–Both cardiovascular benefits and increase in diabetes seem likely.
There is no more eagerly awaited question in cardiovascular medicine than the clinical role of the PCSK9 inhibitors. The first reports from a series of outcomes trials are not due until next year. But two large genetic studies published this week deliver strong indirect evidence that PCSK9 inhibitors will likely have a clinical profile similar to statins. The studies, published in the New England Journal of Medicine and Lancet Diabetes and Endocrinology, provide a fascinating suggestion of the potential benefits of the drugs. But the studies also confirm that the new drugs, like statins, will likely raise the risk of diabetes in some patients.
In both papers researchers used a Mendelian randomization design to examine the impact on important clinical outcomes of natural genetic variations in people enrolled in large prospective cohorts. The researchers looked at the effect of variants of the PCSK9 gene that naturally produce the effect that the PCSK9 inhibitors are designed to mimic and compared this effect to the effect of HMGCR variants that naturally produce the effect of statins.
This is “fascinating and immensely helpful research, harnessing the power of large scale genetic studies to help unravel the link between LDL-C lowering (previously attributed to statins only) and incident diabetes mellitus,” said James Stein (University of Wisconsin).
Both studies reached similar conclusions. The broad effects of PCSK9 inhibitors are likely to be similar to the effects of statins. People with a high PCSK9 genetic score had significantly lower LDL levels and reduced rates of myocardial infarction and other major coronary and cardiovascular events. These differences occurred in a dose-response fashion, so that those with the highest genetic scores had the largest reductions in LDL and clinical events. The pattern was similar in people with HMGCR variants that produce the same effect as statins.
The studies suggest that PCSK9 inhibitors will reduce coronary events by about 19%, roughly similar to the effect of statins. The findings also suggest that the effects are additive, so that PCSK9 inhibitors will lead to further reduction in events when given on top of statin therapy.
But Sek Kathiresan (Massachusetts General Hospital) cautioned against “using gene variants in therapeutic target genes to anticipate the efficacy and safety of pharmacological manipulation of a given target gene.” His “principal caveat,” he said, “is that gene variants alter a gene lifelong and pharmacologic intervention often starts later in life and is of shorter duration. As such, I would be cautious in extrapolating the effect size seen in the genetics to the drug trials.”
Increase in Risk of Diabetes
The risk of diabetes for people with the PCSK9 variants increased by about 11%, which, again, was similar to the increased risk for people with the statin variants. In the NEJM study the excess risk was only seen in people with impaired fasting glucose levels at baseline.
The association of statins with diabetes, which first emerged with the JUPITER trial, was controversial at first but is now widely accepted. Whether the same association would be found with the PCSK9 inhibitors has been an open question. The new studies provide the first strong evidence that the PCSK9 inhibitors will likely have the same effect.
“It’s fantastic to see this puzzling observation, first denied, then ridiculed, now proven to be true,” said Stein. “It appears that lowering LDL levels by increasing LDL receptor expression (as with statins, ezetimibe, and PCSK9 inhibitors) will reduce cardiovascular disease risk and increase diabetes with similar dose effects once LDL is considered. The glycemic effect is small but real. These data suggest that drugs that reduce LDL by mechanisms that affect the LDL receptor will reduce CVD events (unless they are unsafe or an off target effect outweighs that benefit) but one should re-double efforts at lifestyle interventions proven to prevent dysglycemia, as these will reduce risk of diabetes mellitus, though through different pathways.”
The authors of the Lancet Diabetes and Endocrinology study emphasized that the diabetes finding do not outweigh the cardiovascular benefits. “In the case of statins, the treatment benefit in terms of CHD risk reduction greatly outweighs any potential adverse effect on risk of type 2 diabetes, partly because the size of the risk reduction in CHD is greater than the risk increase in type 2 diabetes, and partly because the absolute risk of CHD in primary prevention populations eligible for statin treatment is greater than the absolute risk of type 2 diabetes.” The NEJM authors wrote that “both PCSK9 and HMGCR variants were associated with a de- creased risk of cardiovascular events among persons with diabetes and those without diabetes.”
Kathiresan said that these papers, along with earlier research, “suggest an inverse biologic link between LDL and type 2 diabetes. The exact mechanism behind this link remains to be worked out.”
The studies also found no evidence for pleiotropic effects of either statins or PCSK9 inhibitors, since the clinical benefits precisely mirrored the reductions in LDL cholesterol. However, the authors of the Lancet Diabetes and Endocrinology study observed that there is still the possibility of off-target effects with the PCSK9 inhibitors, though such effects are less likely with monoclonal antibodies than with small molecules.
“The clinical relevance of these findings will need to wait for findings from ongoing clinical trials and should focus on an assessment of the benefits and risks, which will need to come from subsequent analyses looking at absolute risks of CHD and diabetes,” said Michael Holmes (Oxford), a co-author of the Lancet Diabetes and Endocrinology study. “Certainly for statins, the overwhelming evidence is that the cardiovascular benefit of statin treatment far outweighs the small increased risk of diabetes that is seen. Indeed, statins are beneficial for patients with diabetes. Similar analyses will need to be conducted for PCSK9 inhibitors. However, the findings from the study suggest that, using genetic variants, PCSK9 inhibitors have almost identical associations with CHD and diabetes as do statins (for a given difference in LDL-C), thus it may well be that the final scenario for PCSK9 inhibitors is similar to what we now understand for statins (i.e. that the cardiovascular benefits greatly outweigh the diabetogenic risks). Patients currently prescribed lipid lowering therapy (such as statins and those currently prescribed PCSK9 inhibitors, e.g. patients with familial hypercholesterolemia) should certainly not stop taking their drugs on the basis of these findings.”