Cholesteryl ester transfer protein (CETP) inhibitors are under active investigation. The first drug in this class, torcetrapib, aroused great interest because it markedly increased HDL and reduced LDL. However, it was withdrawn from clinical trials because it increased cardiovascular events and deaths in the treat-ment group. Anacetrapib and dalcetrapib are analogs currently in clinical trials.
TREATMENT WITH DRUG COMBINATIONS
Combined drug therapy is useful (1) when VLDL levels are significantly increased during treatment of hypercholester-olemia with a resin; (2) when LDL and VLDL levels are both elevated initially; (3) when LDL or VLDL levels are not nor-malized with a single agent, or (4) when an elevated level of Lp(a) or an HDL deficiency coexists with other hyperlipi-demias. The lowest effective doses should be used in combina-tion therapy and the patient should be monitored more closely for evidence of toxicity.
This combination is sometimes useful in treating patients with familial combined hyperlipidemia who are intolerant of niacin or statins. However, it may increase the risk of cholelithiasis.
This synergistic combination is useful in the treatment of familial hypercholesterolemia but may not control levels of VLDL in some patients with familial combined hyperlipoproteinemia. Statins should be given 1 hour before or at least 2 hours after the resin to ensure their absorption.
This combination effectively controls VLDL levels during resin therapy of familial combined hyperlipoproteinemia or other disor-ders involving both increased VLDL and LDL levels. When VLDL and LDL levels are both initially increased, doses of niacin as low as 1–3 g/d may be sufficient in combination with a resin. The niacin-resin combination is effective for treating heterozygous familial hypercholesterolemia.The drugs may be taken together, because niacin does not bind to the resins. LDL levels in patients with heterozygous familial hypercholesterolemia require daily doses of up to 6 g of niacin with 24–30 g of resin.
This regimen is more effective than either agent alone in treating hypercholesterolemia. Experience indicates that it is an efficacious and practical combination for treatment of familial combined hyperlipoproteinemia.
This combination is highly synergistic in treating primary hyper-cholesterolemia and has some use in the treatment of patients with homozygous familial hypercholesterolemia who have some recep-tor function.
Fenofibrate appears to be complementary with most statins in the treatment of familial combined hyperlipoproteinemia and other conditions involving elevations of both LDL and VLDL. The combination of fenofibrate with rosuvastatin appears to be well tolerated. Some other statins may interact unfavorably owing to effects on cytochrome P450 metabolism. In any case, particular vigilance for liver and muscle toxicity is indicated.
These agents act in a complementary fashion to normalize cholesterol in patients with severe disorders involving elevated LDL. The effects are sustained, and little compound toxicity has been observed. Effective doses of the individual drugs may be lower than when each is used alone; for example, as little as 1–2 g of niacin may substantially increase the effects of the other agents.