AMP-activated protein kinase acts as a sensor of energy status in cells. When increased ATP availability is required, AMP kinase increases fatty acid oxidation and insulin sensitivity, and inhibits cholesterol and triglyceride biosynthesis. Although the trials to date have been directed at decreasing LDL-C levels, AMP kinase activation may have merit for management of the metabolic syndrome and diabetes. An agent combining AMP kinase activation and ATP citrate lyase inhibition is in clinical trials.
These are circular sugar polymers that can solubilize hydrophobic drugs for delivery and are approved for this purpose. They can also solubilize cholesterol from tissue sites such as arteriosclerotic plaque. Early stage animal studies on this potential therapeutic activity are in progress.
Combined drug therapy is useful (1) when VLDL levels are significantly increased during treatment of hypercholesterolemia with a resin; (2) when LDL and VLDL levels are both elevated initially; (3) when LDL or VLDL levels are not normalized with a single agent, or (4) when an elevated level of Lp(a) or an HDL deficiency coexists with other hyperlipidemias. The lowest effective doses should be used in combination therapy and the patient should be monitored more closely for evidence of toxicity. In combinations that include resins, the other agent (with the exception of niacin) should be separated temporally to ensure absorption.
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.
This combination effectively controls VLDL levels during resin therapy of familial combined hyperlipoproteinemia or other disorders 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.
If the maximum tolerated statin dose fails to achieve the LDL cholesterol goal in a patient with hypercholesterolemia, niacin may be helpful. This combination may be useful in the treatment of familial combined hyperlipoproteinemia.
This combination is synergistic in treating primary hypercholesterolemia and may be of use in the treatment of patients with homozygous familial hypercholesterolemia who have some receptor 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 especially 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.
COMBINATIONS OF RESINS, EZETIMIBE, NIACIN, & REDUCTASE INHIBITORS
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.
These agents can be used together to achieve maximal reduction of LDL. Because of the need for parenteral administration of PCSK9 antibody and its expense, this therapy is reserved for patients with familial hypercholesterolemia or atherosclerotic vascular disease who do not respond adequately to other regimens.