Dual pathway inhibition: Attacking cholesterol on two fronts

Based on a presentation by Christie M. Ballantyne, MD

NEW ORLEANS—From a historical perspective, the lipid management field looks a lot like the field of hypertension. Early on in1 hypertension treatment, patients were treated with higher or more frequent doses of single anti-hypertensive agents, often hydrochlorothiazide, until blood pressure (BP) was under control. There were questions about how low to go and whether even to treat elevated systolic pressure in the elderly.

Christie M. Ballantyne, MD, said that standard practice in hypertension today is much more aggressive. "Now we end up having much lowertargets in high-risk patients," he said. "There is a lot more focus on, obviously, combination therapy, which is required to get to these targets." Depending on the study, the average number of drugs to reach BP goals has ranged from about 2.7 to 3.7.

The field of lipid management and atherosclerosis is younger but has followed a similar course. The first National Cholesterol Education Program Adult Treatment Panel (ATP) guidelines, published in 1988, recommended a low-density lipoprotein (LDL) cholesterol goal of <130 mg/dL for individuals with coronary heart disease (CHD) or 2 CHD risk factors. In 1993, ATP II established a separate category for individuals with CHD and set a secondary prevention LDL cholesterol goal of &#8804;100 mg/dL, essentially saying that 100 mg/dL was sufficient. Now, ATP III guidelines have removed the "equal" sign and set a goal of <100 mg/dL for patients with CHD or CHD risk equivalents and also set a lower threshold for initiation of therapy in these high-risk patients (JAMA. 2001;285:2486-2497). "So [removing the equal sign] is a nuance but a very important one," Dr Ballantyne noted.

What is an appropriate LDL cholesterol goal?

The continuing evolution of the guidelines highlights the questions of just how low an LDL cholesterol target is good enough and how to get there. In a study of 2829 high-risk patients (Am J Cardiol. 2003;92:79-81), 52% did not reach their LDL cholesterol goal on initial doses of statin therapy, but only 45% had the dose titrated—most of them only once. Of those who had their medication doses titrated, 69% were still not at goal at 6- to 8-month follow-up. (Of the 1464 patients not at goal on initial statin dose, only 203 [14%] reached their goal within 6 months.)

Evidence from several quantitative coronary angiography trials showed that overall, atherosclerotic lesions progressed in patients who received statin monotherapy, as assessed by decreases in minimum lumen diameter, although at a slower rate than in patients on placebo (Curr Opin Lipidol. 1997;8:354-361). From the rates of progression according to LDL cholesterol levels achieved with statin therapy or placebo, Dr Ballantyne estimated that a patient "would need an LDL of around 70" to have no net progression of lesions.

A new mechanism for getting to goal

Mounting evidence points to an LDL cholesterol goal substantially <100 mg/dL for high-risk patients. How to get there is the problem. Statin titration yields only small incremental gains. One idea is to start at more effective (higher) doses, particularly in light of the evidence that the dose is often not titrated.

Dr Ballantyne said statins are "extremely safe and effective" medications. But at maximal doses, liver function test abnormalities increase, and "a few more cases of myopathy" may occur, as well as more potential for drug interactions. So for many patients, statins may reach their point of maximum efficacy with acceptable tolerability before LDL cholesterol is reduced to an optimal level.

Beyond inhibiting cholesterol synthesis with statins, the next step is to concomitantly block cholesterol absorption from the intestine, Dr Ballantyne said.

Bile acid sequestrants bind bile acids in the intestine, preventing the reabsorption of bile acids into the ileal enterocyte and causing them to be eliminated in the feces; the result is increased conversion of cholesterol into bile acids and consequently increased expression of LDL receptors, leading to reduced plasma LDL cholesterol levels. Ezetimibe, the first selective cholesterol absorption inhibitor, acts by a different mechanism. At the brush border, it blocks the Niemann-Pick C1 Like 1 protein pathway, which plays a critical role in transport of cholesterol into the intestinal epithelial cell.

Whereas bile acid sequestrants may raise serum triglyceride levels, ezetimibe does not. It has no effect on the absorption of lipid-soluble vitamins, and it raises levels of high-density lipoprotein (HDL) cholesterol. Furthermore, a 10-mg oral dose can be given at any time of day because of its long half-life, and it recirculates in the enterohepatic circulation, with very minimal systemic exposure to the drug.

Efficacy of combination therapy

In 1 study, ezetimibe added to statin therapy lowered LDL cholesterol by 21% compared with placebo. It also raised HDL cholesterol and lowered triglycerides (Am J Cardiol. 2002;90:1084-1091) (Figure). Based on ATP II goals in effect at the time of the trial, more patients reached LDL cholesterol goals with a statin plus ezetimibe compared with a statin plus placebo (71% vs 19%, respectively; P < .001). Adverse effects were similar in the 2 groups.

A trial in which ezetimibe 10 mg plus simvastatin across a range of doses was compared with simvastatin monotherapy across the same dose range showed that ezetimibe 10 mg plus simvastatin 10 mg provided a 44% reduction in LDL cholesterol from baseline at 12 weeks—the same as simvastatin 80 mg alone (J Am Coll Cardiol. 2002;40:2125-2134). In a similar study in which ezetimibe 10 mg or placebo was combined with atorvastatin across a range of doses, ezetimibe 10 mg plus atorvastatin 10 mg provided a similar reduction in LDL cholesterol (50%) to that provided by atorvastatin 80 mg alone (51%) (Circulation. 2003;107:2409-2415).

Pooling results from these 2 studies also showed that ezetimibe combined with various doses of simvastatin raised serum HDL cholesterol levels by 8% to 11% versus 3% to 6% for various doses of atorvastatin alone (Curr Ath Repts. 2004;6:52-59). "So there is very good lipid efficacy when you use a statin and you add ezetimibe," Dr Ballantyne said.

Besides LDL cholesterol lowering and a moderate increase in HDL cholesterol, ezetimibe may provide additional benefits, Dr Ballantyne said. One is a reduction in remnant chylomicron cholesterol. Second, if cholesterol is reduced in hepatocytes, LDL receptors will be upregulated, which will also reduce very-low-density lipoprotein remnants.

C-reactive protein (CRP) is another marker for cardiovascular risk. Ezetimibe in combination with simvastatin or atorvastatin lowers CRP more than either statin alone (Am J Cardiol. 2003;92:1414-1418; Circulation. 2003;107:2409-2415).

As Dr Tabas discussed (see page 3), phytosterols may independently raise the risk of atherogenesis, and ezetimibe significantly lowered serum levels of campesterol (27%) and sitosterol (25%) compared with placebo (Circulation. 2004;109:966-971). Dr Ballantyne noted that in the Scandinavian Simvastatin Survival Study (4S) "people who were high absorbers of campesterol and sitosterol didn't seem to get as much [LDL] benefit from statins" (Arterioscler Thromb Vasc Biol. 2000;20:1340-1346). He said high-dose statin therapy can actually slightly increase phytosterol levels over time.

In summary, Dr Ballantyne said that statin therapy is often insufficient to reduce LDL cholesterol to target levels in practice. Greater reductions can be achieved by targeting other cholesterol pathways besides synthesis. "The combination of a statin and the cholesterol absorption inhibitor ezetimibe leads to significantly greater reductions in LDL cholesterol and triglycerides, and an increase in HDL cholesterol versus statin monotherapy," he concluded. "This combination has been shown to be safe and well tolerated, similar to statin alone or statin plus placebo."

Additional benefits of the combination of statins and ezetimibe include reductions in non-HDL cholesterol, remnant lipoprotein cholesterol, and CRP. Further research may determine whether lowering plasma phytosterols may also reduce cardiovascular risk.