Which antilipemic medication reduces synthesis of triglycerides in the liver?

Dyslipidemia is a major risk factor for coronary heart disease [CHD], and current guidelines support low-density lipoprotein cholesterol [LDL-C] as a primary target of therapy.1 Previous studies suggest that increasing high-density lipoprotein cholesterol [HDL-C] and reducing triglycerides and small LDL particles may also have a positive impact in prevention.2 These factors are considered secondary targets of lipid management. Most lipid-altering drugs have a sound overall safety profile and are generally well tolerated.1

Episodes of severe hepatotoxicity remain rare for most drugs. The exception is high-dose, sustained-release [SR] niacin. Overall, the incidence of drug-induced hepatotoxicity may be prevented if both providers and patients are aware of potential contributing factors.

Clinical Presentation

Drug-induced hepatotoxicity secondary to lipid-altering agents includes acute liver failure, hepatitis, cholestasis, and most commonly transaminitis, an asymptomatic elevation in serum transaminases.3 Acute liver failure is extremely rare, and data suggest that minor asymptomatic elevations of aspartate transaminase [AST] and alanine transaminase [ALT] do not necessarily precede acute liver failure.3 Possible signs and symptoms of liver problems include unusual fatigue or weakness, loss of appetite, upper abdominal pain, dark-colored urine, and yellowing of the skin or whites of the eyes [jaundice].4

Hepatotoxicity by Drug Class

The major classes of lipid-altering agents include the statins, bile acid resins [BARs], fibric acid derivatives [fibrates], cholesterol absorption inhibitors, niacin, and fish oil [TABLE 1].1,4-9 Because reports of hepatotoxicity are extremely limited with fish oil and BARs, these drug classes will not be a focus of this review. Additionally, red yeast rice [RYR] is an available supplement with potential lipid-altering properties. Reports of hepatotoxicity with this agent are also limited and will not be discussed. However, practitioners should be aware that RYR typically contains varying amounts of lovastatin, and therefore should be utilized with applicable precautions.10

Cholesterol agents cause hepatotoxic effects through various mechanisms. For instance, statins undergo hepatic metabolism following gastrointestinal [GI] absorption, while other classes such as BARs and the cholesterol absorption inhibitor ezetimibe primarily target the GI tract but indirectly affect the liver.11

Statins

Statins [e.g., atorvastatin, fluvastatin, lovastatin, pitavastatin, pravastatin, rosuvastatin, simvastatin] produce marked reductions in LDL-C by inhibiting 3-hydroxy-3-methylglutaryl-coenzyme A [HMG-CoA] reductase, the rate-limiting step in cholesterol synthesis.1 This inhibition decreases cholesterol production, causing an increase in LDL-receptor expression and enhanced removal of LDL-C from the circulation. Although statins have moderate effects on lowering triglycerides and increasing HDL-C, they remain first-line therapy because of their LDL-C lowering. More importantly, results from multiple clinical trials have demonstrated that statins significantly reduce major coronary events and overall mortality among primary and secondary prevention populations.1,12 Statins also reduce inflammation, improve endothelial function, and stabilize atherosclerotic plaque, independent of their lipid effects.3,12

Clinical trial findings indicate that the overall risk of hepatotoxicity with statins is low. The most common hepatic adverse event involves asymptomatic increases in ALT and AST. This dose-dependent reaction usually occurs within the first year of therapy, but may present at any time.3,13 It has been noted that elevations are usually reversible with a dose reduction and may normalize with the same continued dosage.1

The National Cholesterol Education Program [NCEP] Adult Treatment Panel III [ATP-III] guidelines provide specific recommendations for monitoring hepatic function including transaminase elevations [TABLE 1].1 For patients with AST/ALT ≤3 times the upper limit of normal [ULN], statin therapy can be continued. If elevations exceed 3 times the ULN, a second liver function evaluation should be conducted. If elevated levels persist, the statin should be discontinued, but attempting a rechallenge or switching to a different statin may be considered.1 Overall elevated transaminase levels ≥3 times the ULN occur in 2,000 mg/day, compared to none in the IR niacin group.25

The differences in hepatotoxicity among formulations are likely explained by two metabolic pathways.22 Conjugation of niacin with glycine to form nicotinuric acid is a low-affinity, high-capacity system, which leads to flushing. The second nonconjugative pathway involves multiple reactions that convert niacin to nicotinamide, and is a high-affinity, low-capacity system with greater potential for hepatotoxicity. IR products will quickly saturate the nonconjugative pathway, with most of the drug being metabolized by conjugation, resulting in increased flushing and a low incidence of hepatotoxicity. Slowly absorbed preparations [e.g., SR niacin] are metabolized primarily by the high-affinity nonconjugative pathway, resulting in less flushing but increased hepatotoxicity.

Pharmacists must inform patients that maximum dosages vary among formulations and dose-dependent hepatotoxicity is possible, especially when patients choose SR formulations in an effort to avoid flushing, reduce cost, or self-treat. Additionally, products may not be interchangeable. For example, if a patient has been maintained on IR niacin at a dose >2,000 mg/day, switching to an equivalent dose of SR niacin would likely result in hepatotoxicity. Lastly, “flush-free” and “no flush” formulations contain very little to no active niacin but list ingredients such as inositol hexanicotinate. These products have not shown the same cardiovascular and lipid-lowering benefits as niacin.22

Conclusion

Severe drug-induced hepatotoxicity is rare for most lipid-altering agents. However, the incidence increases with certain agents and in the presence of other contributing factors. Appropriate monitoring may limit hepatotoxic events. Asking pertinent questions and gathering needed information will help determine the risk for hepatotoxicity with lipid-altering therapy. Key information includes identifying disease states that may predispose the patient to increased risk for liver damage and obtaining a complete medication and supplement list to check for potential interactions. Pharmacists may also educate patients on the importance of reporting any unusual signs or symptoms of hepatotoxicity and adhering to laboratory and clinic appointments.

Which antilipemic medication is beneficial for patients with primary hypercholesterolemia?

Cholestyramine: It is used as adjunctive therapy to diet to reduce elevated serum cholesterol in patients with primary hypercholesterolemia [elevated LDL] who do not respond adequately to diet and to treat pruritus associated with partial biliary obstruction.

Which class of medications is most effective in reducing triglyceride levels?

Fibrates remain the most effective agents in lowering triglyceride levels and should be limited to this use.

Which antilipemic medication inhibits VLDL synthesis by liver cells?

Gemfibrozil [Lopid] Fibric acid antilipemic agent that effectively reduces serum TGs and favorably alters lipoprotein levels; the mechanism of action is unknown, but gemfibrozil may inhibit lipolysis, the secretion of VLDL, and hepatic fatty acid uptake.

Which medications reduce cholesterol synthesis in the liver?

Statins are competitive inhibitors of HMG-CoA reductase, which leads to a decrease in cholesterol synthesis in the liver.

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