastatin 80mg. This was in subgroups with 2 or more risk factors for diabetes. Not all findings were statistically significant so there is uncertainty about the size of the effect4.

 

References

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1)National Institute for Health and Care Excellence. Cardiovascular disease: Risk Assessment and reduction, including lipid modification 2014 [Internet]. [London]: NICE; 2014 [updated 2016 Sep]. (Clinical guideline [CG181])

2)Sattar N, Preiss D, Murray HM et al. Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials. Lancet 2010; 375(9716): 735-742

3)Macedo AF, Taylor FC, Casas JP et al. Unintended effects of statins from observational studies in the general population: systematic review and meta-analysis. BMC Med 2014; 12: 51

4)Waters DD, Ho JE, DeMicco D et al. Predictors of New-Onset Diabetes in Patients Treated With Atorvastatin: Results From 3 Large Randomized Clinical Trials. J Am Coll Cardiol 2011; 14: 1535-1545

5)Armitage J. The safety of statins in clinical practice. Lancet 2010; 370(9601): 1781-1790

6)Collins R, Reith C, Emberson J et al. Interpretation of the evidence for the efficacy and safety of statin therapy. Lancet 2016; 388(10059): 2532-2561

7)Abramson JD, Rosenberg HG, Jewell N, Wright JM. Should people at low risk of cardiovascular disease take a statin? BMJ 2013; 347 :f6123

8)Buettner C, Davis RB, Leveille SG et al. Prevalence of musculoskeletal pain and statin use. J Gen Intern Med 2008 Aug; 23(8): 1182-1186

9)Mansi I, Frei CR, Pugh MJ et al. Statins and Musculoskeletal Conditions, Arthropathies, and Injuries. JAMA Intern Med 2013; 173(14): 1318–1326

10)Wood FA, Howard JP, Finegold JA et al. N-of-1 Trial of a Statin, Placebo, or No Treatment to Assess Side Effects. N Engl J Med 2020; 383: 2182-2184

11)Herrett E, Williamson E, Brack K et al. Statin treatment and muscle symptoms: series of randomised, placebo controlled n-of-1 trials BMJ 2021; 372 :n135

Fibrates

No longer recommended as first-line treatment for cardiovascular prevention, but may be an option for those unable to take statins.

Fibrates slightly reduce the risk of non-fatal MI compared to placebo.

There is no evidence of additional benefit from adding a fibrate to a statin for most primary prevention patients.

They may have a role in those with hypertriglyceridaemia or familial hyperlipidaemia, usually under specialist supervision.

No treatment
With treatment
ARR -- Absolute Risk Reduction
NNT -- Number Needed to Treat
RRR -- Relative Risk Reduction
No treatment
3 people have a non-fatal MI over 5 years
With treatment
2 people have a non-fatal MI over 5 years
ARR 1% Absolute Risk Reduction
NNT 100 Number Needed to Treat
RRR 33% Relative Risk Reduction

If 100 people like this take a fibrate over 5 years,1 will avoid a non-fatal MI compared with if they hadn't taken a fibrate

No treatment
2 deaths over 5 years
With treatment
2 deaths over 5 years
ARR 0% Absolute Risk Reduction
NNT n/a Number Needed to Treat
RRR 0% Relative Risk Reduction

There will be 2 deaths over 5 years among 100 people like this whether they take a fibrate or not

No treatment
7 people will have a non-fatal MI over 5 years
With treatment
7 people will have a non-fatal MI over 5 years
ARR 0% Absolute Risk Reduction
NNT n/a Number Needed to Treat
RRR 0% Relative Risk Reduction

There will be 7 non-fatal MIs over 5 years among 100 people like this whether they add a fibrate to statin therapy or not

No treatment
2 strokes over 5 years
With treatment
2 strokes over 5 years
ARR 0% Absolute Risk Reduction
NNT n/a Number Needed to Treat
RRR 0% Relative Risk Reduction

There will be 2 strokes over 5 years among 100 people like this whether they add a fibrate to statin therapy or not

No treatment
8 deaths over 5 years
With treatment
8 deaths over 5 years
ARR 0% Absolute Risk Reduction
NNT n/a Number Needed to Treat
RRR 0% Relative Risk Reduction

There will be 8 deaths over 5 years among 100 people like this whether they add a fibrate to statin therapy or not

Gastrointestinal side effects

1 in 10-100

Source: BNF

More

A Cochrane review1 of fibrate v placebo trials reported discontinuation due to side effects in 29% of fibrate users compared to 26% of those on placebo.

  • not statistically significant
  • VERY LOW quality evidence

Rise in serum creatinine

11% of fibrate users (approximately), not thought to be clinically significant.

It is thought that fibrates increase creatinine production rather than impair renal excretion.

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A Cochrane review1 of fibrate v placebo trials reported raised creatinine in 24% of fibrate users compared to 13% of those on placebo.

  • statistically significant but VERY LOW quality evidence

An American fibrate safety review2 reported a 12% average increase in serum creatinine, though formal eGFR testing showed no reduction in renal function.

Myopathy and rhabdomyolysis

6 per 10,000 person years of treatment (approximately).

More

Two observational studies provide the estimate above4,5.

The second study5 reports a higher (but still very low) rate of hospitalisation with rhabdomyolysis of 14 per 10,000 years with the combination of fenofibrate and atorvastatin.

These have not been detected in systematic reviews of RCTs of fibrates1,3 .

The BNF warns of the potential interaction between statins and fibrates and provides specific recommendations.

 

References

1)Jakob T, Nordmann AJ, Schandelmaier S et al. Fibrates for primary prevention of cardiovascular disease events. Cochrane Database of Systematic Reviews 2016, Issue 11. Art. No.: CD009753

2)Davidson MH, Armani A, McKenney JM, Jacobson TA. Safety considerations with fibrate therapy. Am J Cardiol 2007; 99(6A): 3C-18C

3)National Institute for Health and Care Excellence. Cardiovascular disease: Risk Assessment and reduction, including lipid modification 2014 [Internet]. [London]: NICE; 2014 [updated 2016 Sep]. (Clinical guideline [CG181])

4)Gaist D, Rodríguez LA, Huerta C et al. Lipid-Lowering Drugs and Risk of Myopathy: A Population-Based Follow-Up Study. Epidemiology 2001; 12(5): 565-569

5)Graham DJ, Staffa JA, Shatin D et al. Incidence of Hospitalized Rhabdomyolysis in Patients Treated With Lipid-Lowering Drugs. JAMA 2004; 292(21): 2585-2590

 

Ezetimibe

NICE recommends ezetimibe as an option for the primary prevention of cardiovascular disease:

  • if statins are contraindicated or not tolerated

and for secondary prevention:

  • to consider where secondary prevention cholesterol targets have not been met despite optimal statin therapy
  • and to consider for additional risk reduction even if targets have been met on optimal statin therapy

Cholesterol targets for secondary prevention are

  • non-HDL cholesterol ≤ 2.6 mmol/L   OR

  • LDL cholesterol ≤ 2.0 mmol/L

The NICE guideline emphasises that decisions about escalting treatment should be made taking into account patient preferences about the potential benefits of extra medication balanced against issues such as co-morbdities, multiple medications and life expectancy.

Statin alone
Statin+ezetemibe
ARR -- Absolute Risk Reduction
NNT -- Number Needed to Treat
RRR -- Relative Risk Reduction
Statin alone
14.8 people have an MI over 7 years
Statin+ezetemibe
13.1 people have an MI over 7 years
ARR 1.7% Absolute Risk Reduction
NNT 59 Number Needed to Treat
RRR 11.5% Relative Risk Reduction

If 100 people with recent ACS take ezetemibe in addition to a statin for 7 years, 1.7 will avoid a further MI compared to those taking a statin alone

Statin alone
4.8 people have a stroke over 7 years
Statin+ezetemibe
4.2 people have a stroke over 7 years
ARR 0.6% Absolute Risk Reduction
NNT 167 Number Needed to Treat
RRR 12.5% Relative Risk Reduction

If 100 people with recent ACS take ezetemibe in addition to a statin for 7 years, 0.6 will avoid a stroke compared to those taking a statin alone

Statin alone
22.2 people have a cardiovascular death over 7 years
Statin+ezetemibe
20.4 people have a cardiovascular death over 7 years
ARR 1.8% Absolute Risk Reduction
NNT 56 Number Needed to Treat
RRR 8.1% Relative Risk Reduction

If 100 people with recent ACS take ezetemibe in addition to a statin for 7 years, 1.8 will avoid a cardiovascular death compared to those taking a statin alone

Statin alone
34.7 people have a combined cardiovascular event
Statin+ezetemibe
32.7 people have a combined cardiovascular event
ARR 2% Absolute Risk Reduction
NNT 50 Number Needed to Treat
RRR 5.8% Relative Risk Reduction

If 100 people with recent ACS take ezetemibe in addition to a statin for 7 years, 2 will avoid a combined cardiovascular event compared to those taking a statin alone

In this trial1 involving 18,144 patients followed up for 7 years, there were no increases in rates of

  • abnormal liver function
  • gallbladder disease
  • muscle disorders

associated with the addition of ezetemibe to simvastatin.

A systematic review of 48 trials involving 28,444 participants2, found that

  • ezetimibe results in little to no difference in adverse events or other undesirable effects compared with placebo, usual care or other lipid-lowering agents.

 

References

1)Cannon CP, Blazing MA, Guigliano RP et al. Ezetimibe Added to Statin Therapy after Acute Coronary Syndromes. N Engl J Med 2015; 372: 2387-2397

2)Wang Y, Zhan S, Du H et al. Safety of ezetimibe in lipid-lowering treatment: systematic review and meta-analysis of randomised controlled trials and cohort studies.

PCSK9 inhibitors alirocumab and evolocumab

NICE recommends these drugs as additional options to consider for the secondary prevention of cardiovascular disease when cholesterol targets have not been met with optimal statin therapy.

Cholesterol targets for secondary prevention are

  • non-HDL cholesterol ≤ 2.6 mmol/L  OR
  • LDL cholesterol ≤ 2.0 mmol/L

The NICE guideline emphasises that decisions about escalting treatment should be made taking into account patient preferences about the potential benefits of extra medication balanced against issues such as co-morbdities, multiple medications and life expectancy.

NICE also recommends these as an option for primary prevention in those with familial hypercholesterolaemia where LDL cholesterol levels are ≥ 5.0 mmol/L on maximally tolerated standard treatment.

  • evidence shows a reduction in cardiovascular events in high-risk patients when given in addition to a statin

  • although they are less effective than statins at reducing cardiovascular endpoints in direct comparisons

They are monoclonal antibodies which protect LDL receptors in the liver, reducing circulating LDL.

    • administered by injection every 2-4 weeks

Statin
8.9 people have a major cardiovascular event over 2.5 years
Statin+PCSK9 inhibitor
7.4 people have a major cardiovascular event over 2.5 years
ARR 1.5% Absolute Risk Reduction
NNT 67 Number Needed to Treat
RRR 16.8% Relative Risk Reduction

If 100 people with previous CVD take a PCSK9 inhibitor in addition to a statin for 2.5 years, 1.5 will avoid a major cardiovascular event compared to those taking a statin alone

Local injection site reaction

2.9% of people developed a local reaction to PCSK9i injections compared to 1.8% with placebo injections in the clinical trial1,2.

Otherwise there were no excess adverse events reported compared to placebo in these trial involving  46,488 people over 3 years.

Nasal complaints and itching

1 in 10 – 1 in 100

Source: BNF

 

Reference

1)ODYSSEY OUTCOMES Committees and Investigators. Alirocumab and Cardiovascular Outcomes after Acute Coronary Syndrome. N Engl J Med 2018; 379:2097-2107

2)FOURIER Steering Committee and Investigators. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N Engl J Med 2017; 376:1713-1722

Inclisiran

Inclisiran is a small interfering RNA which limits production of PCSK9, increasing uptake of LDL-cholesterol and thereby lowering levels in blood (BNF).

NICE recommends this as additional option to consider for the secondary prevention of cardiovascular disease when cholesterol targets have not been met with optimal statin therapy.

Cholesterol targets for secondary prevention are

  • non-HDL cholesterol ≤ 2.6 mmol/L or
  • LCL cholesterol ≤ 2.0 mmol/L

The NICE guideline emphasises that decisions about escalting treatment should be made taking into account patient preferences about the potential benefits of extra medication balanced against issues such as co-morbdities, multiple medications and life expectancy

Statin
10.2 people have a major cardiovascular event over 1 1/2 years
Statin + incliseran
7.6 people have a major cardiovascular event over 1 1/2 years
ARR 2.6% Absolute Risk Reduction
NNT 38 Number Needed to Treat
RRR 25.8% Relative Risk Reduction

If 100 people with established cardiovascular disease take incliseran in addition to a statin for 1 1/2 years, 2.6 fewer will have a major cardiovascular event compared to those taking a statin alone

Local injection site reactions occurred in approximately:

  • 3.6% of people receieving incliseran injections compared to 0.7% in those receiving placebo injections1

No other side effects are reported by the BNF.

No other side effects or harms due to incliseran were detected in a systematic review of 5 RCTs of incliseran involving 4226 patients over 1 1/2 years2.

 

References

1)National Institute for Health and Care Excellence. Cardiovascular disease: risk assessment and reduction, including lipid modification – Escalation of Therapy update [Internet]. [London]: NICE; 2023 (Clinical guideline [CG181])

2)Cicero A,Fogacci F, Zambon A et al.Efficacy and safety of inclisiran a newly approved FDA drug: a systematic review and pooled analysis of available clinical studies. American Heart Journal Plus: Cardiology Research and Practice Volume 13, 2022, 100127.

Bempedoic acid

Bempedoic acid has a  restricted recommendation from NICE1

  •  this was made in 2021 based on it’s cholesterol lowering effect, before evidence about cardiovascular outcomes
  • since then, there is emerging evidence of benefits on cardiovascular outcomes, but this has not yet been appraised by NICE3

It is an adenosine triphosphate citrate lyase (ACL) inhibitor which inhibits cholesterol synthesis in the liver, thereby lowering LDL-cholesterol (BNF).

Criteria for prescription in England (NICE):

Bempedoic acid Patients with or without established CHD, in whom statins are contraindicated or not tolerated and where LDL-C is not “controlled well enough” with ezetemibe. To be given in combination with ezetemibe1

 

Bempedoic acid harms:

Uric acid levels are increased on average, by 49umol/l by bempedoic acid.

Incidence of gout attacks is increased depending on history and uric acid level:

                                             Rates of gout attacks per person per year
Previous gout history Placebo Bempedoic acid
History of gout, urate >ULN* 9.5% 23%
History of gout, urate normal 0% 5.7%
No history of gout, urate >ULN 0.4% 3.1%
No history of gout, urate normal 0.2% 0.3%

* Upper limit of normal. Not defined in this study, suggest use local laboratory recommendation

Anaemia

  • was reported in 4.9% of patients treated with bempedoic acid and 2% of patients treated with placebo
    • anaemia was defined as a drop in Hb of ≥2g/dL to reach below the upper limit of normal
    • it is unclear if this is statistically or clinically significant

Data source: safety analysis of 4 randomised controlled trials involving 3621 patients2.

 

References

1)National Institute for Health and Care Excellence. Bempedoic acid with ezetimibe for treating primary hypercholesterolaemia or mixed dyslipidaemia. Technology Appraisal Guidance. (TA694) April 2021

2)Bays HE, Banach M, Catapano AL et al. Bempedoic acid safety analysis: Pooled data from four phase 3 clinical trials. Journal of Clinical Lipidology 2020; 14(5): 649-659

3)CLEAR Outcomes Investigators. Bempedoic Acid and Cardiovascular Outcomes in Statin-Intolerant Patients.N Engl J Med 2023; 388:1353-1364