Hypertriglyceridemia: A Review of Clinical Relevance and Treatment Options: Focus on Cerivastatin

Hans-Willi M. Breuer, Abteilung für Innere Medizin, St. Carolus-Krankenhaus Görlitz, Carolusstr. 212, 02827 Görlitz, Germany 

Curr Med Res Opin. 2001;17(1):60-73. 

In This Article

Triglyceride-lowering Therapies

TG levels respond well to dietary control and increased exercise[45]. This should be the first-line nonpharmacological therapy - 20-24% reductions in TG levels and reduced progression of CHD have been observed with these life-style modifications[45].

The SCRIP[76] and Heidelberg[45] studies data have shown that a reduction in total fat intake to < 25% of total calories and saturated fat as 6% of total calories gave the best results. However, extreme reduction in fat intake to < 10% of total calories can cause an increase in TG levels due to a compensatory increase in endogenous VLDL-C secretion[45]. Exogenous saturated fat can increase TGRLP levels,especially in association with alcohol consumption[45]. The LHS (Lyon Diet Heart Study)[77] and the GISSI[78](Gruppo Italiano per lo Studio della Sopravvivenzanell' Infarto) prevention studies showed that increasing omega-3 FA in the diet reduced TG levels in patients with high baseline TG, but made no difference in subjects with low baseline TG levels.Three to four grams/day of omega-3 FA reduced TG by 25-30%. GISSI demonstrated that supplementing the classic Mediterranean diet with one 1 g capsule of omega-3 FA per day, led to a 20% reduction in mortality over the 3.5-year follow-up of 11,000 survivors of myocardial infarction.

Some have suggested that drugs to lower TG should be used conservatively and are only indicated when TG > 4.5 mmol/l (> 400 mg/dl); after dietary methods have failed; or if other risk factors are present[53]. The AHA/ACC guidelines for the management of patients with acute myocardial infarction[13] advocate aggressive lipid-modifying therapy for all patients with TG levels > 2.2 mmol/l(> 200 mg/dl) regardless of HDL-C and LDL-C levels.

Pharmacological treatment directed at lowering TG and increasing HDL-C is appropriate in certain cases, even when the TC level is normal. In certain comorbid conditions, such as nephrotic syndrome,renal disease and organ transplant patients, aggressive lipid-lowering therapy may decrease CHD risk[26]. Pharmacological therapy can be divided into two groups: TG-lowering drugs (fibrates and nicotinic acid) and cholesterol-lowering drugs (HMG CoA reductase inhibitors).

The choice of treatment depends on the mode of pathogenesis present. TGRLP formed as a result of raised TG levels can be directly atherogenic.Alternatively, an increase in CHD risk can be due to the indirect metabolic consequences of raised TG,such as raised levels of post-prandial LP, large VLDLC,small dense LDL-C, decrease in HDL-C and increase in serum levels of prothrombotic coagulation factors. Both modes of pathogenesis may occur indifferent forms of dyslipidemia[45]. For treatment of the first, a statin would be most effective, and, for the second, a fibrate or nicotinic acid would be the best way of reducing risk. Studies[6,39,40] have shown that in fact a combination works best to bring all lipid parameters to target and to maximise the reduction in CHD risk.

Nicotinic acid lowers TG directly by inhibiting adipose tissue lipases, thus reducing substrate for availability for VLDL-C synthesis[45]. Reductions of 20-40% have been seen. Fibrates have a higher potency, reducing TG levels by 20-55%[45]. As with statins, the TG-lowering effect of fibrates is most pronounced in those patients with very high TG levels[45]. In the HHS[58], gemfibrozil produced a 35-45% reduction in TGs in patients with non-HDLC(LDL, VLDL and IDL-C) > 5.2 mmol/l(> 200 mg/dl). In the BIP bezafibrate trial[72,73], patients with TG levels > 2.2 mmol/l (> 200 mg/dl) showed a 40% reduction in TG, whereas patients with TG < 2.2 mmol/l (< 200mg/dl) showed a 25% decrease. In the VA-HIT gemfibrozil study, a 31% reduction in TG was observed in patients with mean baseline TG levels of 1.8 mmol/l (160 mg/dl)[74]. However, despite gemfibrozil's ability to reduce TG,raise HDL-C and normalise LDL-C composition, in some patients it can bring about an increase in LDLC levels[79,80].

Statins reduce TG levels indirectly by enhancing the expression of LDL-C receptors in the liver and by inhibiting VLDL-C and LDL-C synthesis via the reduction of apoB[3,65]. An increase in the cholesterol content of VLDL-C and LDL-C, an increase in TG-rich HDL-C and a reduction in cholesterol ester transfer protein (CETP) activity is also observed[65]. This leads to a reduction in VLDL-C synthesis and subsequently higher HDL-C levels and the formation of fewer potentially atherogenic small dense LDL-C particles[34]. Lovastatin was shown[43,81] to normalise the size of IDL-C, VLDL-C and LDL-C particles thereby reducing their atherogenic potential; the mass is inversely related to atherogenic potential, and high TG levels causes them to be smaller and more dense than normal[81].

The magnitude of the TG-lowering effect is similar to that of LDL-C for each statin and is dependent on the pretherapy baseline TG level[31,33]; in a recent pooled analysis of 4411 patients, cerivastatin 0.4 mg achieved a reduction in TG of up to 37%, and cerivastatin 0.8 mg a reduction in TG of up to 43% (Figure 4). The ratios of mean change in TG to mean change in LDL-C (-TG/-LDL-C) are roughly the same across all statins and all doses. The increase in HDL-C is also baseline TG dependent[31].

Figure 4.

Percentage change (25th-75th percentile) in fasting TG after treatment with (A) cerivastatin 0.4 mg and (B) cerivastatin 0.8 mg, at three TG baseline ranges: < 1.7 mmol/l (< 150 mg/dl), 1.7-2.8 mmol/l (150-250 mg/dl) and > 2.8 mmol/l (> 250 mg/dl). (Bayer AG: data on file, 2001)

Figure 4.

Percentage change (25th-75th percentile) in fasting TG after treatment with (A) cerivastatin 0.4 mg and (B) cerivastatin 0.8 mg, at three TG baseline ranges: < 1.7 mmol/l (< 150 mg/dl), 1.7-2.8 mmol/l (150-250 mg/dl) and > 2.8 mmol/l (> 250 mg/dl). (Bayer AG: data on file, 2001)

This TG baseline-dependent effect may be due to reduction of VLDL-C when the TG baseline is high,by inhibiting cholesterol synthesis, thereby inhibiting the assembly and secretion of VLDL-C[70].

Trials comparing statins[29,30,33,35,36,38] have shown that the newer statins (cerivastatin and atorvastatin) are more effective in lowering TC, LDL-C and TG and bring a higher percentage of patients to NCEP-defined target lipid levels than the older statins for TG, HDL-C, LDL-C and TC.

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