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Macrovascular Residual Risk Studies

13 December 2016
GLAGOV: benefit with intensive LDL-lowering, but residual risk persists
Results from the GLAGOV (Global Assessment of Plaque Regression With a PCSK9 Antibody as Measured by Intravascular Ultrasound) study shows that despite intensive statin therapy, about 50% of patients do not have regression of atheroma. While adding a PCSK9 inhibitor to further decrease low-density lipoprotein cholesterol (LDL-C) results in further regression, about one-third of patients still do not regress, indicating the need to target other factors beyond LDL-C
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 2016 Nov 15. doi: 10.1001/jama.2016.16951. [Epub ahead of print]
Objective: To determine the effects of PCSK9 inhibition with evolocumab on progression of coronary atherosclerosis in statin-treated patients.
Study design: Multicentre, double-blind, placebo-controlled, randomized IVUS trial in 197 centres in North America, Europe, South America, Asia, Australia, and South Africa. Eligible patients were randomized (1:1) to treatment with statin alone (placebo) or evolocumab 420 mg monthly plus statin (evolocumab).
Study population: 968 patients (mean age 59.8 years, 28% women) with angiographic coronary disease and on a stable statin dose for at least 4 weeks (plasma LDL-C ≥80 mg/dl or between 60 and 80 mg/dl if 1 major or 3 minor cardiovascular risk factors). Mean baseline LDL?C was 92.5 mg/dl.
Efficacity measure: Primary endpoint: nominal change in percent atheroma volume (PAV) from baseline to week 78, as assessed by IVUS
Secondary endpoints:
· Nominal change in normalized total atheroma volume (TAV) from baseline to week 78
· Percentage of patients with plaque regression at week 78
Methods: Intravascular ultrasound imaging (IVUS) assessment was performed at baseline and week 78, and evaluated by researchers who were unaware of treatment status. The change in PAV (or TAV) was calculated as the PAV (or TAV) at 78 weeks minus the PAV at baseline. Regression was defined as any decrease in PAV or TAV from baseline. Data were analysed using a step-down statistical approach, i.e. the primary endpoint was first tested at the 0.05 significance level, and then the secondary end points were tested at the 0.05 significance level in sequential order. All p-values were two-sided with a p<0.05 considered statistically significant.
Main results:

Of the 968 patients enrolled, 484 were allocated to placebo (statin alone) and 484 to evolocumab (on top of statin). At the time of randomization, 60% were receiving high-intensity statin therapy and 39% were on moderate-intensity statin therapy.

The mean duration of treatment was 17.6 months. Overall, 846 patients had evaluable imaging at baseline and follow-up.

 Treatment with evolocumab significantly lowered LDL-C levels, from 93.0 mg/dl in the placebo group to 36.6 mg/dl (time-weighted mean difference, p<0.001). This greater LDL-C lowering was associated with significantly greater reduction in PAV and TAV at follow-up compared with placebo (Table). In addition, significantly more patients regressed on evolocumab than on statin alone (64.3% versus 47.3%, p<0.001).


Table. Change* in IVUS parameters from baseline to follow-up


Evolocumab (added to statin)


Placebo (statin alone)


Treatment difference

PAV, %

−0.95 (−1.33 to −0.58)

0.05 (−0.32 to 0.42)

−1.0 (−1.8 to −0.64)


TAV, mm3

−5.80 (−8.19 to −3.41)

−0.91 (−3.29 to 1.47)

−4.9 (−7.3 to −2.5)


* Change given as least-squares mean change with 95% confidence interval

Authors’ conclusion: Among patients with angiographic coronary disease treated with statins, addition of evolocumab, compared with placebo, resulted in a greater decrease in PAV after 76 weeks of treatment. Further studies are needed to assess the effects of PCSK9 inhibition on clinical outcomes.


GLAGOV evaluated the impact of additional LDL-C lowering on progression of coronary atherosclerosis in patients with established coronary disease who were receiving optimized, stable background statin therapy. The results of the study show that further LDL-C lowering with the PCSK9 inhibitor evolocumab (to a value beyond the current recommended goal of <70 mg/dl or 1.8 mmol/L) in very high risk patients is associated with plaque regression. However, regression was not evident in all patients on evolocumab suggesting the need to target other risk factors.

 The patient cohort was managed by best evidence-based therapy, with antiplatelet therapy received by almost all (96%), a beta-blocker by 76%, and over 50% were on an agent targeting the renin-angiotension system. However, lipid data suggested that a proportion of patients had residual hypertriglyceridaemia (as indicated by the interquartile range at baseline, with upper limit of 173 mg/dl) despite statin therapy. This finding is relevant in the light of a recent study which highlighted the importance of elevated triglycerides to plaque progression, irrespective of LDL-C levels.1

 Lowering LDL-C is the primary focus for preventing cardiovascular events in high risk patients. As shown by GLAGOV, lowering LDL-C beyond current guideline goals, does not induce plaque regression in all patients; alternative strategies targeting other risk factors are needed.  Targeting other lipid-related risk factors such as elevated triglycerides, a marker for triglyceride-rich lipoproteins and their remnants, should not be discounted.2-4


1. Puri R, Nissen SE, Shao M et al. Non-HDL cholesterol and triglycerides: implications for coronary atheroma progression and clinical events. Arterioscler Thromb Vasc Biol 2016;36:2220-8.

2. Libby P. The forgotten majority: unfinished business in cardiovascular risk reduction. J Am Coll Cardiol 2005;46:1225–1228.

3. Fruchart JC, Sacks F, Hermans MP et al. The Residual Risk Reduction Initiative: a call to action to reduce residual vascular risk in patients with dyslipidemia. Am J Cardiol 2008;102(10 Suppl):1K-34K.

4. Fruchart JC, Davignon J, Hermans MP et al. Residual macrovascular risk in 2013: what have we learned? Cardiovasc Diabetol. 2014 Jan 24;13:26.

Key words residual cardiovascular risk; triglycerides; intravascular ultrasound study; plaque; regression