Atherosclerotic plaque regression with intense Apo B lipoprotein lowering

The results of GLAGOV, reported at AHA Scientific Sessions and now published in JAMA (1) are of keen interest to the clinical community, with the major outcomes study FOURIER with evolocumab expected early in 2017.

IVUS 3

GLAGOV is the first intravascular ultrasound (IVUS trial to evaluate the impact of combination treatment of a non-statin lipid lowering agent (LLT), in this instance a PCSK9 inhibitor (evolocumab), with a statin on coronary atherosclerosis progression. It should also be noted that GLAGOV is also the first (IVUS) trial in patients with incident coronary atherosclerosis that was performed on a background of optimized, stable background statin therapy, as reflected in the lowest mean baseline low-density lipoprotein cholesterol level (LDL-C, 93.0 mg/dl) of any IVUS trial to date.

Over a treatment period of 76 weeks (one of the shortest duration of any IVUS trial involving LLTs to date), LDL‑C decreased by 60% to 36.6 mg/dl in the evolocumab-treated group, well below the ESC/EAS recommended LDL-C goal of 70 mg/dl for very high risk patients. Analysis of the primary endpoint, percentage change in atheroma volume (PAV), revealed a least squares mean of 0.95% plaque regression in the intervention group (n=484) relative to an increase of 0.05% in the placebo (background statin treatment alone). The secondary endpoint, change in total atheroma volume, also was indicative of significantly greater plaque regression in the evolocumab arm versus placebo. In fact, PAV regressed in 64% of individuals on evolocumab plus statin compared to 47% on statin alone. Thus, in summary, the greater reduction in LDL-C with the addition of the PCSK9 inhibitor evolocumab to statin therapy resulted in greater regression of atheroma when compared with statin alone.

The key question is: How do these results compare to those in earlier statin monotherapy trials (ASTEROID and SATURN) using IVUS technology?

ASTEROID (2), which showed a significant degree of coronary atherosclerosis regression (0.79% as median PAV, p<0.001) with intensive statin therapy (rosuvastatin 40 mg/day) compared with baseline, was conducted in statin-naïve patients for a period of 24 months. This degree of regression may have resulted from a predominance of vulnerable lipid-rich, “virgin” plaque in these statin-naïve patients. In SATURN (3) coronary plaque regression of 1.22% was obtained with the same intensive statin regimen as ASTEROID over a 24-month period; in this trial, some 60% of patients had received statin treatment for up to 3 months in the year preceding trial inclusion.

The results of GLAGOV clearly show that for patients at very high risk who are on stable intensive or moderate statin therapy with on-treatment LDL-C levels of about 90 mg/dl, stable statin treatment can achieve significantly greater regression when their LDL-C levels are reduced further. Thus, LDL-C lowering mediated by a nonstatin drug, in this case a PCSK9 inhibitor, on top of stable intensive statin therapy, can provide significant additional plaque regression. Importantly, further LDL lowering to levels significantly below the ESC/EAS goal of 70 mg/dl (36 mg/dl) with the addition of evolocumab, is consistent with greater clinical benefit, as judged by additional plaque regression over and above that obtained with intensive statin therapy alone.

Finally, it is important to bear in mind that coronary plaque regression induced by statin therapy has been shown to be synonymous with plaque remodeling, favouring plaque stabilization, and ultimately reductions in cardiovascular events. It can therefore be inferred that the additional 1% of plaque regression induced in the GLAGOV trial by a PCSK9 inhibitor on top of background statin may favour enhanced plaque stability. Insight into the potential for translation of the antiatherosclerotic action of the evolocumab/statin combination into reduction in cardiovascular outcomes over and above that provided by statin therapy alone will be provided by the ongoing FOURIER intervention trial.

References

  1. Nicholls SJ, Puri R, Anderson T et al. Effect of evolocumab on progression of coronary disease in statin-treated patients. The GLAGOV randomized clinical trial. JAMA. doi:10.1001/jama.2016.16951. Published online November 15, 2016.
  2. Nissen SE, Nicholls SJ, Sipahi I et al; ASTEROID Investigators. Effect of very high-intensity statin therapy on regression of coronary atherosclerosis: the ASTEROID trial. JAMA 2006;295:1556-65. PUBMED www.ncbi.nlm.nih.gov/pubmed/16533939
  3. Nicholls SJ, Ballantyne CM, Barter PJ et al. Effect of two intensive statin regimens on progression of coronary disease. N Engl J Med 2011;365:2078-87. PUBMED www.ncbi.nlm.nih.gov/pubmed/22085316
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5 thoughts on “Atherosclerotic plaque regression with intense Apo B lipoprotein lowering

  1. PCSK9-inhibitors should be a godsend for those who can’t achieve halfway acceptable lipid aboB control with conservative (statin) treatment alone but don’t qualify for apheresis either.
    Given the baseline LDL-C in this trial we may well see significant endpoint benefit, but in light of the diminishing (absolute) returns at the lower end of apoB concentrations and the high cost of treatment I somewhat doubt we will see this becoming a mainstream therapy for a significant number of patients soon.

    • Hi Dolph

      Thanks for the comment. You are correct about the prohibitive cost of PCSK9-I. Some cost effective studies have been performed indicating until the price is US 4000 per year we are unlikely so see mainstream use of the drugs.

      Blessings
      Cardiologydoc

      • It’s me who has to thank you. I was glad to see another post of yours after thinking you had abandoned this blog. But I guess interesting news don’t always come in as a constant stream.

        By the way. Can you point me to something authoritative about the role of mast cells in atherosclerosis?
        I did read a lot of older (and at times ancient…) papers during the last weeks on that topic after stumbling across some contradictory works on the role of a few antihistaminic drugs on the progression of the disease.

  2. Hi Dolph

    The whole role of inflammatory cells (including mast cells) and cytokines (inflammatory mediators) is being investigated in trials by Paul Ridker (of JUPITER fame).

    See these refs.

    22. Ridker PM. Testing the inflammatory hypothesis of atherothrombosis: scientific rationale for the cardiovascular inflammation reduction trial (CIRT). J Thromb Haemost 2009;7:332–9. http://dx.doi.org/10.1111/j.1538-7836.2009.03404.x
    23. Ridker PM, Lüscher TF. Anti-inflammatory therapies for cardiovascular disease. Eur Heart J 2014;35:1782–91.http://dx.doi.org/10.1093/eurheartj/ehu203

    Regards
    Cardiologydoc

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