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Evidence-Based Diabetes Management December 2017

Perspectives of a Lipidologist: LDL Cholesterol Testing, PCSK9 Inhibitors

Mary Caffrey
BRINTON: The FOURIER trial, which was the main study of one of the PCSK9 inhibitors, evolocumab, is a landmark trial. It is the first clinical cardiovascular outcomes trial looking at this new class—there’s another on its way; we’re going to have results in the next few months—but just taking the FOURIER trial, first, what we see is proof of principle. Adding a PCSK9 to a statin is helpful in terms of additional risk reduction beyond what is available with a statin alone. But then, a very large piece, and this is both clinically and scientifically important, is the question of the relationship between LDL cholesterol measured by whatever means—usually the Friedewald—the relationship between LDL cholesterol on treatment and cardiovascular outcomes. The biggest question here is: Can LDL be too low? Is there harm, or maybe lack of benefit, in having that LDL go ever lower? And the answer from the FOURIER data is “no.”10 The benefit is there, and the harm is not there. There appears to be no such thing as [an LDL] cholesterol that is too low.

[This is] in contrast to glucose, where we have hypoglycemia, a very serious concern clinically, and hypotension, also very serious. [Those] are life-threatening situations if we are not careful. [But] for LDL cholesterol, we don’t appear to have any downside for getting that LDL below 40 [mg/dL] or even below 20 [mg/dL]. FOURIER has really given us convincing data for additional benefit and no additional harm, even for an LDL in the less-than-20 [mg/dL] range. We’ve been concerned about this. I think FOURIER is of an adequate size and adequate power to give us confidence as we go forward to ever-more-aggressive LDL-lowering treatment.

EBDMTM: At the American College of Cardiology Scientific Sessions in March, physicians took note of the cardiovascular benefits that were seen with Repatha as well as studies that showed the difficulty clinicians experience when prescribing PCSK9 inhibitors.11 Has the reimbursement experience changed in recent months for this class of therapy?

BRINTON: We have a wonderful new tool in the field of lipid management and that is this new class of drugs, the PCSK9 inhibitors. They are marvelous because they are so effective in lowering LDL. They work really nicely on top of a statin; if we have someone who is statin-intolerant we are still allowed to use them as long as we have given statins a fair chance. So, then the question is: Can we actually have access to these drugs? And because they are expensive, access has been a big issue. The managed-care people are able to put a few roadblocks in the way—a little extra paperwork—that does make it harder for clinicians to write a PCSK9 inhibitor. Is that getting better? Is it still an issue?

The quick answer is, in my experience, it has changed very little. Maybe we have changed a little in terms of our approach to this, possibly some of the payers are little more relaxed. We do have convincing trial data now with the FOURIER study with evolocumab; we should have similar data soon with the other drug, which is alirocumab. I’m hopeful that this will become less of an issue. But it remains a very important fact that just simply writing a prescription for a PCSK9 inhibitor does not give one immediate access to the drug. On the one hand, we know that we shouldn’t just be using this drug widely for everyone who happens to have high cholesterol. On the flip side, if we have patients who really need additional LDL lowering, [if] we have done everything possible with a statin, we’re certainly considering, in most of these cases, use of ezetimibe. [That] has now gone generic, so we have greater access to ezetimibe. In the case where patients still have a high residual LDL cholesterol level and they have high residual cardiovascular risk, then adding a PCSK9 inhibitor is a good thing to do, and access remains an important issue.

References

1. Guidance for industry: diabetes mellitus—evaluating cardiovascular risk in new antidiabetic therapies to treat type 2 diabetes. FDA website. www.fda.gov/ downloads/Drugs/.../Guidances/ucm071627.pdf. Published December 2008. Accessed November 3, 2017.

2. Schofield JD, Liu Y, Rao-Balakrishna P, Malik RA, Soran H. Diabetes dyslipid- emia. Diabetes Ther. 2016;7(2):203-219. doi: 10.1007/s13300-016-0167-x.

3. Sabatine MS, Giugliano RP, Wiviott SD, et al; Open-Label Study of Long-Term Evaluation against LDL Cholesterol (OSLER) Investigators. Efficacy and safety of evolocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015;372(16):1500-1509. doi: 10.1056/NEJMoa1500858.

4. Robinson JG, Farnier M, Krempf M, et al; ODYSSEY LONG TERM Investigators. Efficacy and safety of alirocumab in reducing lipids and cardiovascular events. N Engl J Med. 2015;372(16):1489-1499. doi: 10.1056/NEJMoa1501031. 5.SabatineMS,GiuglianoRP,KeechAC,etal;FOURIERSteeringCommitteeand Investigators. Evolocumab and clinical outcomes in patients with cardiovascular disease. N Engl J Med. 2017;376(18):1713-1722. doi:10.1056/NEJMoa1615664.

6. Caffrey M. Praluent benefits for diabetes patients seen in pair of PCSK9 stud- ies. The American Journal of Managed Care® website. ajmc.com/conferences/ ada-2017/praluent-benefits-for-diabetes-patients-seen-in-pair-of-pcsk9-stud- ies. Published June 11, 2017. Accessed November 3, 2017.

7. Sabatine MS, Leiter LA, Wiviott SD, et al. Cardiovascular safety and efficacy of the PCSK9 inhibitor evolocumab in patients with and without diabetes and the effect of evolocumab on glycaemia and risk of new-onset diabetes: a prespecified analysis of the FOURIER randomized controlled trial [published online September 14 ,2017]. Lancet Diab Endocrin. doi: 10.1016/S2213- 8587(17)30313-3.

8. Lotta LA, Griffin SJ. PCSK9 inhibition and type 2 diabetes [published online September 14, 2017]. Lancet Diab Endocrin. doi: 10.1016/S22138587(17)30321-2.

9. Quest Diagnostics moves to convenient nonfasting cholesterol testing with improved method for assessing heart disease risk and aiding treatment decisions [news release]. Secaucus, NJ: Quest Diagnostics; September 7, 2017. newsroom.questdiagnostics.com/2017-09-07-Quest-Diagnostics-Moves-to-Convenient-Nonfasting-Cholesterol-Testing-with-Improved-Method-for- Assessing-Heart-Disease-Risk-and-Aiding-Treatment-Decisions. Accessed November 2, 2017.

10. Giugliano RP, Pedersen TR, Park JG, et al; FOURIER Investigators. Clinical efficacy and safety of achieving very low LDL-cholesterol concentrations with the PCSK9 inhibitor evolocumab: a prespecified secondary analysis of the FOURIER trial. Lancet. 2017;390(10106):1962-1971. doi: 10.1016/S01406736(17)32290-0.

11. Caffrey M. Data show it’s hard to fill PCSK9 prescriptions, confirming cardiologists’ complaints. The American Journal of Managed Care® website. ajmc.com/conferences/acc-2017/data-show-its-hard-to-fill-pcsk9-pre- scriptions-confirming-cardiologists-complaints. Published March 19, 2017. Accessed November 3, 2017.
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