Insulin-Statin-PCSK9 Links Point to New Treatment Horizons

June 17, 2016

INNSBRUCK, AUSTRIA — Statin therapy raises plasma levels of proprotein convertase subtilisin kexin type 9 (PCSK9) in a dose-dependent fashion, and diabetes further increases levels of the biomarker regardless of statin dosage, suggests an analysis of >1700 patients with either CHD or diabetes selected from a much larger trial[1].

The findings illuminate what seems to be an intricate dance with the PCSK9 molecule played out by statins, PCSK9 inhibitors, and diabetes, one that may help explain the profound cholesterol-lowering effect of combining statins with either of the available PCSK9 inhibitors, alirocumab (Praluent, Sanofi/Regeneron Pharmaceuticals) and evolocumab (Repatha, Amgen).

In further speculation, the PCSK9 connection may also account for the slightly elevated risk of diabetes seen with statin therapy and raises the possibility that PCSK9 inhibitors might lower cardiovascular risk in diabetics who don't have coronary heart disease.

"We found that PCSK9 levels are positively correlated with atorvastatin dose, which confirms the results of smaller trials that have investigated this effect," according to Dr Benoit Arsenault (Institut Universitaire de Cardiologie et de Pneumologie de Québec, QC).

"But we also showed for the first time that there is a dose-response effect of statin therapy on plasma PCSK9 levels," he told heartwire from Medscape. And, "We found that regardless of atorvastatin dose, the presence of type 2 diabetes was associated with higher PCSK9 levels."

Role of Diabetes and Insulin Levels

The observations came from the ILLUMINATE "biomarker substudy," which Arsenault presented here at the European Atherosclerosis Society 2016 Congress. It included 1744 patients—by design, half of whom were diabetic—from the ILLUMINATE trial's total of 15,067 with CHD with or without diabetes.

The subanalysis also provided evidence that insulin resistance and diabetes status influences PCSK9 levels, Arsenault said. There were highly significant correlations between PCSK9 levels and not only those of total cholesterol, LDL cholesterol, and triglycerides, but also those of glucose, insulin, and the homeostatic model assessment of insulin resistance (HOMA-IR) (all P<0.0001).

Also, levels of PCSK9 were overall significantly elevated in the diabetics compared with nondiabetics (357 ng/mL and 338 ng/mL, respectively; P=0.001), independent of statin dosage, but they also climbed with increasing dose levels of atorvastatin, which in the trial was given at 10, 20, 40, and 80 mg/day.

It's been appreciated and observed, notably in the primary-prevention JUPITER trial, that statin therapy raises PCSK9 levels through a known mechanism, according to Arsenault: statins diminish intracellular cholesterol, which in turn upregulates LDL receptors. The body responds by raising levels of PCSK9, whose job it is to degrade LDL receptors, "putting the brakes" on them, as he explained.

So PCSK9 upregulation is an unwanted side effect of statin therapy, "and most likely explains why we don't get the same LDL lowering [with statins] that we get with the PCSK9 inhibitors," he said.

It also suggests why the pairing of a statin with an inhibitor of PCSK9 can have an almost unprecedented dampening effect on LDL cholesterol.

Success Following Failure

The PCSK9-inhibitor story is in notable contrast to that of a class of lipid-modifying agents that failed spectacularly at the randomized-trial stage, the cholesteryl ester transfer protein (CETP) inhibitors—as covered extensively by heartwire .

Indeed, the ILLUMINATE trial itself provided one such demonstration for the CETP inhibitor torcetrapib (Pfizer) almost a decade ago. Its patients randomized to torcetrapib plus atorvastatin, compared with atorvastatin alone, showed a striking 72% jump in HDL-cholesterol levels and 25% drop in LDL cholesterol over 1 year (P<0.001 for both), but also a 25% increased risk of cardiovascular events (P=0.001) and 58% rise in all-cause mortality (P=0.006).

With CETP inhibitors now mostly of historical interest in cardiology, the current ILLUMINATE biomarker substudy adds a footnote. It selected its cohort from the main study so that one-third had received atorvastatin plus torcetrapib and two-thirds atorvastatin plus placebo.

Three months into randomized therapy, in an analysis limited solely to patients with diabetes, PCSK9 levels had risen by 16.1 ng/mL in the torcetrapib group (P=0.04) but remained essentially flat in the placebo group. The torcetrapib effect in diabetes was significant but admittedly minor, Arsenault said. There was no apparent effect of torcetrapib on PCSK9 among nondiabetics. Interestingly in the overall trial, as previously reported, torcetrapib treatment had been associated with drops in both glucose levels and insulin resistance as measured by HOMA-IR.

The Way Forward

With PCSK9-inhibitor therapy for dyslipidemia in its infancy, awaiting the results of even a first mortality trial, the biomarker study and other research raises the question of whether PCSK9 inhibition with statins would be more potent against dyslipidemia in diabetics compared with nondiabetics, according to Arsenault. It also raises the question of "whether PCSK9 inhibitors will decrease cardiovascular risk in patients with diabetes who don't have cardiovascular disease—that would be an interesting hypothesis to test!"

He pointed to a third PCSK9 inhibitor still wending its way through clinical trials, bococizumab (Pfizer), which has reportedly "met its primary end points" of LDL-cholesterol lowering in at least two small studies in the Studies of PCSK9 Inhibition and the Reduction of Vascular Events (SPIRE) series of trials. They include two massive randomized mortality trials in "high-risk" patients on background dyslipidemia therapy. Both are scheduled for completion in 2018.

Pfizer funded ILLUMINATE. Arsenault discloses receiving research funding from Pfizer and Ionis and honoraria or expenses from Pfizer.

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