New cholesterol guidelines: Worth the wait?
GROUP 1: PEOPLE WITH CLINICAL ASCVD
Advantages of the new guidelines
- They appropriately recommend statins in the highest tolerated doses as first-line treatment for this group at high risk.
- They designate all patients with ASCVD, including those with coronary, peripheral, and cerebrovascular disease, as a high-risk group.
- Without target LDL-C levels, treatment is simpler than before, requiring less monitoring of lipid levels. (This can also be seen as a limitation, as we discuss below.)
Limitations of the new guidelines
- They make follow-up LDL-C levels irrelevant, seeming to assume that there is no gradation in residual risk and, thus, no need to tailor therapy to the individual.
- Patients no longer have a goal to strive for or a way to monitor their progress.
- The guidelines ignore the pathophysiology of coronary artery disease and evidence of residual risk in patients on both moderate-intensity and high-intensity statin therapy.
- They also ignore the potential benefits of treating to lower LDL-C or non-HDL-C goals, thus eliminating consideration of multidrug therapy. They do not address patients with recurrent cardiovascular events already on maximal tolerated statin doses.
- They undermine the potential development and use of new therapies for dysplipidemia in patients with ASCVD.
Case 1: Is LDL-C 110 mg/dL low enough?
A 52-year-old African American man presents with newly discovered moderate coronary artery disease that is not severe enough to warrant stenting. He has no history of hypertension, diabetes mellitus, or smoking. His systolic blood pressure is 130 mm Hg, and his body mass index is 26 kg/m2. He exercises regularly and follows a low-cholesterol diet. He has the following fasting lipid values:
- Total cholesterol 290 mg/dL
- HDL-C 50 mg/dL
- Triglycerides 250 mg/dL
- Calculated LDL-C 190 mg/dL.
Two months later, after beginning atorvastatin 80 mg daily, meeting with a nutritionist, and redoubling his dietary efforts, his fasting lipid concentrations are:
- Total cholesterol 180 mg/dL
- HDL-C 55 mg/dL
- Triglycerides 75 mg/dL
- Calculated LDL-C 110 mg/dL.
Comment: Lack of LDL-C goals is a flaw
The new guidelines call for patients with known ASCVD, such as this patient, to receive intensive statin therapy—which he got.
However, once a patient is on therapy, the new guidelines do not encourage repeating the lipid panel other than to assess compliance. With intensive therapy, we expect a reduction in LDL-C of at least 50% (Table 1), but patient-to-patient differences in response to medications are common, and without repeat testing we would have no way of gauging this patient’s residual risk.
Further, the new guidelines emphasize the lack of hard outcome data supporting the addition of another lipid-lowering drug to a statin, although they do indicate that one can consider it. In a patient at high risk, such as this one, would you be comfortable with an LDL-C value of 110 mg/dL on maximum statin therapy? Would you consider adding a nonstatin drug?
A preponderance of data shows that LDL plays a causal role in ASCVD development and adverse events. Genetic data show that the LDL particle and the LDL receptor pathway are mechanistically linked to ASCVD pathogenesis, with lifetime exposure as a critical determinant of risk.5,6 Moreover, randomized controlled trials of statins and other studies of cholesterol-lowering show a reproducible relationship between the LDL-C level achieved and absolute risk (Figure 1).7–24 We believe the totality of data constitutes a strong rationale for targeting LDL-C and establishing goals for lowering its levels. For these reasons, we believe that removing LDL-C goals is a fundamental flaw of the new guidelines.
The reason for the lack of data from randomized controlled trials demonstrating benefits of adding therapies to statins (when LDL-C is still high) or benefits of treating to specific goals is that no such trials have been performed. Even trials of nonpharmacologic means of lowering LDL-C, such as ileal bypass, which was used in the Program on the Surgical Control of the Hyperlipidemias trial,20 provide independent evidence that lowering LDL-C reduces the risk of ASCVD (Figure 1).
In addition, trials of nonstatin drugs, such as the Coronary Drug Project,25 which tested niacin, also showed outcome benefits. On the other hand, studies such as the Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides: Impact on Global Health26 and Treatment of HDL to Reduce the Incidence of Vascular Events27 trials did not show additional risk reduction when niacin was added to statin therapy. However, the study designs arguably had flaws, including requirement of aggressive LDL-lowering with statins, with LDL-C levels below 70 to 80 mg/dL before randomization.
Therefore, these trials do not tell us what to do for a patient on maximal intensive therapy who has recurrent ASCVD events or who, like our patient, has an LDL-C level higher than previous targets.
For this patient, we would recommend adding a second medication to further lower his LDL-C, but discussing with him the absence of proven benefit in clinical trials and the risks of side effects. At present, lacking LDL-C goals in the new guidelines, we are keeping with the ATP III goals to help guide therapeutic choices and individualize patient management.
GROUP 2: PEOPLE WITH LDL-C ≥ 190
Advantages of the new guidelines
- They state that these patients should receive statins in the highest tolerated doses, which is universally accepted.
Limitations of the new guidelines
- The new guidelines mention only that one “may consider” adding a second agent if LDL-C remains above 190 mg/dL after maximum-dose therapy. Patients with familial hypercholesterolemia or other severe forms of hypercholesterolemia typically end up on multidrug therapy to further reduce LDL-C. The absence of randomized controlled trial data in this setting to show an additive value of second and third lipid-lowering agents does not mean these agents do not provide benefit.
