Implementation is the challenge: CME Session Highlights

Sunday highlighted a series of CME sessions covering topical questions in lipid lowering therapy.

The session ‘Novel pathways for intensive lipid lowering’ discussed how to address the two key issues in managing lipids in current practice: 1) insufficient lowering of low-density lipoprotein cholesterol (LDL‑C), a major causal risk factor for atherosclerotic cardiovascular disease, and 2) statin side effects, in particular statin-associated muscle symptoms (SAMS).

It is more than evident from the DA VINCI study (1), an observational study in 18 European countries in nearly 6,000 patients prescribed lipid lowering therapy for primary or secondary prevention, that LDL-C management is far from optimal, particularly among those patients most at risk. This is despite the 2019 European Society of Cardiology (ESC)/EAS dyslipidaemia guidelines emphasising the need for combination therapy to attain LDL-C goal in high-risk patients (2). In DA VINCI, only about one in five patients with established atherosclerotic cardiovascular disease achieved the 2019 ESC/EAS recommended LDL-C goal, and the use of statin combination therapy was limited (1).

One of the key contributing factors to poor LDL-C goal attainment is SAMS, a common problem leading to non-adherence with statin treatment, and impacting clinical outcome (3). Statin side effects are often encouraged by mistruths in media coverage (4). Over the last five years there has been much debate regarding the veracity of SAMS. Observational studies provide support, whereas results from blinded controlled trials did not identify any difference in the prevalence of muscle symptoms in patients on statin treatment or placebo (5,6).  Most recently, the SAMSON (N of 1) trial reported that 90% of statin side effects were also reported with placebo or no drug treatment (placebo/nocebo effect), highlighting the issue of misattribution of symptoms on statin therapy (7). As discussed by Professor Erik Stroes (Academic Medical Center, Amsterdam, the Netherlands), accumulating data indicate that there are a minority of patients reporting true SAMS (as defined by a past EAS Consensus Panel statement) (8), much less than that reported in observational studies. The influence of the clinician is critical for the successful management of these patients. Insights from the ongoing TaSINI trial, which is assessing the effect of additional cognitive behavioural therapy (9), as well as the expanding armamentarium of no statin therapies, are much anticipated.

As with other major cardiovascular risk factors, there needs to be a ‘sea change’ in thinking about lipid management. According to Professor Stephen Nicholls (Monash University, Melbourne, Australia), this extends to measuring lipids earlier and more frequently, overcoming clinical inertia in follow-up, and moving to consider the spectrum of atherogenic lipoproteins, not just LDL-C.

As proposed recently (10), combination lipid lowering therapy should be increasingly recognised as the norm rather than the exception. This very much aligns with approaches to the management of other major risk factors, including elevated blood pressure and blood glucose, where clinicians routinely consider combination therapy, rather than a ‘wait and see’ approach that has been inherent in lipid management. In recognition of the need for improvements in implementation, the EAS has recently published a Task Force Statement providing practical guidance for the use of combination lipid lowering therapy in clinical practice (11). Professor Alberico Catapano (University of Milan, Italy) discusses the guidance here.

Non-statin LDL-C lowering therapies now include ezetimibe, the PCSK9 monoclonal antibodies, inclisiran, and bempedoic acid, the last available as either a single agent or as a fixed dose combination with ezetimibe. As discussed by Professor Ulrich Laufs (University of Leipzig, Germany), this novel ATP citrate lyase inhibitor, which targets hepatic cholesterol synthesis upstream of statins, has been shown to be effective both as monotherapy and on top of statins (12,13). In fixed combination with ezetimibe, LDL-C lowering of ~35% on top of statins (~45% in statin-naïve patients) has been reported (14). The outstanding question is whether this therapeutic approach reduces cardiovascular events. This is being evaluated in the CLEAR OUTCOMES trial in 14,000 patients with SAMS, with results expected in 2023.

In concluding remarks, Professor Kausik Ray (Imperial College, London, UK) highlighted the challenge of implementation. ‘We need new implementation approaches to ensure best practice in the management of at-risk patients with dyslipidaemia.’

Find more at the meeting 


  1. Ray KK, Molemans B, Schoonen WM, et al. EU-Wide Cross-Sectional Observational Study of Lipid-Modifying Therapy Use in Secondary and Primary Care: the DA VINCI study. Eur J Prev Cardiol 2020 Aug 28;zwaa047.
  2. Mach F, Baigent C, Catapano AL, et al. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J 2020;41:111-88.
  3. Serban M-C, Colantonio LD, Manthripragada AD et al. Statin intolerance and risk of coronary heart events and all-cause mortality following myocardial infarction. J Am Coll Cardiol 2017;69:1386–95.
  4. Nelson AJ, Puri R, Nissen SE. Statins in a distorted mirror of media. Curr Atheroscler Rep 2020;22(8):37.
  5. Thompson PD. What to believe and do about statin-associated adverse effects. JAMA 2016;316:1969-70.
  6. Gupta A, Thompson D, Whitehouse 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 2017;389:2473-81.
  7. 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;383:2182-4.
  8. Stroes ES, Thompson PD, Corsini A et al. Statin-associated muscle symptoms: impact on statin therapy—European Atherosclerosis Society Consensus Panel Statement on Assessment, Aetiology and Management. Eur Heart J 2015; 36: 1012–22.
  9. Tudor K, Brooks J, Howick J, et al. Tackling statin intolerance with n-of-1 trials (TaSINI) in primary care: protocol for a feasibility randomised trial to increase statin adherence. BMJ Open 2020;10(2):e033070.
  10. Packard CJ, Chapman MJ, Sibartie M, Laufs U, Masana L. Intensive low-density lipoprotein cholesterol lowering in cardiovascular disease prevention: opportunities and challenges. Heart 2021; Epub ahead of print:
  11. Averna M, Banach M, Bruckert E, et al. Practical guidance for combination lipid-modifying therapy in high- and very-high-risk patients: A statement from a European Atherosclerosis Society Task Force. Atherosclerosis 2021;325:99-109.
  12. Ray KK, Bays HE, Catapano AL, et al. Safety and efficacy of bempedoic acid to reduce LDL cholesterol. N Engl J Med 2019;380:1022-32.
  13. Goldberg AC, Leiter LA, Stroes ESG, et al. Effect of bempedoic acid vs placebo added to maximally tolerated statins on low-density lipoprotein cholesterol in patients at high risk for cardiovascular disease: the CLEAR Wisdom Randomized Clinical Trial. JAMA 2019;322:1780-18.
  14. Ballantyne CM, Laufs U, Ray KK, et al. Bempedoic acid plus ezetimibe fixed-dose combination in patients with hypercholesterolemia and high CVD risk treated with maximally tolerated statin therapy. Eur J Prev Cardiol 2020;27:593-603.
Share this: