HDL Levels Are Markers of CVD Risk

Low high-density lipoprotein cholesterol (HDL-C) levels predict cardiovascular disease (CVD) risk. In small studies, interventions that increase HDL-C levels also appeared to reduce CVD risk and atherosclerosis burden. These observations, coupled with biologically plausible mechanisms by which raising HDL-C has salutary effects on reverse cholesterol transport, make HDL a promising target for CVD risk-reducing therapy. However, HDL-C levels may merely be surrogate markers of CVD risk, rather than an appropriate target of therapy. The problems with treating surrogate endpoints in medicine have been well-described. Before assuming that increases in HDL-C pharmacologically mediated are beneficial, several points need to be considered.

Measuring HDL

First, the cholesterol content of HDL is a surrogate for the number of circulating HDL particles, and the HDL particle, not the cholesterol it carries, has its putative biological effects. An intervention that raises HDL-C without raising the concentration of HDL particles may be biologically ineffective. For example, inhibition of cholesteryl ester transfer protein (CETP) increases HDL-C levels, but whether those particles participate in reverse cholesterol transport, or if they merely represent HDL particles that are “constipated” with cholesterol, remains unclear. Even if they do participate in reverse cholesterol transport, if the HDL particles that result from CETP inhibition do not have the other antiatherogenic benefits of HDL, such as its anti-inflammatory and antioxidant functions, the observed increases in HDL-C may not reduce CVD risk. Indeed, some naturally occurring CETP gene mutations are associated with high HDL-C but not reduced risk of CVD, whereas others are associated with low HDL-C and decreased CVD risk.

Confounders

Second, the observed association between low HDL-C and increased CVD risk may be confounded by other metabolic derangements found in most patients with low HDL-C, such as increased low-density lipoprotein (LDL) and small LDL particle concentrations (i.e., increased apolipoprotein B), hypertriglyceridemia, insulin resistance and hypercoagulability.

In the Framingham Offspring Study, as HDL-C decreased to below 40 mg/dL, LDL-C decreased, but LDL and small LDL particle concentrations increased. Given the strong associations between LDL particles/apo B and CVD risk, much of the association between low HDL-C and increased CVD risk may be due to the strong association between low HDL-C and high apo B. In the Familial Atherosclerosis Treatment Study, changes in LDL buoyancy and apo B predicted coronary atherosclerosis regression, not changes in HDL-C. In the VA-HIT study, the effects of gemfibrozil on total LDL-C and small LDL particles were as predictive of CVD events as were the effects of this medication on HDL particles, whereas HDL-C levels did not predict CVD events.

In this context, the strongest effects on CVD risk reduction of pharmacologically raising HDL-C were observed in individuals with hypertriglyceridemia and high apo B(as with gemfibrozil in the VA-HIT and Helsinki Heart studies) and in individuals with high LDL-C (as with niacin in the HATS Study and the Coronary Drug Project). Perhaps the failure of fenofibrate to reduce CVD risk in the ACCORD study and niacin to reduce CVD risk in the AIM-HIGH study were because the main effects of these pharmacologic interventions were on apo B excess, not on HDL-C, and in the absence of particle excess, treating HDL-C or triglycerides was unimportant.

A third consideration is that raising HDL-C may be important only in subsets of patients with certain metabolic derangements or that increases in HDL-C levels observed after starting a medication may be irrelevant to its effects on all outcomes when the medication’s effects on lipoprotein fractions are considered. For example, if the ongoing Heart Protection Study 2-THRIVE shows a benefit of adding niacin to statin therapy, did the increase in HDL-C or changes in other lipoproteins mediate the changes in CVD risk? The focus on CETP inhibitors has been on HDL-C; however, anacetrapib also reduces levels of LDL-C. The HDL-C effects may be a distraction, as they may be for niacin and fenofibrate.

Other Effects

Finally, even if pharmacologic manipulation of HDL-C reduces CVD risk, other, off-target effects might increase CVD risk. Torcetrapib and estrogen are examples of agents that increase HDL-C levels but also increased CVD risk in clinical trials.

HDL-C remains a surrogate marker of CVD risk, and the hypothesis that raising HDL-C can reduce CVD risk is unproven. Even if an intervention raises HDL-C and reduces CVD risk, proving that the observed increase in HDL-C had anything to do with the salutary effects of the intervention will be difficult, since lipoprotein metabolism is so complex. This situation emphasizes that the true test of an intervention is its effect on hard clinical endpoints, not its effect on surrogate markers such as lipid levels.

Key References

Fleming TR, DeMets DL. Surrogate end points in clinical trials: Are we being misled? Ann Intern Med. 1996;125:605-613.
Agerholm-Larsen B, Nordestgaard BG, Steffensen R, Jensen G, Tybjaerg-Hansen A. Elevated HDL cholesterol is a risk factor for ischemic heart disease in white women when caused by a common mutation in the cholesteryl ester transfer protein gene. Circulation. 2000;101:1907-1912.
Agerholm-Larsen B, Tybjærg-Hansen A, Schnorh P, Steffensen R, Nordestgaard BG. Common cholesteryl ester transfer protein mutations, decreased HDL cholesterol, and possible decreased risk of ischemic heart disease: The Copenhagen City Heart Study. Circulation. 2000;102:2197-2203.
Otvos JD, Collins D, Freedman DS, et al. Low-density lipoprotein and high-density lipoprotein particle subclasses predict coronary events and are favorably changed by gemfibrozil therapy in the Veterans Affairs High-Density Lipoprotein Intervention Trial. Circulation. 2006;113:1556-1563.
Otvos JD. The surprising AIM-HIGH results are not surprising when viewed through a particle lens. J Clin Lipidol. 2011;5:368-370.