Reducing low-density lipoprotein cholesterol – treating to target and meeting new European goals

Abstract

Many hypercholesterolaemic patients fail to achieve target low-density lipoprotein cholesterol (LDL-C) levels in clinical practice. In part, this failure is related to inadequate efficacy of commonly used statins in reducing LDL-C and to difficulties inherent in dose titration. The availability of statins that produce large decreases in LDL-C at starting doses could significantly improve treatment of patients by facilitating achievement of LDL-C goals. The multi-national MERCURY I trial has shown that rosuvastatin at its starting 10-mg dose enables more patients to reach target LDL-C levels and reduces LDL-C more than starting or higher doses of other commonly used statins. In addition, post hoc analyses of data from trials comparing rosuvastatin with atorvastatin, simvastatin and pravastatin indicate that rosuvastatin enables more hypercholesterolaemic patients to reach the newly published LDL-C goals in the Third Joint Task Force European guidelines, including the most aggressive goals, than do other statins at starting doses and across dose ranges. Improved goal achievement at starting doses, as well as the concomitant greater reduction in LDL-C, may constitute an important advantage in clinical practice.

Coronary heart disease, Low-density lipoprotein cholesterol, Statins, Mercury I, Joint Task Force European guidelines, Hypercholesterolaemia

Introduction

Many patients with dyslipidaemia do not meet their target cholesterol goals, which is of particular concern with patients with coronary heart disease (CHD) or at high risk of CHD.^1,2 Only 41.7% of patients participating in the European Action on Secondary Prevention by Intervention to Reduce Events (EUROASPIRE) II study achieved the total cholesterol goal of <5.0 mmol/l.¹ In the Lipid Treatment Assessment Project (L-TAP) survey, conducted in the United States, only 38% of patients met older, less aggressive LDL-C goals (compared with the more recent National Cholesterol Education Program Adult Treatment Panel III [ATP III] guidelines).^2,3 The availability of statins that are more effective in reducing LDL-C at starting doses could contribute significantly to improved treatment of patients in clinical practice.

Relationship between low-density lipoprotein cholesterol levels and coronary heart disease risk reduction

LDL-C is causally linked to atherosclerosis and CHD events. Statins effectively and predictably reduce coronary events in proportion to the extent to which they reduce LDL-C, evidenced by the relationship between LDL-C levels achieved during treatment and proportions of patients with CHD events in statin and placebo groups in long-term statin trials.⁴ These trials also show that absolute CHD risk and absolute benefit of treatment are greater in patients with existing CHD (secondary prevention). For any level of LDL-C, there are a number of factors additional to existing CHD that increase risk for future CHD events. These include low high-density lipoprotein cholesterol (HDL-C), elevated triglycerides, elevated C-reactive protein, diabetes, smoking and hypertension. The absolute benefits (number of cardiac events prevented for given number of patients treated) of statin therapy are also greater in the presence of such additional risk factors.

The recently published Heart Protection Study⁵ included a very large population of patients (20,536) with CHD or who were at high risk of CHD. In this trial, simvastatin treatment produced a similar proportional (% reduction) of CHD events at all initial LDL-C levels (Fig. 1). Patients with pre-treatment LDL-C of <3.0, 3.0–3.5 or >3.5 mmol/l (<115, 115–135, >135 mg/dl) all achieved similar 1.0 mmol/l (40 mg/dl) reduction in LDL-C relative to placebo, and similar linear relationship between LDL reduction and clinical benefit. These data suggest that there is no lower limit of pre-treatment LDL-C below which statins fail to produce benefit.

Fig. 1

Relationship between low-density lipoprotein cholesterol (LDL-C) level during treatment and CHD event rate according to baseline LDL-C level in the Heart Protection Study. Higher point for each baseline LDL-C represents placebo and lower point represents statin group. (Data are from the Heart Protection Study Collaborative Group.⁵)

Low-density lipoprotein cholesterol goals in high-risk patients

As a result of accumulating data from statin trials, there is now remarkable uniformity among lipid-lowering guidelines. It is generally recommended that a target LDL-C <2.6 mmol/l (100 mg/dl) be attained in patients at the highest risk of CHD – i.e., those with established CHD or a 10-year CHD risk >20%. Such a target level is recommended by the ATP III guidelines,³ the Third Joint European guidelines,⁶ the Australian Lipid Management guidelines⁷ and the Japan Atherosclerosis Society guidelines.^8,9 However, there has been a general failure to achieve target cholesterol levels in high-risk patients in clinical practice. Although significant advances have been made in recent years in actually providing lipid-lowering therapy for high-risk patients, goal achievement rates remain low. As shown in Table 1, the proportion of CHD patients receiving lipid-lowering therapy improved from 32% to 63% between the EUROASPIRE I survey (1995–1996) and the EUROASPIRE II survey (1999–2000);¹ however, only half of CHD patients were at the Second Joint European guidelines total cholesterol goal of <5.0 mmol/l (190 mg/dl) in the EUROASPIRE II survey. In Australia, the Victoria (VIC)-II survey also showed an improvement in proportion of CHD patients receiving lipid-lowering therapy compared with an earlier survey, but three quarters of patients remained above the Australian total cholesterol goal of <4.0 mmol/l (155 mg/dl).¹⁰

Table 1

Surveys of use of lipid-lowering therapy and achievement of total cholesterol goals in coronary heart disease patients in Europe and Australia

	CHD Patients (%)
	Europea			Australiab
	EUROASPIRE I (1995–1996)	EUROASPIRE II (1999–2000)	VIC-I	VIC-II
Receiving lipid-lowering therapy	32	63	60	87
Achieving total cholesterol goalc	21	49	4	26

a

From EUROASPIRE I and II Group.¹

b

From Vale et al.¹⁰

c

EUROASPIRE I and II used a total cholesterol goal of <5.0 mmol/l (190 mg/dl). VIC-I and -II used a total cholesterol goal of <4.0 mmol/l (155 mg/dl).

Failure to achieve lipid goals leaves patients at excess risk for CHD and there are multiple potential reasons for such failure. They may include inadequate dietary and lifestyle changes and inadequacy of drug therapy. At currently used doses, many patients do not achieve sufficient cholesterol reductions to reach LDL targets. There are difficulties inherent in dose titration, which requires repeated visits and blood sampling, which likely contribute to undertreatment. Compliance and concordance may also be diminished by the need for repeated dose adjustment and/or polypharmacy, and the more rapidly treatment goals are achieved with any therapy, the more likely patients are to be adherent to such therapy. There are therefore potential benefits of efficient lipid-lowering treatment that allows rapid achievement of lipid goals without the need for additional drugs or dose titration.

MERCURY I trial

The MERCURY I trial compared the efficacy of the starting dose of rosuvastatin with commonly used doses of atorvastatin, simvastatin and pravastatin in achieving target LDL-C goals recommended for high-risk patients by the Second Joint European guidelines¹¹ and ATP III guidelines.³ The trial, performed in 224 centres in 16 countries, enrolled 3161 adults with primary hypercholesterolaemia and history of atherosclerotic disease, CHD or type 2 diabetes. After a 6-week dietary run-in and washout phase, patients were randomised to open-label treatment with rosuvastatin 10 mg, atorvastatin 10 or 20 mg, simvastatin 20 mg or pravastatin 40 mg for 8 weeks (period 1) (Fig. 2). According to initial randomisation, approximately half of patients in each comparator statin group were then switched to rosuvastatin 10 or 20 mg for the atorvastatin group for an additional 8 weeks (period 2).

Fig. 2

Design of the MERCURY I trial (Adapted with permission from Schuster et al.¹²)

As shown in Fig. 3, treatment with rosuvastatin 10 mg resulted in achievement of the Second Joint European guidelines LDL-C goal of <3.0 mmol/l (116 mg/dl) in 88% of patients, significantly more than the proportion achieving goal with atorvastatin 10 mg (76%,

\(P{<}0.0001\)

⁠), simvastatin 20 mg (69%,

\(P{<}0.0001\)

⁠) and pravastatin 40 mg (62%,

\(P{<}0.0001\)

⁠).¹² The ATP III LDL-C goal of <2.6 mmol/l (100 mg/dl) was achieved by significantly more patients with rosuvastatin 10 mg (80%) than with atorvastatin 10 mg (63%,

\(P{<}0.001\)

⁠) and versus atorvastatin 20 mg (74%,

\(P{<}0.01\)

⁠) (Fig. 4). Rosuvastatin 10 mg also brought significantly more patients to the ATP III goal than did simvastatin 20 mg (54%) or pravastatin 40 mg (45%). The mean reduction in LDL-C from baseline with rosuvastatin 10 mg (47%) was significantly greater than that observed with both atorvastatin 10 mg (37%,

\(P{<}0.0001\)

⁠) and atorvastatin 20 mg (44%,

\(P{<}0.0001\)

⁠) at 8 weeks. All treatments were well tolerated. No cases of myopathy were observed. Asymptomatic elevation of creatine kinase >10 times the upper limit of normal were reported in 1 patient receiving rosuvastatin 10 mg and in 1 patient receiving atorvastatin 20 mg. No cases of significantly elevated liver enzymes were observed in the trial. The ability to achieve LDL-C goals in a greater proportion of patients and reduce LDL-C significantly more with the starting dose of rosuvastatin than with starting or higher doses of other statins, with no excess risk, may constitute an important advantage in improving treatment in clinical practice.

Fig. 3

Proportions of patients achieving Second Joint European guidelines low-density lipoprotein cholesterol (LDL-C) goal of <3.0 mmol/l (115 mg/dl) after 8 weeks of treatment with rosuvastatin 10 mg, atorvastatin 10 or 20 mg, simvastatin 20 mg or pravastatin 40 mg in the MERCURY I trial. (Reproduced with permission from Schuster et al.¹²)

Fig. 4

Top: Proportions of patients achieving ATP III guidelines low-density lipoprotein cholesterol (LDL-C) goal of <100 mg/dl (2.6 mmol/l) after 8 weeks of treatment with rosuvastatin 10 mg, atorvastatin 10 or 20 mg in the MERCURY I trial. (Adapted with permission from Schuster et al.¹²) Bottom: Mean LDL-C reductions from baseline with rosuvastatin 10 mg vs atorvastatin 10 and 20 mg. (Data are from Schuster et al.¹²)

New European goal achievement with rosuvastatin and other statins in hypercholesterolaemic patients

Rosuvastatin is also highly effective at bringing hypercholesterolaemic patients to the new LDL-C goals of the Third Joint Task Force European guidelines.⁶ These guidelines propose LDL-C targets of <2.5 mmol/l (100 mg/dl) and <3.0 mmol/l (115 mg/dl) based on the presence of established cardiovascular disease or other risk factors, a 10-year risk for fatal cardiovascular disease using the SCORE system and the initial level of LDL-C and total cholesterol. Post hoc analyses of data from trials comparing rosuvastatin with other statins in hypercholesterolaemic patients assessed goal achievement using the new European risk criteria and LDL-C targets.

Analysis of pooled data from trials (prospectively designed for pooling) comparing rosuvastatin 10 mg with common starting doses of other statins over 12 weeks in hypercholesterolaemic patients (LDL-C⩾4.1 and <6.5 mmol/l [⩾160 and <250 mg/dl], triglycerides <4.5 mmol/l [400 mg/dl])¹³ showed marked superiority of rosuvastatin in permitting patients to reach the Third Joint Task Force European LDL-C goals (Figs. 5 and 6). Data from three trials comparing rosuvastatin 10 mg with atorvastatin 10 mg showed that rosuvastatin brought 66% of patients to LDL-C goals compared with 36% for atorvastatin

\((P{<}0.001)\)

⁠, including 52% vs 12.8% of those with a goal of <2.5 mmol/l (97 mg/dl). Separate analysis of data from high-risk patients in this trial, who had a European LDL-C goal of <2.5 mmol/l (97 mg/dl), showed that this target was achieved in 51.6% (66/128) of rosuvastatin patients vs 12.6% (16/127) of atorvastatin patients

\((P{<}0.001)\)

⁠.¹⁴ In two trials comparing rosuvastatin 10 mg with simvastatin 20 mg and pravastatin 20 mg, LDL targets were achieved in 73.9% of rosuvastatin patients, 36.9% of simvastatin patients (⁠

\(P{<}0.001\)

⁠) and 11.9% of pravastatin patients (⁠

\(P{<}0.001\)

⁠).

Fig. 5

Proportions of hypercholesterolaemic patients achieving Third Joint Task Force European guidelines low-density lipoprotein (LDL-C) goals after 12 weeks of treatment with rosuvastatin (RSV) 10 mg or atorvastatin (ATV) 10 mg.

Fig. 6

Proportions of hypercholesterolaemic patients achieving Third Joint European guidelines low-density lipoprotein cholesterol (LDL-C) goals after 12 weeks of treatment with rosuvastatin (RSV) 10 mg, simvastatin (SIM) 20 mg or pravastatin (PRA) 20 mg.

The US multicentre STELLAR trial^15,16 compared rosuvastatin, atorvastatin, simvastatin and pravastatin across their dose ranges over 6 weeks in 2431 hypercholesterolaemic patients (LDL-C⩾4.1 and <6.5 mmol/l [⩾160 and <250 mg/dl], triglycerides <4.5 mmol/l [400 mg/dl]). As shown in Figs. 7 and 8, rosuvastatin treatment allowed more patients to achieve the European goals, including the goal of <2.5 mmol/l (97 mg/dl). The respective proportions of patients reaching their treatment goals were 68.6–86.3% with rosuvastatin 10–40 mg, 43.7–74.5% with atorvastatin 10–80 mg, 20.0–66.3% with simvastatin 10–80 mg and 2.5–21.7% with pravastatin 10–40 mg. The respective proportions of patients reaching their goal of <2.5 mmol/l (97 mg/dl) were 42.2–75.0% with rosuvastatin, 18.8–57.1% with atorvastatin, 2.4–36.0% with simvastatin and 0.0–7.8% with pravastatin.

Fig. 7

Proportions of patients achieving Third Joint European guidelines low-density lipoprotein cholesterol (LDL-C) goals after 6 weeks of treatment with rosuvastatin 10–40 mg, atorvastatin 10–80 mg, simvastatin 10–80 mg, or pravastatin 10–40 mg in the STELLAR trial.

\(P\)

values from logistic regression; significance level adjusted to

\(P{<}0.002\)

account for multiple comparisons:

\(^{*}P{<}0.002\)

vs rosuvastatin 10 mg,

\(^{{\dagger}}P{<}0.002\)

vs rosuvastatin 20 mg,

\(^{{\ddagger}}P{<}0.002\)

vs rosuvastatin 40 mg.

Fig. 8

Proportions of patients achieving Third Joint Task Force European guidelines low-density lipoprotein cholesterol (LDL-C) goal of <2.5 mmol/l (97 mg/dl) after 6 weeks of treatment with rosuvastatin 10–40 mg, atorvastatin 10–80 mg, simvastatin 10–80 mg or pravastatin 10–40 mg in the STELLAR trial.

Conclusion

Statins reduce risk of CHD in proportion to the degree to which they reduce LDL-C. LDL-C targets have been recommended to optimise risk reduction in lipid-lowering therapy. Many patients, particularly those with or at high risk for CHD, do not achieve target levels in clinical practice. The availability of statin treatment that is more effective in reducing LDL-C can contribute to improved lipid-lowering therapy in patients across all risk strata by bringing more patients to goal at the starting dose, reducing requirements for dose titration and ensuring that a greater proportion of patients overall achieve target LDL cholesterol levels.