Cardioprotective Effect of PCSK9 Inhibitors Should Outweigh Potential Harm of Diabetes Risk

MedicalResearch.com Interview with:
Brian A. Ference, M.D
Division of Cardiovascular Medicine
Wayne State University School of Medicine
Detroit, MI

MedicalResearch.com: What are the main findings?

Response: Lifelong exposure to modestly lower plasma LDL-C levels caused by rare loss-of-function mutations in the PCSK9 gene is associated with a substantially lower lifetime risk of developing cardiovascular disease. This discovery motivated the development of monoclonal antibodies directed against PCSK9 which have now been shown to reduce plasma LDL-C levels by 50-60%. The cardiovascular medicine community is early anticipating the results of two large cardiovascular outcome trials that will determine if lowering LDL-C levels by inhibiting PCSK9 will reduce the risk of cardiovascular events.

Because monoclonal antibodies and other therapies directed against PCSK9 are designed to recapitulate the phenotype of PCSK9 loss-of-function mutations, we reasoned that it may be possible to anticipate the efficacy and safety results of the ongoing cardiovascular outcome studies by more precisely characterizing the effect of genetic variants in the PCSK9 gene on the risk of both cardiovascular events and new onset diabetes.

To do this, we a constructed genetic score consisting of multiple independently inherited variants in the PCK9 gene to create an instrument that mimics the effect of PCSK9 inhibitors. We then compared the effect of genetic variants that mimic the effect of PCSK9 inhibitors with the effect of genetic variants in the HMGCR gene that mimic the effect of statins to make inferences about the likely effect of PCSK9 inhibitors on the risk of cardiovascular events and new onset diabetes as compared to treatment with a statin.

MedicalResearch.com: What are the main findings?

Response: We found that genetic variants that mimic PCSK9 inhibitors and statins have very similar effects on the risk of cardiovascular disease per unit lower LDL-C. This effect was similar for multiple different cardiovascular outcomes and in all subgroups studied.

Furthermore, we also found that genetic variants that mimic the effect of PCSK9 inhibitors and statins had very similar effects on the risk of new onset diabetes; but that this increased risk was limited to persons with impaired fasting glucose for both genetic variants.

When present together, genetic variants that mimic combined therapy with both PCSK9 inhibitors and statins had additive effects on reducing the risk of cardiovascular events, but also had additive effects on increasing the risk of diabetes.

In further analyses, the effect of genetic variants that mimic the PCSK9 inhibitors statins on the risk of both cardiovascular events and diabetes appeared to be mediated through a common mechanism involving the LDL receptor.

MedicalResearch.com: What should readers take away from your report?

Response: Because monoclonal antibodies are designed to recapitulate the phenotype of PCSK9 loss-of-function mutations, the results of our study may accurately anticipate the results of the ongoing cardiovascular outcome trials evaluating the effect of PCSK9 inhibitors.

Our study suggests that genetic variants that mimic the effect of PCSK9 inhibitors and statins have biologically equivalent effects on the risk of cardiovascular events and diabetes per unit lower LDL-C. Therefore, PCSK9 inhibitors and statins are likely to have therapeutically equivalent effects on these outcomes.

More specifically our study suggests, that like statins, PCSK9 inhibitors should reduce the risk of cardiovascular events by about 20% per mmol/L (38.7 mg/dl) reduction in LDL-C. However, our study also suggests that, like statins, PCSK9 inhibitors may increase the risk of new onset diabetes.

Importantly, our study also suggests that that, as with statins, the cardioprotective effect of treatment with a PCSK9 inhibitor should far outweigh any potential harm from an increased risk of diabetes caused by treatment with a PCSK9 inhibitor; and that, as with statins, any increased risk of new onset diabetes during treatment with a PCSK9 inhibitor should be limited to persons with impaired fasting glucose.

MedicalResearch.com: What recommendations do you have for future research as a result of this study?

Response: Although our study suggests that the increased risk of diabetes caused by inhibition of PCSK9 and HMGCR may be mediated by up-regulation of the LDL receptor in the pancreatic beta islet cells, further research is needed to clarify how PCSK9 inhibitors and statins may increase the risk of diabetes, and to better characterize the effects of new onset diabetes caused by either of these agents.

More generally our study also suggests that as pharmaceutical companies increasingly focus on developing novel therapies that attempt to recapitulate the phenotype of causal mutations, it may be possible to use these genetic variants to accurately anticipate the efficacy and safety of these new therapies by designing “naturally randomized trials” like the one described in our study.

MedicalResearch.com: Thank you for your contribution to the MedicalResearch.com community.

Citation:

Variation in PCSK9 and HMGCR and Risk of Cardiovascular Disease and Diabetes
Brian A. Ference, M.D., Jennifer G. Robinson, M.D., M.P.H., Robert D. Brook, M.D., Alberico L. Catapano, Ph.D., M. John Chapman, Ph.D., David R. Neff, D.O., Szilard Voros, M.D., Robert P. Giugliano, M.D., George Davey Smith, M.D., D.Sc., Sergio Fazio, M.D., Ph.D., and Marc S. Sabatine, M.D., M.P.H.
N Engl J Med 2016; 375:2144-2153
December 1, 2016DOI: 10.1056/NEJMoa1604304

Note: Content is Not intended as medical advice. Please consult your health care provider regarding your specific medical condition and questions.

More Medical Research Interviews on MedicalResearch.com

[wysija_form id=”5″]