This document provides a summary of a presentation on statins. It discusses the benefits of statins in reducing cardiovascular events and mortality in both primary and secondary prevention. It addresses several controversies around statins, including their association with diabetes, cognitive impairment, cancer, and hemorrhagic stroke. While some modest risks are noted, the overall benefits of statins in reducing cardiovascular risk are found to outweigh these potential risks. The document emphasizes the importance of statin adherence to achieve optimal outcomes and addresses targets for LDL and non-HDL cholesterol levels according to recent guidelines.

1. Welcome!
Mastering cholesterol to optimise CVD
prevention – Statins: Friend or foe?
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2. Statins: Friend or foe?
Tawfiq Choudhury Consultant Interventional Cardiologist and Research Lead -
Lancashire Cardiac Centre, Blackpool Teaching Hospitals
Rocco Hadland Practice Pharmacist - Civic Medical Centre, Bebington

3. Global burden of CVD and LDL cholesterol
 Reducing LDL cholesterol by 1 mmol/l reduces major
cardiovascular events by 21%
Source: Cholesterol Treatment Trialists meta-analysis

4. For every 1000 people treated with statin for 5 years, per
1mmol/L LDL reduction AVOIDS:
Primary Prevention
 18 major coronary events
 12 coronary revascularisation
 5 strokes
 25 major vascular events
Secondary Prevention
 30 major coronary events
 27 coronary revascularisation
 8 strokes
 48 major vascular events
Source: CTT. Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90 056 participants in 14 randomised trials of statinsLancet 2005; 366: 1267–78
Intensive statin regimen (40–80mg atorvastatin or 20–40mg rosuvastatin), could reduce
LDL-C by 2mmol/L and prevent twice as many major vascular events

5. Source: Interpretation of the evidence for the effi cacy and safety of statin
therapy Lancet 2016; 388: 2532–61
MVE = major vascular event
(coronary deaths or myocardial infarctions,
strokes, and coronary revascularisation
procedures)

6. Intensive lipid lowering and atheromatous plaque
Source: Giovanni D G. Impact of lipid lowering on coronary atherosclerosis moving from the lumen to the artery wallAtherosclerosis 367 (2023) 8–14

7. Source: F. Gragnano, P. Calabro / Atherosclerosis 269 (2018) 219 e228
Achieved LDL-C and change in PAV

8. Conclusion so far
 LDL-C reduction associated with reduction in major vascular events
 Statins effective in primary and secondary prevention in terms of reducing major vascular
events and mortality

9. Statins and secondary prevention
Source: Statins for Heart Disease Prevention (With Known Heart Disease) – TheNNT www.thennt.com/nnt/statins-for-heart-disease-prevention-with-known-heart-disease/#

10. Size of the prize (regional example)
Source: Innovation Agency, Academic Health Science Network for the North West Coast

11. ESC 2019
AAC NHSE NICE 2022

12. Statin controversies and areas lacking clarity

13. Are all muscle aches related to statins?
 Most prevalent reason for refusal of statin therapy is statin associated muscular symptoms
 However, this deprives patients of important CVD prevention and quickly labels them as “statin
intolerant”
 The Nocebo effect:
 In the ASCOT-LLA trial, between atorvastatin 10mg and placebo, there was a blinded phase and non-
blinded extension phase
 Interestingly, the blinded phase had no difference in muscle related adverse event (AE) between statin and
placebo BUT once open-label (i.e, participant knew what they were taking), the statins trial arm had a
significantly higher muscle related AE rate
Source: Gupta A et al. Adverse events associated with unblinded, but not with blinded, statin therapy in the Anglo-Scandinavian Cardiac Outcomes Trial—Lipid-Lowering Arm (ASCOT-LLA): a
randomised double-blind placebo-controlled trial and its non-randomised non-blind extension phase. Lancet P2473-2481, JUNE 24, 2017

14. Nocebo effect
 N-of-1 trial (atorvastatin 20mg, placebo or empty bottle each for 1 month in a random sequence in
patients who had discontinued statin)
 In patients who had discontinued statin therapy because of side effects, 90% of the symptom burden
elicited by a statin challenge was also elicited by placebo
Source: Frances A. Wood et al. N-of-1 Trial of a Statin, Placebo, or No Treatment to Assess Side Effects. NEJM 383;22 nejm.org November 26, 2020

15. VERDICT?
 Nocebo effect accounts for a significant proportion of muscle symptoms reported by patients
 Important to be aware of this phenomenon
 Addressing patient concerns, patient education and avoiding spreading misinformation is key

16. Do statins cause diabetes?
 Statin therapy increases the risk of diabetes by 9%–12% (meta-analyses of statin trials)
Source: Laakso M. Diabetes Secondary to Treatment with Statins. Curr Diab Rep (2017) 17: 10 DOI 10.1007/s11892-017-0837-8

17.  Cholesterol Treatment Trialists collaborative :
 50-100 new DM cases per 10,000 treated with statin over 5 years
 However, 150-300 major vascular events PREVENTED per 10,000 individuals treated with a statin over same period
(with 1-2mmol/L LDL-C reduction)
However, DM and statin - benefits outweigh risks
Source: Collins R et al. Interpretation of the evidence for the effi cacy and safety of statin therapy Lancet 2016; 388: 2532–61

18. VERDICT?
Benefit of CVD reduction with statin use outweighs
the risk of new onset Diabetes mellitus

19. Are statins for the elderly?
Source: Statin Selection in the Elderly: How Old Is Too Old? (medscape.org)

20. Cholesterol Treatment Trialists’ meta-analysis
 14483 (8%) of 186,854 participants in the 28 trials were older than 75 years
 Statin therapy produces significant reductions in major vascular events irrespective of age
 Less direct evidence of benefit among patients older than 75 years who do not already have evidence of
occlusive vascular disease
Source: CTT. Efficacy and safety of statin therapy in older people: a meta-analysis of individual participant data from 28 randomised controlled trials Lancet 2019; 393: 407–15

21. Statins in the elderly - PROSPER trial
 RCT n=5804; 70-82y; history of or risk factors for CVD
 40mg pravastatin vs placebo
 Average follow-up: 3.2 years
 Primary endpoint: coronary death, non-fatal MI, and fatal or non-fatal stroke
 Pravastatin reduced incidence of the primary endpoint by 15%
 Coronary death and non-fatal MI risk reduced (19%; p=0.006) and mortality from coronary disease fell by 24%
(p=0.043)
Source: Kulbertus H, Scheen AJ. L'étude clinique du mois. L'étude PROSPER (PROspective study of pravastatin in the elderly at risk) [The PROSPER Study (PROspective study of pravastatin in the elderly at
risk)]. Rev Med Liege. 2002 Dec;57(12):809-13. French. PMID: 12632840.

22. Considerations in the elderly
 Geriatric syndromes are defined as multifactorial, non-disease specific conditions that are increasingly
common with advancing age
 Factors such as cognitive impairment, frailty and polypharmacy need to be taken into account
 Shared decision making
 Further trials awaited (STAREE and PREVENTABLE)

23. Ongoing trials that might answer some of the questions
Source: Montgomery S, et al. Heart 2022;108:1090–1097. doi:10.1136/heartjnl-2021-320154

24. VERDICT?
 Evidence from trials indicates that statin therapy produces significant reductions in major vascular events
irrespective of age
 However, there is “less direct evidence of benefit among patients aged >75 years who do not already
have evidence of occlusive vascular disease” (ESC 2019)
 Shared decision making and consideration of geriatric syndromes important
 Key goal of therapy is to extend healthy life expectancy and reduce disability lifespan
 High risk population-qualifying patients should be prescribed statins and age as a factor should not be
considered alone

25. Do statins cause dementia or mild cognitive impairment (MCI)?
 Paper by Zhou et al
 18,846 participants ≥65 years of age
 No difference in incidence of dementia or MCI between statin and no statin
 In the PROSPER trial, Pravastatin had no effect on cognitive functions or incapacity
Source: Zhou et al. J Am Coll Cardiol 2021;77:3145–56

26. Statins and cognition
 No clear evidence, to date, to suggest statins have a propensity to significantly contribute to adverse
cognitive effects
 We should not dismiss patient-reported cognitive effects. Assess to rule out other potential causes
 Baseline assessment of cognition pre-statin not recommended at this time
 Further studies ongoing (STAREE and PREVENTABLE)

27. VERDICT?
No clear link between statins and cognitive
impairment at this point in time

28. Statins and cancer
 79,751 patients
 5013 first cancers
 No difference in cancer incidence or location of cancer between statin treatment and placebo
Source: Efficacy and safety of cholesterol-lowering treatment: prospective meta-analysis of data from 90 056 participants in 14 randomised trials of statins Cholesterol Treatment Trialists’ (CTT) Collaborators
www.thelancet.com Vol 366 October 8, 2005

29. VERDICT?
No link between cancer and statins

30. Statins and Chronic Kidney Disease (CKD)
 CKD has a strong association with dyslipidemia
 CVD is the leading cause of morbidity and mortality in the CKD population
 Statin therapy can decrease cardiovascular events in patients with pre- end-stage CKD and in renal
transplant patients, but NOT in those already on dialysis
 Atorvastatin is the preferred statin for CKD

31. VERDICT?
Statins beneficial in CKD but not when on dialysis

32. Statins and haemorrhagic stroke
 SPARCL trial: 4,731 patients with prior cerebrovascular disease
 Allocation to atorvastatin 80mg daily vs placebo
 Reduction in ischemic stroke (218 [9·2%] vs 274 [11.6%]; p=0·008);
 Possible increase in haemorrhagic stroke (55 [2·3%] vs 33 [1·4%]; p=0·02);
 CTT meta-analysis: 21% (95% CI 5–41; p=0·01) increase
 5–10 hemorrhagic strokes per 10,000 patients in whom LDL-C is reduced by 1–2 mmol/L for 5 years
 Overall stroke reduced
Stroke: The Stroke Prevention by Aggressive Reduction in Cholesterol Levels (SPARCL) InvestigatorsHigh-Dose Atorvastatin after Stroke or Transient Ischemic Attack. n engl j med
355;6 www.nejm.org august 10, 2006

33. VERDICT?
Statins increase incidence of haemorrhagic stroke but
reduce overall stroke risk

34. Can LDL be too low?
 No evidence from multiple trials that very low LDL (to 1mmol/L) is harmful
 A meta-analysis indicates that very low LDL-C levels on intensive lipid-lowering treatments is not
associated with any adverse event and maintains a persistent reduction of cardiovascular events
Source: Patti G et al. Safety and efficacy of very low LDL-cholesterol intensive lowering: a meta-analysis and meta-regression of randomized trials. European Heart Journal - Cardiovascular
Pharmacotherapy (2023) 9, 138–147

35. VERDICT?
No evidence that very low LDL is associated with
adverse effects

36. Statin adherence
 Statin effectiveness limited by adherence
 Greater lipid control with higher statin adherence
 Protective relationship between statin adherence and CVD outcomes for both primary and secondary
prevention
 High adherence levels lead to reduced future healthcare costs via decreased hospitalisations

37. Statin adherence: Difference between primary and
secondary prevention population
 Compared with primary prevention group, the secondary prevention group was 1.56 (95% CI 1.52–1.60,
p<0.0001) times more likely to be adherent to statins and 0.67 (95% CI 0.65–0.69, p<0.0001) times
more likely to discontinue statin treatment
 Likely affected by multiple factors such as age, gender, ethnicity, socioeconomics and of course,
misinformation in the media (nocebo/drucebo effect)
 Strategies to overcome these barriers are key
Source: Sigglekow F, Horsburgh S, Parkin L (2020) Statin adherence is lower in primary than secondary prevention: A national follow-up study of new users. PLoS ONE 15(11): e0242424.

38. Scale of the problem
 NHS Long Term Plan – CVD priority
 Aims: Prevent 150,000 strokes, MI and dementia cases
 LDL-C is a proven risk factor for CVD

39. Quality and Outcomes Framework (QOF)
New 2023/24 QOF indicator - CHOL001
 Percentage of patients on the QOF Coronary Heart Disease, Peripheral Arterial Disease, Stroke/TIA or
Chronic Kidney Disease Register who are currently prescribed a statin, or where a statin is declined or
clinically unsuitable, another lipid-lowering therapy
 14 points
 Threshold 70-95%

40. Quality and Outcomes Framework (QOF)
New 2023/24 QOF indicator - CHOL002
 Percentage of patients on the QOF Coronary Heart Disease, Peripheral Arterial Disease, or Stroke/TIA
Register, who have a recording of non-HDL-C in the preceding 12 months that is lower than 2.5
mmol/L, or where non-HDL-C is not recorded a recording of LDL-C in the preceding 12 months that
is lower than 1.8 mmol/L
 16 points
 Threshold 20-35%

41. NICE CG 181 CVD: Risk assessment & reduction
Primary prevention
 QRISK2 to assess risk up to 84 years
 Prioritise those with 10-year CVD risk >10
 Discuss lifestyle modification before treatment
 Offer atorvastatin 20mg OD
 Non-HDL-C reduction >40% from pre-treatment baseline

42. LDL-C versus non-HDL-C
 Total cholesterol is an important predictor of CVD
 Non-high density lipoprotein cholesterol (non-HDL-C): The difference between total and HDL-C is a
powerful risk factor
 Non-HDL-C has replaced low-density lipoprotein cholesterol (LDL-C) as the primary target for reducing
cardiovascular risk
 Non-HDL-C combination of atherogenic lipoproteins which includes LDL, VLDL, IDL , and lipoprotein-a

43. Non-HDL-C
 Better predictor of mortality
 Men: high Non-HDL C is 2x mortality risk
 Women: high Non-HDL C is 2.5x mortality risk

44. First of two REALLY useful documents!

45. Second REALLY useful document!

46. Risks and benefits
 Treatment
 No treatment
 Risk of side effects

47. JBS 3 2014, Joint British Societies’ consensus recommendations
for the prevention of CVD
 Calculates ‘lifetime risk’
 Encourages patient to lower their risk through lifestyle changes
 Re-evaluate before stating statins

48. 2019 ESC Guidelines

49. 2019 ESC Guidelines

50. ESC Treatment targets

51. ESC Treatment targets

52. Statin intensity
 20% to 30% reduction is low intensity
 31%-40% is medium intensity
 Reduction of >40% is high intensity

53. Adverse effects of statins
 Poor response often due to poor adherence
 may be genetic
 Muscle effects: Statin related muscle symptoms
 Myopathy
 Rhabdomyolysis
 Altered LFTs (elevation of ALT)
 GI effects
 Headache
 Rash and hypersensitivity

54. Actions to take for suspected statin related muscle symptoms
 ? Statin reluctance or statin intolerance
 Baseline muscle aches and pains
 Check TFT (hypothyroid predisposes to myopathy)
 Measure creatine kinase (CK)
 CK <3x upper limit of normal plus mild symptoms
 Reduce dose and repeat CK in 1month
 CK <3x upper limit of normal plus moderate/severe symptoms
 Stop statin for 2 weeks. If symptoms resolve, restart lower dose or alternative statin
 CK >3x upper limit of normal: Stop statin and consider alternatives

55. Statin intolerance
 Tried three different statins
 Consider intermittent dosing (rosuvastatin)
 Consider ezetimibe monotherapy or inclisiran (secondary prevention)
 Tolerating ezetimibe but not achieving targets:
 Consider adding in bempedoic acid, and/or
 Consider inclisiran (secondary prevention)
 If lipid lowering targets not achieved:
 Seek support from Advice and Guidance service, or
 Refer to lipid clinic if appropriate

56. Assessing effect
 Measure lipids after three months of treatment
 Aim for >40% reduction in non-HDL-C, or non-HDL-C <2.5mmol/L or LDL-C <1.8mmo/L
 If target not achieved:
 Discuss adherence
 Optimise adherence to diet and lifestyle
 Consider increasing dose if on less than atorvastatin 80mg (alternative rosuvastatin 20mg-40mg)
 Add ezetimibe and/or consider inclisiran (secondary prevention)

57. Ezetimibe
 Indicated as option if statin contraindicated or not tolerated
 Can be co-administered with a statin if LDL not controlled after initial statin dose titration of dose
titration limited by intolerance
 Doubling statin dose = 6% reduction in lipid levels
 Adding ezetimibe can give reduction of 21-27%
 Ezetimbe monotherapy reduces LDL-C by 15-22%

58. Bempedoic acid with ezetimibe
 In combination with a statin in patients unable to achive LDL-C target with maximum tolerated dose of
statin plus ezetimibe
 Monotherapy: Where patient is statin intolerant or statin is contraindicated and unable to achieve LDL-C
targets
 Check baseline eGFR (do not start if eGFR <30ml/min)
 Check baseline LFTs and uric acid (do not start in severe hepatic impairment e.g. Child-Pugh C or active
gout)
 Check baseline FBC (particularly haemoglobin-Hb level)
 Consider drug interactions e.g. simvastatin

59. Inclisiran for secondary prevention
 Inhibits PCSK9 production by interfering with RNA, thus reducing LDL-cholesterol levels
 Added to maximally tolerated statin and dietary measures if not achieving treatment targets in
secondary prevention
 NICE recommends for:
 Patients with a history of cardiovascular disease e.g. ACS, coronary/arterial revascularisation, CHD, ischaemic
stroke or peripheral arterial disease (PAD)
 with persistent LDL-C levels >2.6 mmol/l despite having the maximum tolerated lipid-lowering therapy (HI
statins and/or ezetimibe)
 Alone or in combination with lipid lowering medication if statin intolerant/contra-indicated

60. Inclisiran for secondary prevention
 Dosing: 284mg subcutaneous injection by HCP into abdomen, upper arm or thigh: baseline, after 3
months, and then every 6 months
 Monitoring: baseline LDL-C (fasting sample if possible), after 3 months, then every 6 months: Full lipid
profile (to calculate LDL-C), liver profile and renal profile
 Checking adherence to other medications
 Side effects/intolerances
 If LDL-C remains ≥2.6mmol/L despite inclisiran therapy for 9 to 12 months following initiation, refer to lipid
clinic
 Use with caution in severe renal impairment (eg CrCl<30ml/min) or requiring haemodialysis (avoid 72
hours after inclisiran dosing)
 Adverse effects: Mild to moderate injection site reactions are transient and resolve; pain, erythema,
rash

61. Final thoughts?

62. Audience questions and answers