Relative Importance of Inflammation and Cholesterol as Determinants of Residual Cardiovascular Risk Among 31,245 Contemporary Statin Treated Patients

1. American College of Cardiology, March 6, 2023, New Orleans, LA
Late Breaking Clinical Trials / Featured Research
Relative Importance of Inflammation and Cholesterol as Determinants
of Residual Cardiovascular Risk
Among 31,245 Contemporary Statin Treated Patients
Paul M Ridker, Deepak L. Bhatt, Aruna D. Pradhan,
Robert J. Glynn, Jean G. MacFadyen, and Steven E. Nissen
on behalf of the PROMINENT, REDUCE-IT and STRENGTH Investigators

2. Among treatment-naïve men and women, inflammation and hyperlipidemia contribute
with similar magnitude to the risks of future atherothrombotic events.
Among those already on a statin, randomized trial data demonstrate that adjunctive LDL-
lowering (PCSK9i, ezetimibe, inclisiran, bempedoic acid) and adjunctive inflammation
inhibition (canakinumab, colchicine) further reduce risk suggesting that “lower is better”
for both biologic processes.
Thus, whether clinicians should choose a second LDL-lowering agent for those already
treated with a statin or alternatively choose an anti-inflammatory agent is uncertain.
Yet, this issue has broad implications for patient care, for clinical guidelines, for cost-
effectiveness, for payer preferences, and for future drug development.
Background and Rationale - I

3. Resolving the question of whether to add a second LDL-lowering agent and/or to consider
an adjunctive inflammation-inhibiting agent requires, in part, an understanding of the
relative importance of inflammation as compared to cholesterol as determinants of
residual cardiovascular risk among contemporary statin-treated patients.
To address this issue, we evaluated the relationships of hsCRP (a clinical biomarker for
residual inflammatory risk) and LDL-C (a clinical biomarker for residual cholesterol risk)
with the incidence of future major adverse cardiovascular events (MACE), cardiovascular
mortality, and all-cause mortality among 31,245 contemporary statin-treated patients
with or at high risk for future atherosclerotic disease.
Background and Rationale - II

4. Population:
Endpoints:
Step I :
Step II :
Step III :
Methods
Statin treated participants in PROMINENT (N = 9,988), REDUCE-IT (N = 8,179)
and STRENGTH (N = 13,078) for a total of 31,245 individuals.
Incident MACE, CV mortality, and all-cause mortality during trial follow-up (3 to 5 years)
Analysts within each trial coordinating center used a common template to compute
adjusted HRs (95%CIs) in proportional hazard models addressing risks for each endpoint
across increasing trial-specific quartiles of hsCRP and LDL-C. All analyses adjusted on an a
priori basis for age, gender, BMI, smoking, blood pressure, history of CVD, and randomized
treatment assignment.
Analysts at the CCVDP in Boston then performed a fixed effects meta-analysis of hsCRP and
LDL-C as determinants for each endpoint in which weighted quartile-specific HRs across
the trials were pooled using the inverse variance of each trial-specific estimated log-
hazard ratio, thus allowing for a single set of fully adjusted summary risk estimates.
In sensitivity analyses, risk estimates were also computed in stratum defined by each
trial’s randomized treatment assignment, and in interaction analyses across clinical
thresholds in wide use for both hsCRP and LDL-C.

5. Characteristic PROMINENT
(N = 9,988)
REDUCE-IT
(N = 8,179)
STRENGTH
(N = 13,078)
Age, years 64 64 63
Female, % 28 29 35
Type 2 Diabetes, % 100 58 70
Body Mass Index, kg/m2 32 31 32
High Intensity Statin, % 72 31 50
Secondary Prevention, % 68 71 56
Triglycerides, mg/dL* 271 216 240
LDL-C, mg/dL* 78 75 75
HDL-C, mg/dL* 33 40 36
hsCRP, mg/L* 2.3 2.2 2.0
Results – I
Clinical characteristics of statin-treated participants in the PROMINENT, REDUCE-IT, and STRENGTH trials
* median

6. Quartile 1 Quartile 2 Quartile 3 Quartile 4
hsCRP (mg/L)
PROMINENT < 1.2 1.2 – 2.3 2.3 – 4.8 > 4.8
REDUCE-IT < 1.1 1.1 – 2.1 2.2 – 4.5 > 4.5
STRENGTH < 1.1 1.1 – 2.0 2.0 – 4.2 > 4.2
Quartile 1 Quartile 2 Quartile 3 Quartile 4
LDL-C (mg/dL)
PROMINENT < 60 60 – 78 78 – 102 > 102
REDUCE-IT < 62 62 – 75 75 – 89 > 89
STRENGTH < 56 56 – 75 75 – 99 > 99
Quartile Cut-points for hsCRP (statin treated)
Quartile Cut-points for LDL-C (statin-treated)
Results – II
Trial-specific cut-points for baseline hsCRP and LDL-C among 31,245 statin-treated participants in the
PROMINENT, REDUCE-IT, and STRENGTH trials were highly consistent with each other

7. Pooled Data (N = 31,245)
Major Adverse Cardiovascular Events (MACE)
PROMINENT
(N = 9,988)
REDUCE-IT
(N = 8,179)
STRENGTH
(N = 13,078)
Results – III Hazard Ratios for Incident MACE Among 31,245 Statin Treated Patients
hsCRP
LDLC
* P < 0.0001 + P < 0.05
HR
1.31
HR
1.07

8. Quartile 1 Quartile 2 Quartile 3 Quartile 4
HR, adjusted* 1.0 1.06 1.17 1.31
95% CI Referent 0.97 – 1.16 1.07 – 1.28 1.20 – 1.43
P-value Referent 0.19 0.001 < 0.0001
Quartile 1 Quartile 2 Quartile 3 Quartile 4
HR, adjusted* 1.0 1.09 1.02 1.07
95% CI referent 1.00 – 1.18 0.93 – 1.11 0.98 – 1.17
P-value referent 0.06 0.37 0.11
Residual Inflammatory Risk (Quartiles of hsCRP)
Residual Cholesterol Risk (Quartiles of LDL-C)
* adjusted for age, gender, body mass index, smoking, blood pressure, prior history of CVD, and randomized treatment assignment
Results – III Hazard Ratios for Incident MACE Among 31,245 Statin Treated Patients

9. Pooled Data (N = 31,245)
Cardiovascular Death
PROMINENT
(N = 9,988)
REDUCE-IT
(N = 8,179)
STRENGTH
(N = 13,078)
Results – IV Hazard Ratios for Cardiovascular Death Among 31,245 Statin Treated Patients
hsCRP
LDLC
* P < 0.0001 + P < 0.05
HR
2.68
HR
1.27

10. Quartile 1 Quartile 2 Quartile 3 Quartile 4
HR, adjusted* 1.0 1.34 1.68 2.68
95% CI Referent 1.09 – 1.64 1.38 – 2.04 2.22 – 3.23
P-value Referent 0.008 < 0.0001 < 0.0001
Quartile 1 Quartile 2 Quartile 3 Quartile 4
HR, adjusted* 1.0 0.96 0.99 1.27
95% CI referent 0.82 – 1.14 0.83 – 1.18 1.07 – 1.50
P-value referent 0.36 0.40 0.009
Residual Inflammatory Risk (Quartiles of hsCRP)
Residual Cholesterol Risk (Quartiles of LDL-C)
* adjusted for age, gender, body mass index, smoking, blood pressure, prior history of CVD, and randomized treatment assignment
Results – IV Hazard Ratios for Cardiovascular Death Among 31,245 Statin Treated Patients

11. Pooled Data (N = 31,245)
All-Cause Mortality
PROMINENT
(N = 9,988)
REDUCE-IT
(N = 8,179)
STRENGTH
(N = 13,078)
Results – V Hazard Ratios for All-Cause Mortality Among 31,245 Statin Treated Patients
hsCRP
LDLC
* P < 0.0001 + P < 0.05
HR
2.42
HR
1.16

12. Quartile 1 Quartile 2 Quartile 3 Quartile 4
HR, adjusted* 1.0 1.34 1.59 2.42
95% CI Referent 1.16 – 1.55 1.38 – 1.83 2.12 – 2.77
P-value Referent 0.0001 < 0.0001 < 0.0001
Quartile 1 Quartile 2 Quartile 3 Quartile 4
HR, adjusted* 1.0 0.98 1.03 1.16
95% CI referent 0.87 – 1.10 0.91 – 1.17 1.03 – 1.32
P-value referent 0.37 0.35 0.025
Residual Inflammatory Risk (Quartiles of hsCRP)
Residual Cholesterol Risk (Quartiles of LDL-C)
* adjusted for age, gender, body mass index, smoking, blood pressure, prior history of CVD, and randomized treatment assignment
Results – V Hazard Ratios for All-Cause Mortality Among 31,245 Statin Treated Patients

13. Cardiovascular
Death
P < 0.0001
Results – VI Interaction Analyses - hsCRP < or >2 mg/L and/or LDLC < or > 70 mg/dL
hsCRP < 2mg/L
hsCRP < 2mg/L
LDLC > 70mg/dL
LDLC < 70mg/dL
P < 0.0001
hsCRP > 2mg/L
LDLC < 70mg/dL
hsCRP > 2mg/L
LDLC > 70mg/dL

14. Summary:
Among contemporary statin-treated patients, residual inflammatory risk as assessed by
hsCRP was a stronger determinant of risk for future cardiovascular events and death than
residual cholesterol risk as assessed by LDL-C.
In sensitivity analysis, we found no evidence of effect modification for any endpoint
in any of the three individual trials when stratified by randomized treatment assignment.
In all three trials, individuals with elevated hsCRP were at high cardiovascular risk
irrespective of LDLC level.

15. • Following statin therapy, should clinicians elect to use a second lipid-lowering agent or
choose instead to use an anti-inflammatory agent?
Implications for practice

16. • Following statin therapy, should clinicians elect to use a second lipid-lowering agent or
choose instead to use an anti-inflammatory agent?
• Consideration of colchicine 0.5 mg po qd for those with stable atherosclerosis and
normal eGFR.
• Consideration of bempedoic acid which, like statin therapy, reduces both LDL-C and
hsCRP
• Consideration of GLP1r agonists and SGLT2 inhibitors, all of which have concomitant
anti-inflammatory effects.
Implications for practice

17. • Following statin therapy, should clinicians elect to use a second lipid-lowering agent or
choose instead to use an anti-inflammatory agent?
• Consideration of colchicine 0.5 mg po qd for those with stable atherosclerosis and
normal eGFR.
• Consideration of bempedoic acid which, like statin therapy, reduces both LDL-C and
hsCRP
• Consideration of GLP1r agonists and SGLT2 inhibitors, all of which have concomitant
anti-inflammatory effects.
• While these data must not be construed to diminish the proven and crucial role of
adjunctive lipid-lowering for those with persistent or refractory hypercholesterolemia,
they do suggest that targeting of LDL-C alone is unlikely to completely reduce
atherosclerotic risk and that inflammatory pathways have yet to be fully exploited to
reduce fatal and nonfatal CV events.
Implications for practice

18. • Following statin therapy, should clinicians elect to use a second lipid-lowering agent or
choose instead to use an anti-inflammatory agent?
• Consideration of colchicine 0.5 mg po qd for those with stable atherosclerosis and
normal eGFR.
• Consideration of bempedoic acid which, like statin therapy, reduces both LDL-C and
hsCRP
• Consideration of GLP1r agonists and SGLT2 inhibitors, all of which have concomitant
anti-inflammatory effects.
• While these data must not be construed to diminish the proven and crucial role of
adjunctive lipid-lowering for those with persistent or refractory hypercholesterolemia,
they do suggest that targeting of LDL-C alone is unlikely to completely reduce
atherosclerotic risk and that inflammatory pathways have yet to be fully exploited to
reduce fatal and nonfatal CV events.
• (IL-1 inhibitors, IL-6 inhibitors, NLRP3 inhibitors, colchicine)
Implications for practice

19. • It is not an either/or situation: In the future, we believe the combined use of
aggressive LDL-lowering and inflammation inhibiting therapies will become standard
of care for almost all atherosclerotic patients.
• Finally, in addition to increasing the use of targeted anti-inflammatory therapies for
atherosclerosis, these data strongly support ongoing ACC/AHA prevention efforts
directed at diet, weight loss, exercise, and smoking cessation, all of which lower
vascular inflammation and lower cardiovascular event rates.
Implications for practice

20. This work was an academic collaboration. No role was played by the funders of
PROMINENT, REDUCE-IT, or STRENGTH trials in the design, analysis, or interpretation of these data.