Statin and nonstatin LLTs present challenges that may limit their use

When considering LLTs for patients, which criteria are most important? Click to explore.

LDL-C reduction efficacy Dose titration Consistency of effect Proven CVOT efficacy Minimizing risk of diabetes Patient tolerability Route of administration Cost and access

When considering LLTs for patients, which criteria are most important? Click to explore.

LDL-C reduction efficacy

Lipid-lowering agent¹

Typical LDL-C reduction (%)¹

High-intensity statins

50%

Low- or moderate-intensity statins

30%

Ezetimibe

24%

Bempedoic acid

17%

Dose titration

Doubling the statin dose results in an incremental LDL-C reduction of only 6%²

Suboptimal consistency of effect is common with some LLTs

Percent change in LDL-C^4,*

Among patients (N=7856) receiving rosuvastatin 20 mg once daily.⁴

*Numbers do not equal 100 due to rounding.

Cardiovascular outcomes trials: measuring therapeutic impact

Association between achieved LDL-C and major coronary event rates⁵

Relative risk reduction per 72-mg/dL reduction in LDL-C: 38%
(relative risk, 0.62 [95% CI, 0.75-0.79]; P<.001)

Relative risk reduction per 70-mg/dL reduction in LDL-C: 38%
(relative risk, 0.62 [95% CI, 0.75-0.79]; P<.001)

Relative risk reduction per 65-mg/dL reduction in LDL-C: 36%
(relative risk, 0.64 [95% CI, 0.75-0.79]; P<.001)

Relative risk reduction per 60-mg/dL reduction in LDL-C: 33%
(relative risk, 0.67 [95% CI, 0.75-0.79]; P<.001)

Relative risk reduction per 55-mg/dL reduction in LDL-C: 31%
(relative risk, 0.69 [95% CI, 0.75-0.79]; P<.001)

Relative risk reduction per 50-mg/dL reduction in LDL-C: 29%
(relative risk, 0.71 [95% CI, 0.75-0.79]; P<.001)

Relative risk reduction per 45-mg/dL reduction in LDL-C: 26%
(relative risk, 0.74 [95% CI, 0.75-0.79]; P<.001)

Relative risk reduction per 40-mg/dL reduction in LDL-C: 24%
(relative risk, 0.76 [95% CI, 0.75-0.79]; P<.001)

Relative risk reduction per 38.7-mg/dL reduction in LDL-C: 23% (relative risk, 0.77 [95% CI, 0.75-0.79]; P<.001)

Relative risk reduction per 35-mg/dL reduction in LDL-C: 22%
(relative risk, 0.78 [95% CI, 0.75-0.79]; P<.001)

Relative risk reduction per 30-mg/dL reduction in LDL-C: 18%
(relative risk, 0.82 [95% CI, 0.75-0.79]; P<.001)

Relative risk reduction per 25-mg/dL reduction in LDL-C: 15%
(relative risk, 0.85 [95% CI, 0.75-0.79]; P<.001)

Relative risk reduction per 20-mg/dL reduction in LDL-C: 13%
(relative risk, 0.87 [95% CI, 0.75-0.79]; P<.001)

Relative risk reduction per 15-mg/dL reduction in LDL-C: 10%
(relative risk, 0.90 [95% CI, 0.75-0.79]; P<.001)

Relative risk reduction per 13-mg/dL reduction in LDL-C: 8%
(relative risk, 0.92 [95% CI, 0.75-0.79]; P<.001)

Move slider to see the impact of LDL-C lowering.

Adapted from Silverman et al. 2016.

Statin use increases the risk of new-onset diabetes and diabetes progression⁶

In a meta-analysis of 19 double-blind trials with a total of 123,940 patients treated with statin or placebo⁶

High-intensity statin therapy was associated with a 36% increased risk of new-onset diabetes

Low- or moderate-intensity statin therapy was associated with a 10% increased risk of new-onset diabetes

In a separate cohort study of 83,022 matched pairs of patients with diabetes, statin use was associated with a 37% increased relative risk of diabetes progression.⁷

16% higher risk of insulin initiation
41% higher risk of new classes of glucose-lowering medication
13% higher risk of persistent hyperglycemia
24% higher risk of ketoacidosis or uncontrolled diabetes

Patient tolerability remains a concern

Although statin therapy remains the standard of care, many patients cannot tolerate optimal doses.⁸

Skeletal muscle-related symptoms reported as muscle soreness, aches, cramps, fatigue, and/or weakness. Myopathy and rhabdomyolysis are rare⁸

Transaminase elevation, confusion, and memory loss are associated with statin intolerance⁸

Statin-associated muscle symptoms are often reported after a statin dose increase⁹

Up to 30% of patients are partially or completely statin intolerant.⁸ Statin intolerance can occur at any time during therapy.¹⁰

Side effects of medication—both feared and experienced—are common reasons patients decline and discontinue LLTs.⁸

Route of administration

Current injectable therapies face significant patient barriers.¹¹

<1% of ASCVD patients were treated with PCSK9i in 2019¹¹

Needle fear affects medication uptake for ≈15% of adult patients¹²

Cost and access pose additional challenges

Increased cost is a main barrier to the use of some available nonstatin therapies.¹³

Up to

1in4

patients’ nongeneric, nonstatin LLTs are denied by insurance¹⁴

12.6% of patients with a history of ASCVD are nonadherent due to medication costs and report¹⁵

Skipping doses¹⁵

Taking lower than prescribed doses¹⁵

Intentionally delaying prescription refills¹⁵

Total Medicare expenditures on LDL-C–lowering therapies was $3.3 billion in 2018¹⁶

Burdensome PA process can discourage physician prescribing and impact patient access¹⁷

High cost-sharing and patient out-of-pocket expenses lead to unfilled prescriptions¹⁸

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ASCVD, atherosclerotic cardiovascular disease; CVOT, cardiovascular outcomes trials; LDL-C, low-density lipoprotein cholesterol; LLT, lipid-lowering therapy; PA, prior authorization; PCSK9i, proprotein convertase subtilisin/kexin type 9 inhibitor.

References: 1. Michaeli DT, Michaeli JC, Albers S, Boch T, Michaeli T. Established and emerging lipid-lowering drugs for primary and secondary cardiovascular prevention. Am J Cardiovasc Drugs. 2023;23(5):477-495. 2. Clem JR, Strain JD, Farver DK. Individualized initiation of statin therapy determined by baseline LDL-C: are you more likely to achieve goal LDL-C? Risk Manag Healthc Policy. 2010;3:1-11. 3. Nodari S, Rocca P, Saporetti A, et al. The combination of ezetimibe and statin: a new treatment for hypercholesterolemia. Heart Int. 2007;3(1):12. 4. Ridker PM, Mora S, Rose L; JUPITER Trial Study Group. Percent reduction in LDL cholesterol following high-intensity statin therapy: potential implications for guidelines and for the prescription of emerging lipid-lowering agents. Eur Heart J. 2016;37(17):1373-1379. 5. Silverman MG, Ference BA, Im K, et al. Association between lowering LDL-C and cardiovascular risk reduction among different therapeutic interventions: a systematic review and meta-analysis. JAMA. 2016;316(12):1289-1297. 6. Reith C, Preiss D, Blackwell L, et al; Cholesterol Treatment Trialists' (CTT) Collaboration. Effects of statin therapy on diagnoses of new-onset diabetes and worsening glycaemia in large-scale randomized blinded statin trials: an individual participant data meta-analysis. Lancet. 2024;12(5):306-319. 7. Mansi IA, Chansard M, Lingvay I, Zhang S, Halm EA, Alvarez CA. Association of statin therapy initiation with diabetes progression: a retrospective matched-cohort study. JAMA Intern Med. 2021;181(12):1562-1574. 8. Cheeley MK, Saseen JJ, Agarwala A, et al. NLA scientific statement on statin intolerance: a new definition and key considerations for ASCVD risk reduction in the statin intolerant patient. J Clin Lipidol. 2022;16(4):361-375. 9. Thompson PD, Panza G, Zaleski A, Taylor B. Statin-associated side effects. J Am Coll Cardiol. 2016;67(20):2395-2410. 10. Bui A, Kwon J, Kim J, Lucas A. Overcoming barriers to statin adherence. US Pharm. 2019;44(6):19-22. 11. Gu J, Sanchez R, Chauhan A, Fazio S, Wong N. Lipid treatment status and goal attainment among patients with atherosclerotic cardiovascular disease in the United States: a 2019 update. Am J Prev Cardiol. 2022;10:100336. 12. McLenon J, Rogers MAM. The fear of needles: a systematic review and meta-analysis. J Adv Nurs. 2019;75(1):30-42. 13. Hao Q, Aertgeerts B, Guyatt G, et al. PCSK9 inhibitors and ezetimibe for the reduction of cardiovascular events: a clinical practice guideline with risk-stratified recommendations. BMJ. 2022;377:e069066. 14. MacDougall DE, Baum SJ, Ahmed CD, McGowan MP, Wilemon KA. Trends in patient access to and utilization of prescribed PCSK9 inhibitors in a large US claims database from 2015 to 2021. Circ Cardiovasc Qual Outcomes. 2024;17(2):e009988. 15. Khera R, Valero-Elizondo J, Das SR, et al. Cost-related medication nonadherence in adults with atherosclerotic cardiovascular disease in the United States, 2013 to 2017. Circulation. 2019;140(25):2067-2075. 16. Sumarsono A, Lalani HS, Vaduganathan M, et al. Trends in utilization and cost of low-density lipoprotein cholesterol-lowering therapies among Medicare beneficiaries: an analysis from the Medicare Part D database. JAMA Cardiol. 2021;6(1):92-96. 17. Navar AM, Taylor B, Mulder H, et al. Association of prior authorization and out-of-pocket costs with patient access to PCSK9 inhibitor therapy. JAMA Cardiol. 2017;2(11):1217-1225. 18. Doggrell SA. Inclisiran, the billion-dollar drug, to lower LDL cholesterol — is it worth it? Expert Opin Pharmacother. 2020;21(16):1971-1974.