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............................................................................................................................................................................. Statins have been shown to reduce C-reactive protein secretion by hepatocytes,539 and a series of clinical trials and post hoc analyses have found that beneficial outcomes after statin therapy relate both to a reduction in cholesterol levels and reduced inflammation.540544

The Justification for the Use of Statins in Prevention: an Intervention Trial Evaluating Rosuvastatin (JUPITER) trial542 demonstrated that in primary prevention for individuals with chronically elevated C-reactive protein (>2 mg/L), statin treatment markedly reduced CV events.545 It is of note that other lipid-lowering agents, such as ezetimibe and more recently the anti-PCSK9 mAbs, do not influence highsensitivity C-reactive protein levels,546,547 but lead to further significant reductions in CV events when added to statin therapy. Specific anti-inflammatory treatment was tested in the Canakinumab Antiinflammatory Thrombosis Outcome Study (CANTOS) trial.548 In patients with previous MI and chronic elevated high-sensitivity C-reactive protein levels, all on optimal medical treatment, including statins, the anti-IL-1b mAb canakinumab dosedependently reduced high-sensitivity C-reactive protein and significantly lowered the rate of recurrent CV events compared with placebo, independently of the level of lipid lowering. Not surprisingly, there was a slight increase in the risk of severe and fatal infections associated with canakinumab. This study was the first to highlight the positive correlation between high-sensitivity C-reactive protein and CV events, where lower achieved high-sensitivity C-reactive protein values were directly correlated with a lower risk of future CV events.548 Nevertheless, the FDA declined to approve canakinumab for CV risk reduction on the strength of data from the CANTOS study. As canakinumab treatment has not been tested against anti-PCSK9 mAb and/or ezetimibe added to statin therapy, the question of residual risk remains for patients with elevated high-sensitivity C-reactive protein despite achieving very low (below goal) LDL-C values, and whether patients with very low LDL-C would benefit from anti-IL-1b treatment or other anti-inflammatory agents. In addition, all currently recommended lipid-lowering drugs, including anti-PCSK9 mAbs, have demonstrated beneficial effects on atherosclerotic plaque composition as well as plaque volume regression; such results are still missing for antiinflammatory treatment. Another anti-inflammatory approach using methotrexate was tested in the Cardiovascular Inflammation Reduction Trial (CIRT).549 Very low-dose methotrexate (10 mg weekly), a proven anti-inflammatory regimen that reduces tumour necrosis factor (TNF), IL-6, and C-reactive protein levels and is widely used in the treatment of RA, was allocated vs. placebo to 7000 stable CAD patients. This study was stopped prematurely due to futility. Interestingly, this regimen of methotrexate had no effect on either IL-6 or high-sensitivity C-reactive protein blood levels in this population, which could explain the neutral results of this trial.550 Based on the current level of evidence, no further recommendations on the use of antiinflammatory agents can be made.551

11 Monitoring of lipids and

enzymes in patients on lipid-lowering therapy

Evidence concerning which tests should be carried out to monitor lipids in patients on treatment is limited. Similar limited evidence applies to tests of possible toxicity, such as ALT and CK. Recommendations stem from consensus rather than evidence-based medicine.

Response to therapy can be assessed at 68 weeks from initiation of therapy, but response to lifestyle may take longer. Standard practice for subsequent follow-up monitoring is 612 months, but such monitoring intervals are arbitrary. As a minimum, LDL-C should be assessed whenever available, but better management decisions will probably occur if a full lipid profile is performed, including HDL-C and TGs. Non-HDL-C or ApoB should also be analysed, and used as a secondary treatment target. A separate issue is the impact of regular lipid monitoring in promoting patient adherence to lifestyle changes or drug regimens that impact positively on their health, as found in a range of studies. It is unclear whether only the process of monitoring is critical in achieving this or whether a combination of education, regular contact, and adherence assessment is required. Where pharmacological lipid-lowering therapy is implemented, safety blood tests are advised, including ALT and CK at baseline, to identify the limited number of patients where treatment is contraindicated. CK should be checked in patients at high-risk for myopathy, such as the very elderly with comorbidities, patients with antecedents of muscle symptoms, or patients receiving interacting drugs. A mild and typically transient elevation of ALT is seen in about 2% of patients and normalization is seen with continuing therapy.240,244,552 Recent reviews are encouraging regarding the safety of long-term statin therapy and statin-induced liver injury is reported to be very uncommon.243,244,553555 ALT is recommended before the start of statin therapy; routine control of ALT during treatment is not recommended but should be performed, if indicated, based on clinical observations. During fibrate therapy, regular ALT control is still recommended. In patients whose liver function tests increase to above three times the ULN, explanations such as alcohol ingestion or NAFLD should be sought, and the levels monitored. If levels remain elevated then lipid-lowering therapy should be stopped, but may be cautiously reintroduced under monitoring after levels have returned to normal. There is no predictive value of routine repeat CK testing for rhabdomyolysis since the level can increase for many reasons, including muscle injury or excess muscular exercise. However, CK must be assessed immediately in patients who present with muscle pain and weakness, and especially in the elderly, and treatment stopped if CK rises to >10 times the ULN. Strategies to handle CK elevations are given in Table 13. Due to the increased frequency of DM during statin treatment,247,249,556,557 regular checks of HbA1c should be considered in patients at high-risk of developing DM and under high-dose statin treatment. Groups to be considered for glucose control are the elderly or those with MetS, obesity, or signs of insulin resistance.

12 Cost-effectiveness of

cardiovascular disease prevention by lipid modification

In 2015, there were >85 million people in Europe living with CVD.558 Aging populations,559 unhealthy diets, smoking, sedentary lifestyles, Downloaded from academic.oup.com/eurheartj/article/41/1/111/5556353 by guest on 07 October 2026