Non–High-Density Lipoprotein Cholesterol and Guidelines for Cholesterol Lowering in Recent History

Stanley S. Levinson, PhD


Lab Med. 2020;51(1):14-23. 

In This Article

Mechanisms by Which Recommended Lipid-lowering Drugs Act

Mechanisms by which the various lipid-lowering agents act help medical professionals to understand how to best reach target values. Statins, bile-acid sequestrants, and ezetimibe all act by reducing intracellular cholesterol levels. Those levels are controlled by the sterol regulatory element-binding proteins (SREBPs),[37] which are transcription factors that bind to the sterol regulatory element DNA sequence TCACNCCAC. As shown in Figure 1, when intracellular cholesterol is low, the SREBP acts to upregulate the LDL receptor. As a result, more receptor is synthesized and more blood cholesterol is transported into the cell, lowering blood cholesterol.

Statins inhibit the 3-Hydroxy 3-methylglutarate coenzyme A (HMG-CoA) reductase step in cholesterol synthesis. This process lowers intracellular cholesterol and upregulates the LDL receptor. Statins are powerful lipid-lowering drugs because they are competitive inhibitors of HMG-CoA reductase, with synthesis inversely proportional to statin dose. Statins are more powerful agents for reducing blood cholesterol (Table 2) than ezetimibe (lower LDLC by 15%–20% or bile-acid sequestrants [lower LDLC by 15%–30%]), as is apparent from their mechanism of action.

Ezetimibe selectively inhibits intestinal cholesterol uptake, reducing intracellular cholesterol.[38] Ezetimibe and its active glucuronide metabolite circulate interhepatically and therefore, there is very little systemic exposure. Ezetimibe added to a moderate-intensity statin (40 mg of simvastatin; IMPROVE IT-Trial)[39] demonstrated a 6.4% statistically significant reduction (P = .02) in ASCVD events. Simvastatin lowered LDLC to 69.5 mg per dL, and 10 mg of ezetimibe further lowered LDLC to 53.7 mg per dL. Nevertheless, a 6.4% reduction was considered too modest, and the Endocrinologic and Metabolic Drugs Advisory Committee of the U.S. Food and Drug Administration (FDA) voted against recommending approval of ezetimibe as an add-on to a statin. Still, patients in that study who were at particularly high risk of recurrent ASCVD events showed a substantial risk reduction (relative risk [RR] reduction, 19%)[40] which is why the most recent guidelines recommend ezetimibe as the first primary second-line therapy after first-line statins (Table 3).[3,40]

Bile-acid sequestrants are a group of ion-exchange resins that bind bile acids in the intestine, thereby disrupting the enterohepatic circulation of bile acids. Because cholesterol is the precursor of bile acids, liver cells synthesize more bile acids, reducing intracellular cholesterol stores. Bile-acid sequestrants are generally recommended as a second-line treatment after ezetimibe (Table 3).

It has been known for some time that besides acting on the LDL receptor, SREBPs act to upregulate protease proprotein convertase subtilisin/kexin type 9 (PCSK9).[37] The protease initiates a process whereby the LDL receptor is degraded (Figure 1). Thus, when low concentrations of intracellular cholesterol cause an increase in the LDL receptor, PCSK9 tries to counteract the effect. More recently, antibodies that inhibit PCSK9 have been developed. These antibodies are named evolocumab and alirocumab; they are subcutaneously injected[41] and reduce LDLC levels approximately 50% beyond those yielded by standard statin therapy. These agents were shown to statistically significantly reduce ASCVD beyond that yielded by a statin by approximately 12% to 15% (RR, 0.85–0.92) and reduce death from any cause (RR, 0.85)[42] over a medium duration of 2.8 years. These agents were approved by the FDA.[2] The combination of a statin and a PCSK9 inhibitor is a powerful tool for reducing blood LDLC because the statin directly inhibits the intracellular cholesterol that increases the LDL receptor and the PCSK9 inhibitor reduces the counteraction that degrades the receptor. Moreover, data from these studies have made it even clearer that the lower the cholesterol, the lower the risk of ASCVD—the lower the better. Because of expense and possible poor compliance in some patient conditions, these agents are recommended as third-line agents except for familial hypercholesterolemia, in which they may be used as second-line agents (Table 3).

Risk-assessment studies are derived from primary populations with a normal incidence of ASCVD, with the possible exception of the CPPT. However, most, if not all, treatment studies have been conducted as secondary prevention studies with high-risk populations, such as patients with type 2 diabetes mellitus, those who have known ASCVD, or those with familial hypercholesterolemia. Moreover, in secondary prevention trials, many subjects have multiple comorbidities, so they are apt to die from factors other than ASCVD, which causes cholesterol lowering to appear to be less effective than it really is. Therefore, although it is clear that the lower the LDLC the better, the exact effect of cholesterol-lowering treatments on persons without ASCVD in the general population remains unclear. Also, from the results of secondary prevention studies, it is clear that the higher the baseline LDLC concentration, the greater the relative effect, so that those with LDLC concentrations less than 70 mg per dL will derive less risk reduction from a 50% lowering than those with cholesterol levels of 160 mg per dL and higher.

Thus, it seems reasonable to define less than 70 mg per dL as a target value for the highest-risk groups and less than 100 mg per dL for those at risk but who do not have ASCVD. Moreover, although PCSK9 inhibitors can reduce LDLC to much lower levels, the added effect on risk reduction is a modest 0.08% to 0.15% (1.08-fold–1.15-fold).

PCSK9 inhibitors are very expensive. Also, many patients undergoing secondary prevention have numerous comorbidities and are already taking many other drugs. Thus, adding a PCSK9 inhibitor would mean the introduction of another drug that is to be taken by injection, with only modest risk reduction. As such, it seems that compliance would be poor. Therefore, it is reasonable to use these inhibitors as third-line drugs for these patients. However, in familiar hypercholesterolemia, in which LDLC is greater than 160 mg per dL, the risk of ASCVD is approximately 5- to 10-fold. Here, there is an expected large risk reduction by reducing LDLC. So, PCSK9 inhibitors are reasonable additives to statins because these patients may have no other comorbidities but a long life expectancy, during which one could reasonably expect good compliance.

One area of weakness in the recent guidelines relates to persons with characteristics of metabolic syndrome. Body mass index (BMI), weight circumference, triglyceride levels, and glucose level are all not included in the Omibus Risk Estimator. Patients with metabolic syndrome and low LDLC may not be identified as being at higher risk, especially those at a young age, because age is by far the most sensitive variable in the risk score. Nevertheless, elevated non-HDLC levels in these patients will usually be recognized as high total cholesterol in the risk calculation. Besides, many will have low HDLC levels and hypertension, so that their lifetime risk will be very elevated compared with the optimal risk. Lifetime risk can be used as a sign to encourage lifestyle changes or even to initiate statin treatment.