Combo drug for aggressive cholesterol management
Vytorin inhibits both cholesterol synthesis and absorption
When we manage hypercholesterolemic states, we must target two pathways: inhibition of cholesterol production and inhibition of cholesterol absorption. And that can be done with one tablet-a tablet that combines the inhibitor of absorption and the inhibitor of production-to produce maximal ldl-[lowering] efficacy, rather than monotherapy with either ezetimibe or with statins. I think that drug is Vytorin."
So said Dr. Augusto Litonjua, president of the Diabetes Center of the Philippines and professor emeritus at the University of the Philippines College of Medicine, in a symposium on aggressive cholesterol management organized by Schering Plough Philippines during the Philippine Diabetes Association annual convention in November.
Hypercholesterolemia is a major risk factor for debilitating cardiovascular disease. Studies show that lowering low-density lipoproteins (ldl) markedly reduces the incidence of coronary heart disease (chd). "A 30-percent reduction in ldl will produce a 30-percent lessened risk for coronary heart disease," said Litonjua.
Statins are strong weapons in the fight against dyslipidemia. Randomized controlled trials support its superiority over placebo in lowering blood-cholesterol levels and reducing the risk of myocardial infarction, stroke, and the need for revascularization. Studies also proved that higher statin dosages correlate with greater reductions in ldl and improved clinical outcomes.
Yet even with the availability of potent lipid-lowering agents, the stringent goals set by the United States National Cholesterol Education Program Adult Treatment Panel III (ncep-atp iii) are not always met. In this protocol, high-risk patients with established cardiovascular disease (cvd) and multiple or poorly controlled risk factors should aim for ldl levels under 70 mg/dL, significantly lower than the previously established limit of 100 mg/dL. "The target should be ldl, rather than total cholesterol, irrespective of what the cholesterol levels are," pointed out Litonjua.
When ldl goals are not met, increasing the statin dosage is a viable option; however, the strategy has its pitfalls. Litonjua cited the "rule of six" in the use of statins: the bulk of ldl-lowering effect is seen in the initial dose. After this initial drop, each doubling of the dose will result in a measly six-percent drop in ldl levels. At maximum dose, only an additional 18-percent reduction is achieved.
Twin targets
Combining a statin with another hypolipidemic agent like ezetimibe presents a promising option.
Statins and ezetimibe have different mechanisms of action. They target the body's two sources of cholesterol: liver production and intestinal absorption (from the diet and biliary secretions); the statins act on the liver while ezetimibe targets the intestines. "To lower the cholesterol, we must attack both," explained Litonjua. Dietary absorption, he pointed out, contributes around 300 to 700 mg/day, while biliary reabsorpiton contributes about 1,000 mg/day.
Statins block cholesterol production by competitively inhibiting the rate-limiting enzyme of cholesterol synthesis: hmg-coa reductase. Doing so upregulates the expression of hepatic ldl receptors and increases clearance of ldl from the blood.
Ezetimibe, in contrast, prevents intestinal absorption of cholesterol. Recent studies suggest that it blocks the Niemann-Pick C1 Like 1 (npc1l1) transporter-a cholesterol shuttle-found in the enterocytes of the proximal small intestine. Here at the brush border of the small intestine, where the npc1l1 proteins are concentrated, is where ezetimibe localizes. When ezetimibe blocks the cholesterol receptors, it also effectively depletes the liver cholesterol stores-the reduced chylomicron remnants, a source of liver cholesterol, which increase the breakdown of ldl by liver ldl receptors and decrease very-low-density-lipoprotein (vldl) secretion.
The ezetimibe-statin combination (Vytorin) targets the body's two sources of cholesterol and leads to greater ldl reduction than statin monotherapy. The Ezetimibe Add-on to Statin for Effectiveness (ease) study demonstrated that the drug combo produced greater decreases (26 percent from baseline) in ldl, regardless of the patients' risk factors, compared with statins alone. Compared with rosuvastatin-"probably the most potent lipid-lowering drug"-the ezetimibe-simvastatin duo exhibited greater ldl-lowering ability across a wide range of doses. At the minimum dose (ezetimibe-simvastatin 10/20 mg v. rosuvastatin 10 mg), the combined therapy lowered ldl 55.8 percent below the baseline compared with 45.8 percent for the statin. At the maximum dose, Vytorin (10/80 mg: dosage adjustment with Vytorin means increasing the statin dose, the ezetimibe dose remains constant) lowered cholesterol levels to 61 percent below the baseline, as against 56.7 percent for rosuvastatin (40 mg). Moreover, six weeks after treatment, 50.1 percent of Vytorin-treated patients, in contrast to 29.4 percent for rosuvastatin, achieved the ldl goal of less than 70 mg/dL.
"The paradigm of cholesterol management must now change and take into consideration this dual inhibition of the two sources of cholesterol that will eventually find themselves into the blood," concluded Litonjua. M
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