Hit or miss: the new cholesterol targets

 

 

Drug treatment to reduce cholesterol to new target levels is now recommended in four moderate- to high-risk patient populations: patients who have already sustained a cardiovascular event, adult diabetic patients, individuals with low density lipoprotein cholesterol levels ≥190 mg/dL and individuals with an estimated 10-year cardiovascular risk ≥7.5%. Achieving these cholesterol target levels did not confer any additional benefit in a systematic review of 35 randomised controlled trials. Recommending cholesterol lowering treatment based on estimated cardiovascular risk fails to identify many high-risk patients and may lead to unnecessary treatment of low-risk individuals. The negative results of numerous cholesterol lowering randomised controlled trials call into question the validity of using low density lipoprotein cholesterol as a surrogate target for the prevention of cardiovascular disease.

 

Source : Hit or miss: the new cholesterol targets

 

Current recommendations

The 2018 AHA/ACC guidelines generally recommend LDL-C lowering drug therapy in the following moderate- and high-risk populations.

• Moderate risk

  • Individuals aged 40–75 with diabetes and LDL-C between 70 and 189 mg/dL

  • Individuals aged 40–75 without atherosclerotic cardiovascular disease (ASCVD) or diabetes with LDL-C between 70 and 189 mg/dL and 10-year ASCVD risk ≥7.5% and <20%

• High risk

  • Individuals with clinical ASCVD (secondary prevention)

  • Individuals with LDL-C ≥190 mg/dL

  • Individuals aged 40–75 without ASCVD or diabetes with LDL-C between 70 and 189 mg/dL and 10-year ASCVD risk ≥20%

     

    (...)

     

    Of the 13 RCTs that met the LDL-C reduction target, only one reported a mortality benefit and five reported a reduction in cardiovascular events. Of the 22 RCTs that did not meet the LDL-C reduction target, four reported a mortality benefit and 14 reported a reduction in cardiovascular events (figure 1). Similar results were seen when analysing only higher quality studies (quality scores A and B, figure 2). The lack of consistent mortality and cardiovascular benefit was seen with all three drug classes. Although PCSK9 inhibitors are currently the most potent drugs for reducing LDL-C, it is not clear from this analysis whether or not this drug class is more likely to produce clinical benefit compared with statins or ezetimibe. In summary, mortality and cardiovascular benefit was more frequently reported in RCTs that did not meet the LDL-C targets than in those that did.

     

    
    Per cent of low density lipoprotein cholesterol (LDL-C) lowering randomised controlled trials that reported benefit.

 

 

Per cent of higher quality low density lipoprotein cholesterol (LDL-C) lowering randomised controlled trials that reported benefit. 

 

 Relationship between the per cent reduction in low density lipoprotein cholesterol (LDL-C) and the absolute risk reduction in cardiovascular events (R, correlation coefficient).

 

What to do now

Cardiovascular disease continues to be the leading cause of death worldwide. Between 2002 and 2013 statin use in the US nearly doubled, cholesterol levels are falling, yet cardiovascular deaths appear to be on the rise.30 31 In Sweden, recent widespread and increasing utilisation of statins did not correlate with any significant reduction in acute myocardial infarction or mortality, while in Belgium a very modest reduction in cardiovascular events was reported between 1999 and 2005, but primarily in elderly individuals not taking statins.32 33 These population studies suggest that, despite the widespread use of statins, there has been no accompanying decline in the risk of cardiovascular events or cardiovascular mortality. In fact, there is some evidence that statin usage may lead to unhealthy behaviours that may actually increase the risk of cardiovascular disease.34 35 The evidence presented in this analysis adds to the chorus that challenges our current approach to cardiovascular disease prevention through targeted reductions of LDL-C. Given the lack of clarity on how best to prevent cardiovascular disease, we encourage informed decision-making. Ideally, this includes a discussion of absolute risk reduction and/or number needed to treat at an individual patient level in addition to reviewing the potential benefits and harms of any intervention.