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Inflammation Contributes to Cardiovascular Risk in Patients Receiving Statin Therapy
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Inflammation and hyperlipidaemia jointly contribute to atherothrombotic disease. However, when people are treated with intensive statin therapy, the relative contributions of inflammation and hyperlipidaemia to the risk of future cardiovascular events might change, which has implications for the choice of adjunctive cardiovascular therapeutics. We aimed to evaluate the relative importance of high-sensitivity C-reactive protein (CRP) and low-density lipoprotein cholesterol (LDLC) as determinants of risk for major adverse cardiovascular events, cardiovascular death, and all-cause-death among patients receiving statins.
We did a collaborative analysis of patients with-or at high risk of-atherosclerotic disease, who were receiving contemporary statins and were participants in the multinational PROMINENT (NCT03071692), REDUCE-IT (NCT01492361), or STRENGTH (NCT02104817) trials. Quartiles of increasing baseline high-sensitivity CRP (a biomarker of residual inflammatory risk) and of increasing baseline LDLC (a biomarker of residual cholesterol risk) were assessed as predictors of future major adverse cardiovascular events, cardiovascular death, and all-cause death. Hazard ratios (HRs) for cardiovascular events and deaths were calculated across quartiles of high-sensitivity CRP and LDLC in analyses adjusted for age, gender, BMI, smoking status, blood pressure, previous history of cardiovascular disease, and randomised treatment group assignment.
31 245 patients were included in the analysis from the PROMINENT (n=9988), REDUCE-IT (n=8179), and STRENGTH (n=13 078) trials. The observed ranges for baseline high-sensitivity CRP and LDLC, and the relationships of each biomarker to subsequent cardiovascular event rates, were almost identical in the three trials. Residual inflammatory risk was significantly associated with incident major adverse cardiovascular events (highest high-sensitivity CRP quartile vs lowest high-sensitivity CRP quartile, adjusted HR 1·31, 95% CI 1·20-1·43; p<0·0001), cardiovascular mortality (2·68, 2·22-3·23; p<0·0001), and all-cause mortality (2·42, 2·12-2·77; p<0·0001). By contrast, the relationship of residual cholesterol risk was neutral for major adverse cardiovascular events (highest LDLC quartile vs lowest LDLC quartile, adjusted HR 1·07, 95% CI 0·98-1·17; p=0·11), and of low magnitude for cardiovascular death (1·27, 1·07-1·50; p=0·0086) and all-cause death (1·16, 1·03-1·32; p=0·025).
Among patients receiving contemporary statins, inflammation assessed by high-sensitivity CRP was a stronger predictor for risk of future cardiovascular events and death than cholesterol assessed by LDLC. These data have implications for the selection of adjunctive treatments beyond statin therapy and suggest that combined use of aggressive lipid-lowering and inflammation-inhibiting therapies might be needed to further reduce atherosclerotic risk.
Disclosure statements are available on the authors' profiles:
Inflammation and cholesterol as predictors of cardiovascular events among patients receiving statin therapy: a collaborative analysis of three randomised trialsLancet 2023 Mar 06;[EPub Ahead of Print], PM Ridker, DL Bhatt, AD Pradhan, RJ Glynn, JG MacFadyen, SE Nissen
From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.
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Much has been written about residual cardiovascular risk due to persistent elevation of LDL-C above the levels that exist in infancy. However, the relative contribution of LDL-C level elevation in a range that is consistent with current guidelines in patients being treated with statins versus the relative contribution of inflammation-related risk as assessed by high-sensitivity C-reactive protein (hs-CRP) level elevation in the contemporary era was unknown. Therefore, data from three recent trials (REDUCE-IT, STRENGTH, and PROMINENT) were pooled to examine these relationships. What was found was that hs-CRP level elevation was a more potent driver of cardiovascular events than LDL-C level elevation. These results suggest that drugs targeting inflammation may provide cardiovascular benefits. Such trials are ongoing with older drugs (eg, colchicine) and newer drugs (eg, IL-6 inhibition with ziltivekimab), and the results are eagerly being awaited. Likely, the potential cardiovascular benefit of any drug targeting inflammation would be complementary to very intense LDL-C level reduction with PCSK-9 inhibition.
Among treatment-naïve individuals, it has long been recognized that both inflammation (assessed by hsCRP levels) and hyperlipidemia (assessed by LDL-C levels) contribute with similar importance to future cardiovascular risk. In modern cardiovascular practice, however, virtually all atherosclerosis patients are treated with statins, drugs that lower both LDL-C and hsCRP levels. Further, among statin-treated patients with atherosclerosis, randomized trials have demonstrated that adjunctive inflammation-inhibiting agents as well as adjunctive lipid-lowering agents further reduce risk. Thus, selecting a second risk-lowering agent beyond statins requires an understanding of the relative importance of “residual inflammatory risk” in comparison with “residual cholesterol risk” among contemporary statin-treated patients.
In new data that are likely to be a wake-up call for cardiologists, it appears that residual inflammatory risk trumps residual cholesterol risk among statin-treated patients. Specifically, in an analysis of 31,245 patients with atherosclerosis on statin therapy who were participants in the contemporary PROMINENT, REDUCE-IT, and STRENGTH trials, hsCRP level in all three trials was a stronger determinant of recurrent cardiovascular events, cardiovascular death, and all-cause mortality than was LDL-C level.1 Perhaps most striking, hsCRP level was a far more powerful predictor of cardiovascular mortality (HR, 2.68; P < .0001) and all-cause mortality (HR, 2.42; P < .0001) than was LDL-C level (comparable HRs, 1.27 and 1.17; P < .03). Moreover, among statin-treated patients with hsCRP levels >2 mg/L, risks for cardiovascular death were high irrespective of LDL-C level.
There are immediate clinical implications of these new data. First, in the setting of secondary prevention, clinicians must measure levels of hsCRP as well as LDL-C if they wish to understand the biologic risks being faced by their patients with atherosclerosis. It is hard to imagine assessing vascular risk by guessing rather than measuring LDL-C level or blood pressure, yet that is exactly what we are doing when we fail to measure inflammation directly.
Second, cardiologists may need to reconsider their choices for adjunctive therapeutics. The relative risk reductions observed in the CANTOS trial of canakinumab (17%) and in the COLCOT (23%) and LoDoCo2 (31%) trials of oral colchicine are, if anything, greater than the risk reductions demonstrated when ezetimibe (8%) or PCSK9 inhibitors (15%) are added to statin therapy.2 Thus, inflammation inhibition appears to be an underutilized target for treatment. And low-dose colchicine (0.5 mg daily) is a very inexpensive intervention, although it should be avoided in those with chronic kidney disease.
Last, lipid lowering and inflammation inhibition are not in conflict but are synergistic. In the future, many believe that all patients with atherosclerosis will be treated with a combination of aggressive cholesterol lowering and inflammation inhibition treatments.
Should we be looking at inflammation markers for residual cardiovascular risk?
With the advent of statin therapy, cardiovascular (CV) diseases have been greatly reduced. However, some patients still have CV events despite high-dose statins. This is referred to as the residual risk. The residual risk is in part still due to LDL-cholesterol (LDL-C) and, hence, the addition of PCSK9 inhibitors has helped reduce the risk further. However, even with very low LDL-C, some patients have CV events.
Some of that residual risk might be from inflammation, which could cause more plaque ruptures, leading to more events. Dr. Ridker pioneered the high-sensitivity C-reactive protein (hs-CRP) test, which can be used to look for inflammation. In 2008, the Jupiter study1 used hs-CRP to identify higher-risk primary prevention patients, and the use of rosuvastatin 20 mg helped to reduce CV events and deaths in these primary prevention patients. However, that study was ahead of its time. The medical community did not feel the need to treat low-risk primary prevention individuals, and, as a result, the inflammation strategy lost momentum.
This current paper takes a different approach to looking for inflammation. Instead of primary prevention patients for whom there was no urgency, the investigators looked at patients already on statins to see whether hs-CRP was connected to more CV events. That would be medically important.
Dr. Ridker and his team looked at data from three studies: PROMINENT (N = 9988), REDUCE-IT (N = 8179), and STRENGTH (N = 13,078). They grouped patients based on their hs-CRP levels into quartiles and then compared the highest quartile group with the lowest. The results showed an increase of 31% in MACE (aHR, 1.31; 95% CI, 1.20–1.43; P < .0001), a 268% increase in cardiovascular mortality (aHR, 2.68; 95% CI, 2.22–3.23; P < .0001), and a 242% increase in all-cause mortality (aHR, 2.42; 95% CI, 2.12–2.77; P < .0001).
Comparing the highest with the lowest LDL-C quartiles did not have such dramatic results. For the MACE outcome, there was no significant difference (aHR, 1.07; 95% CI, 0.98–1.17; P = ·11) between the highest and lowest LDL-C quartiles. For CV death, there was a 27% increase (aHR, 1.27; 95% CI, 1.07–1.50; P = .0086), and, for all-cause death, there was a 16% increase (aHR, 116; 95% CI, 1.03–1.32; P = .025). Therefore, not nearly as dramatic as with the hs-CRP comparison.
What this tells us is that, once people are on good statin therapies, the LDL-C residual risk becomes diminished, which is a good thing. In other words, the threat of LDL-C has been reduced. However, the presence of inflammation will drive future CV events.
Perhaps we should put appropriate patients on statins and then check their hs-CRP levels after they are on high-dose statins. If the hs-CRP level is high, then those patients are still at risk of CV events, and, hence, we must double our efforts to reduce this risk. Right now there are no affordable, proven therapies to reduce inflammation; therefore, we need to go back to the basics. We need to work harder to get these patients to quit smoking, reduce abdominal obesity, reduce stress, improve sleep, and improve their diet.
My other concern is about patients with inflammation from long COVID. My fear is that COVID-19 inflammation may also increase the rate of CV events, which will affect a large number of people.
For now, LDL-C is still a good CV event predictor; but, once patients are on statin therapy and the LDL-C level is within the low range, we need to look for other things that can drive CV events, and inflammation looks like the new enemy that we must defend our patients against. Just like in real war, the first step is to know our enemies and then we can defeat them.