3 ms·

The real question is, though, is drug therapy something that should be pushed on otherwise healthy (non-FHC/high risk) individuals in order to reduce mortality.

by briHass 11y ago

The real question is, though, is drug therapy something that should be pushed on otherwise healthy (non-FHC/high risk) individuals in order to reduce mortality. The PCSK9 research paper you linked has the percentage dead after 15 years (starting at an average of 55 yr/o) at 10.7% for those without the mutation and 8.3% for those with it. Assuming they actually work identically to the mutation, maybe one could argue that the $$$ cost of the new PCSK9 targeting drugs will be worth it to save 2.4%, but we have zero long term data on their safety. There is certainly some evidence [1] that the risk for diabetes could be higher...much like the current statins. I don't think we have anything even approaching a complete picture on the interplay between CHD, cholesterol, and overall mortality. Until the picture becomes clearer, it doesn't seem prudent to push drug therapy as strongly as it typically is. [1] http://www.ncbi.nlm.nih.gov/pubmed/20026049 http://www.ncbi.nlm.nih.gov/pubmed/20026049 The coincidence of statins falling out of patent and the rush to develop PCSK9 drugs is not lost on me.

carbocation 11y ago
To rephrase the exact same data, 15-year mortality is ~30% higher among those with the normal variant compared to those with the cholesterol-lowering variant. That is an enormous mortality effect. Based on the mechanism by which statins are postulated to cause diabetes (and LDLR-dependent mechanism), PCSK9 inhibitors may also cause diabetes, though it's not yet known. From a mortality perspective, this is irrelevant because we know that statins (and PCSK9 mutations) reduce mortality despite (probably) causing diabetes. The timing of statins falling off patent is essentially uncorrelated with anything - there was a multi-year gap with atorvastatin off patent before the PCSK9 inhibitors were approved, which makes no sense if you would like to invoke a patent conspiracy. With the advent of genetically-informed early phase research, you will continue to see new drugs come out at an increasing frequency (reversing the trend over the past few decades of fewer approvals). The link from cholesterol -> CHD -> mortality is as clear as anything in biology (clear enough for the basis for this work to have won a Nobel prize decades ago).

by briHass 11y ago

carbocation 11y ago

To rephrase the exact same data, 15-year mortality is ~30% higher among those with the normal variant compared to those with the cholesterol-lowering variant. That is an enormous mortality effect. Based on the mechanism by which statins are postulated to cause diabetes (and LDLR-dependent mechanism), PCSK9 inhibitors may also cause diabetes, though it's not yet known. From a mortality perspective, this is irrelevant because we know that statins (and PCSK9 mutations) reduce mortality despite (probably) causing diabetes. The timing of statins falling off patent is essentially uncorrelated with anything - there was a multi-year gap with atorvastatin off patent before the PCSK9 inhibitors were approved, which makes no sense if you would like to invoke a patent conspiracy. With the advent of genetically-informed early phase research, you will continue to see new drugs come out at an increasing frequency (reversing the trend over the past few decades of fewer approvals). The link from cholesterol -> CHD -> mortality is as clear as anything in biology (clear enough for the basis for this work to have won a Nobel prize decades ago).