Meta analysis published in JAMA Cardiology supports a return to LDL targets and lower mg/dL leveis in high risk patients.
A meta-analysis by Sabatine and colleagues published in JAMA Cardiology on 1 August 2018 supports not only a return to LDL targets, but a suggestion to go far lower than 70 mg/dL in high-risk patients. Previous outcomes research by the Cholesterol Treatment Trialists Collaboration (CTTC) showed that treatment with statins, in patients who had a baseline LDL of levels of about 3.4 mmol/L (131.5 mg/dL), was associated with a 22% reduction in major vascular events per 1-mmol/L (38.7 mg/dL) lowering of LDL-C.
Sabatine and colleagues examined results from the FOURIER trial of Repatha, IMPROVE-IT of Zetia (ezetimibe), which is now known to target the Niemann-Pick C1-Like 1 transporter, and REVEAL of cholesteryl ester transfer protein (CETP) inhibitor anacetrapib. In a subset of patients in CTTC statin studies with a mean LDL-C at baseline/control of 1.7 mmol/L (65.7 mg/dL), the relative risk for major vascular events per 1-mmol/L (38.7 mg/dL) reduction in LDL-C was 22%. In the studies of non-statin drugs on top of statins, the median baseline/control arm of LDL-C ranged from 1.6 mmol/L to 1.8 mmol/L (63 mg/dL to 70 mg/dL) and the relative risk reduction for major vascular events per 1-mmol/L (38.7-mg/dL) reduction in LDL-C was 21%. Morevover LDL lowering "was not associated with an increased risk of serious adverse events, myalgias and/or myositis, elevation in the level of aminotransferases, new-onset diabetes, hemorrhagic stroke, or cancer,"according to the article.
The authors noted that benefits were seen in patient populations starting as low as a median of 1.6 mmol/L (63 mg/dL) and achieving levels as low as a median of 0.5 mmol/L (21 mg/dL) – and there was no difference between the drug classes."The clinical benefit per millimoles per liter reduction in LDL-C was virtually identical for statins, ezetimibe, PCSK9 inhibition, and CETP inhibition, despite these drugs having different effects on other risk markers such as high-density lipoprotein cholesterol, lipoprotein(a), and high-sensitivity C-reactive protein. This observation reinforces the notion that the reduction in LDL-C (or more broadly, atherogenic apolipoproteinB-containing particles) is the primary driver of clinical benefit," the article concluded. Sabatine et al.,acknowledged that levels achieved in the non-statin studies are much lower than those advised in guidelines for high-risk patients, that is the range from 1.8 mmol/L to 2.6 mmol/L (from 70mg/dL to 100mg/dL). The authors concluded that the "thresholds as low as approximately 0.5 mmol/L or 20 mg/dL, would further reduce cardiovascular risk."
The results of the meta-analysis conflict with another meta-analysis published by Eliano Navarese of the Inova Vascular and Heart Institute of Northern Virginia and colleagues in JAMA Cardiology on 17 April 2018. That study found that more intensive LDL-C lowering was associated with a higher reduction in cardiovascular mortality risk in studies, but only for those with LDL-C baseline levels over 100 mg/dL.
Weill Cornell Medicine cardiologist Antonio Gotto said in an editorial accompanying Sabatine et.al.'s study that the meta-analysis was "extremely well done" and that the results are encouraging and make a "strong case" for updating the current AHA/ACC guidelines.He commented that the assessment was not all positive, as it excluded the ODYSSEY outcomes study where the greatest benefit was in those with LDL-C of 100 mg/dL or more.In ODYSSEY, patients who had LDL-C levels at 100 mg/dL had a 24% lower rate of major adverse cardiovascular events (MACE), according to a pre-specified analysis, versus 15% overall, the latter of which is lower than the 21% figure reported for non-statin drugs in the meta-analysis. Would including the Praluent study have dragged down the results for non-statins in those with lower baseline LDL-C ?. The Sabitine investigators did a calculation that showed that the inclusion of ODYSSEY would have had a minimal effect on the reported results.
See
- Efficacy and Safety of Further Lowering of LDL Cholesterol in Patients Starting With Very Low Levels
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