Triglyceride Lowering Drugs

The two major goals of the treatment of hypertriglyceridemia are the prevention of cardiovascular disease and pancreatitis. Here we discuss the drugs used for the treatment of hypertriglyceridemia: (niacin, fibrates, omega-3-fatty acids, volanesorsen (available in Europe) and lipoprotein lipase gene therapy (alipogene tiparvovec- no longer available). Niacin decreases total cholesterol, TGs (20-50% decrease), LDL-C, and Lp(a). Additionally, niacin decreases small dense LDL resulting in a shift to large, buoyant LDL particles. Moreover, niacin increases HDL-C. Skin flushing, insulin resistance, and other side effects have limited the use of niacin. The enthusiasm for niacin has greatly decreased with the failure of AIM-HIGH and HPS-2 Thrive to decrease cardiovascular events when niacin was added to statin therapy. The omega-3-fatty acids eicosapentaenoic acid (C20:5n-3) (EPA) and docosahexaenoic acid (C22:6n-3) (DHA) lower TGs by 10-50% but do not affect total cholesterol, HDL-C, or Lp(a). LDL-C may increase with EPA + DHA when the TG levels are markedly elevated (>500mg/dl). EPA alone does not increase LDL-C. Omega-3-fatty acids have few side effects, drug interactions, or contraindications. Numerous studies of low dose omega-3-fatty acids on cardiovascular outcomes have failed to demonstrate a benefit. However, in the JELIS trial and REDUCE-IT trial high doses of EPA alone reduced cardiovascular events while in the STRENGTH trial high dose EPA+DHA did not reduce cardiovascular events. Fibrates reduce TG levels by 25-50% and increase HDL-C by 5-20%. The effect on LDL-C is variable. If the TG levels are very high (>500mg/dl), fibrate therapy may result in an increase in LDL-C, whereas if TGs are not markedly elevated fibrates decrease LDL-C by 10-30%. Fibrates also reduce apolipoprotein B, LDL particle number, and non-HDL-C and there may be a shift from small dense LDL towards large LDL particles. Fibrates do not have any major effects on Lp(a). Monotherapy with fibrates appears to reduce cardiovascular events in patients with high TG and low HDL-C levels. Whether the addition of fibrates to statin therapy will reduce cardiovascular disease is uncertain. In patients with diabetes fibrates appear to slow the progression of microvascular disease. Volanesorsen is an antisense oligonucleotide that inhibits the production of apolipoprotein C-III. In patients with the familial chylomicronemia syndrome (FCS) volanesorsen decreases TG by 77% (mean decrease of 1712 mg/dl) with 77% of the patients having TG levels less than 750 mg/dl. In addition, volanesorsen treatment resulted in decreases in non–HDL-C by 46%, and VLDL-C by 58% and increases in HDL-C by 46%, LDL-C by 136%, (LDL-C increased from 28 to 61 mg/dl), and total apolipoprotein B by 20%. Studies have suggested that volanesorsen may reduce episodes of pancreatitis. Patients with FCS have also reported that volanesorsen improved symptoms and reduced interference of FCS with work/school responsibilities. Of concern has been decreases in platelet levels with 47% of patients treated with volanesorsen developing platelet counts below100 x 109/L. Alipogene tiparvovec is a gene therapy that was used in patients with Familial Lipoprotein Lipase deficiency with episodes of pancreatitis. Therapy with alipogene tiparvovec results in the expression of lipoprotein lipase in muscle, which accelerates the clearance of TG rich lipoproteins. Studies have suggested a decrease in episodes of pancreatitis. Alipogene tiparvovec is no longer available. Thus, a number of drugs are available for the treatment of hypertriglyceridemia and may be employed when lifestyle changes are not sufficient. For complete coverage of all related areas of Endocrinology, please visit our on-line FREE web-text, WWW.ENDOTEXT.ORG .