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

Combination Therapy

Patients with combined hyperlipidemia need to lower elevated LDL-C, TC and TG levels simultaneously and increase the diminished HDL-C levels. Dietary therapy alone is often ineffective inpatients with combined dyslipidemias (i.e. those with several abnormal lipid parameters). These patients often show a greater improvement with combined therapy[6,37,39,40,45], i.e. a combination of statins and fibrates or nicotinic acid, than with monotherapy. Fibrate monotherapy has a minor effect on LDL-C level relative to statins.Consequently, fibrates may not be effective monotherapy in the majority of dyslipidemias.Statins raise HDL-C, lower LDL-C and TG, and, at higher concentrations, also have inhibitory effects on VLDL-C secretion, which indirectly reduces TG further[32]. Combined therapy has been shown to exert a highly effective improvement of the lipid triad and decreases all non-HDL-C levels.

Product information for statins and fibrates generally states that combination therapy with these agents is not recommended, owing to an increased risk of myopathy[37,39]. Combination therapy must be used with care and probably avoided in the elderly; in those with acute or serious chronic illness (especially chronic renal disease); those requiring surgery; and those on multiple medications or cyclosporin,macrolides or antifungals[41]. However, excellent therapeutic response can be achieved with appropriate safety monitoring.

Combined fluvastatin and bezafibrate therapy was investigated for efficacy and safety in the Fluvastatin Alone and in Combination Treatment (FACT) study(n 333)[39]. The most effective treatment,fluvastatin 40 mg plus bezafibrate 400 mg, was well tolerated.

Gemfibrozil and lovastatin therapies alone and in combination with each other were compared inpatients with familial combined hyperlipidemia(FCHL), who exhibited raised levels of TG, VLDLC and apolipoprotein B (apo B), normal to moderately raised TC, and low HDL-C. Gemfibrozil monotherapy reduced TG and increased HDL-C levels, and lovastatin monotherapy reduced LDL-C levels. Combination therapy with these agents produced additive effects on reduction in total-C,TG, LDL-C and apo B, with concomitant elevations in HDL-C. Combination therapy was suggested to be the treatment of choice in these patients with highly atherogenic FCHL[40].

Statin plus nicotinic acid has been shown to be an effective aggressive therapy for patients in JNC-VI Risk Groups B and C (see Table 2 for definitions)where the lipid targets are more stringent.Combination therapy not only successfully modifies the lipid profile, but can also bring about regression of coronary lesions and a reduction in coronary events[82]. However, only low doses of nicotinic acid are well tolerated and side-effects include, among others, hepatotoxicity, hyperglycemia and hyperuricemia[41]. Adverse events associated with higher doses of niacin include severe flushing[45].

For the subgroup of patients whose dyslipidaemia cannot be controlled with fibrate or statin therapy alone, combination therapy may be the way forward.Further trials are urgently required in this area to establish the safety and efficacy of these combination therapies. Several studies comparing statin and fibrate monotherapy with combination therapy are currently either in the early stages or in the process of recruiting. These studies include FACTOR(Fenofibrate and Cerivastatin Treatment OptimizingResponse), FACE-UP (Fenofibrate Associated toCErivastatin in Uncontrolled Patients) and LDS(Lipids in Diabetes Study)[45]. FACTOR is a multicentre,randomised, double-blind study of the safety and effectiveness of cerivastatin in combination with fenofibrate, compared to cerivastatin alone,fenofibrate alone and placebo in patients with type 2 diabetes. The primary objective is to compare the percentage change from baseline in LDL-C of cerivastatin 0.4 mg in combination with fenofibrate 200 mg versus placebo for 12 weeks. Secondary objectives are (1) to compare the safety and efficacy of cerivastatin 0.4 mg in combination with fenofibrate 200 mg to cerivastatin 0.4 mg alone and fenofibrate 200 mg alone, and (2) to evaluate the changes in HDL-C, VLDL-C, Lp(a), total cholesterol and triglycerides. Finally, LDS is currently investigating whether fenofibrate and cerivastatin,either alone or in combination, reduce initial CHD events in patients with diabetes mellitus[83]. The primary outcome measurements are based on achieving target LDL-C and TG levels assigned depending on the clinical risk assessment of the patient. It is envisaged that the LDS trial will provide endpoint data on this new fenofibrate-cerivastatin combination therapy.

Patients with type 2 diabetes dyslipidemia tend to have normal LDL-C and raised TG and also suffer from other metabolic syndrome factors years before developing diabetes (e.g. weight gain, hypertension(HT), hyperlipidemia, etc). Many may have clinical CHD, which places them in a very high-risk category.Diabetes doubles the risk of CHD mortality in these patients. In diabetic patients without evidence of existing CHD, the risk of developing heart disease is much higher than in non-diabetics with a double or triple risk[41,51,52,84]. The 4S69 and CARE studies[68] suggest that statin therapy significantly reduces coronary-associated morbidity in diabetics with CHD.Aggressive statin therapy is also recommended in hyperlipidemic diabetics without CHD to correct the lipid levels to the NCEP-defined targets[85]. The ongoing Lipids in Diabetes study (LDS)[83] is assessing the fenofibrate/cerivastatin combination or single therapy to reduce CHD events in diabetics. Endpoint data will confirm a TG target level - currently estimated by NCEP at < 2.2 mmol/l (< 200 mg/dl).A lower target has been advocated in women and in diabetics, and some recent data suggest that CHD EVENTS increase as TG exceeds 1.1 mmol/l(100 mg/dl) irrespective of HDL-C levels and BMI[1,45,86].

LDL-C lowering to established targets remains the primary objective of statin therapy[7,8,9,10,11,12,13,14,15,16,17,18,19,20]. Although NCEP criteria were not utilised in the landmark statin outcomes studies employing lovastatin,pravastatin and simvastatin, reduction in plasma levels of LDL-C was associated with a significant reduction in the incidence of CHD events in at-risk subjects[41,45,46,67,70,71,72,73]. Application of the NCEP guidelines was designed to provide recommendations for the treatment of hypercholesterolemia based on risk assessment models, such as Framingham and NHANES. However, in real world clinical practice, it has been demonstrated that the attainment of NCEP goals are below expectations. For example, the Lipid Treatment Assessment Project (L-TAP) survey was undertaken to determine the percentage of patients receiving lipid-lowering therapy that achieved LDL-C targets (as determined by NCEP guidelines)[87,88]. L-TAP surveyed nearly 5000 patients in the USA, all of whom were receiving dietary or pharmacological lipid-lowering therapy; 84.6% received treatment with lipid-lowering drugs. Of those patients treated with a statin as monotherapy, between 32% and 46% of patients reached target LDL-C levels[87,88].Treatment did not include the efficacious newer statins, namely cerivastatin and atorvastatin, which have been shown to achieve extremely high levels of NCEP target attainment[32,33,34,36,38,41]. The L-TAP survey included patients treated with simvastatin, fluvastatin,lovastatin and pravastatin as monotherapy,although doses were not reported.

The objective of the recently completed Canadian trial, CAVEAT[30] (Cerivastatin and Atorvastatin-Verifying Effective Attenuation of Triglycerides), was to compare the efficacy and safety of cerivastatin and atorvastatin in 342 men and women aged 18-80 years with combined type IIb dyslipidemia. Patients received cerivastatin 0.4 mg, cerivastatin 0.8 mg,atorvastatin 10 mg or atorvastatin 20 mg once daily for eight weeks. The primary endpoint of this study was the mean percentage reduction in triglycerides.Secondary endpoints included changes in other lipid parameters. Additional analyses were performed to determine the percentage of patients reaching NCEP goal.

Both drugs showed similar reductions in median TG levels - 24.5% and 31.7% for cerivastatin 0.4 mg and 0.8 mg, respectively, and 22% and 28.6% for atorvastatin, 10 mg and 20 mg, respectively (Figure 5).

Figure 5.

Comparison of TG-lowering efficacy of cerivastatin and atorvastatin: intent-to-treat population - eight-week endpoint (CAVEAT)

Irrespective of eligibility status, cerivastatin 0.4 mg and 0.8 mg brought 79% and 95%, respectively, of patients to NCEP LDL-C target compared to 82% and 83% of patients treated with atorvastatin 10 mg and 20 mg, respectively. Cerivastatin 0.8 mg enabled significantly more patients overall (95% vs. 83%;p < 0.05) to reach LDL-C target than atorvastatin 20 mg (Figure 6).

Figure 6.

Comparison of NCEP LDL-C target attainment: percentage of patients brought to target (all risk factor groups in the study population combined)

Cerivastatin 0.4 mg-treated patients showed a trend towards higher percentage increases in HDL-C levels than atorvastatin 10 mg (p 0.053) (Figure 7). A more significant difference in HDL-C levels was seen between treatment with cerivastatin 0.8 mg and atorvastatin 20 mg doses ( p < 0.006). Both drugs were well tolerated.

Figure 6.

Comparison of NCEP LDL-C target attainment: percentage of patients brought to target (all risk factor groups in the study population combined)

In summary, the results of the CAVEAT study demonstrated that cerivastatin improved triglyceride and HDL-C levels and NCEP goal attainment in a manner similar to, or better than, atorvastatin, inpatients with mixed dyslipidemia.

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