LDL cholesterol: should guidelines include targets?

Abstract

Elevated low-density lipoprotein cholesterol (LDL-C) is associated with adverse cardiovascular outcomes. The strategy of target-based LDL-C lowering to reduce the risk of coronary heart disease and secondary event rates is now well established. However, the strategy for treating to a target LDL-C, and whether there is a lower threshold level for LDL-C continues to be debated. We present, and critically analyze the evidence for a target-based LDL-C lowering strategy, and the safety and efficacy of intensive plasma LDL-C-lowering with traditional, and novel LDL-lowering therapies below current guideline targets.

Keywords::

• LDL-C
• lipid lowering therapy
• treatment targets

In the current era of evidence-based medicine, reaching low-density lipoprotein cholesterol (LDL-C) or total cholesterol levels has been advocated by the third adult treatment panel (ATPIII) in the treatment of hyperlipidemia and has been widely adopted by the medical community [1]. These recommendations have been developed based on careful examination of existing evidence regarding the atherogenicity of LDL-C, which typically makes up 60–70% of the total serum cholesterol, and the clinical impact of its lowering. LDL-C contains a single apolipoprotein, namely, apo B-100 and has been identified by ATPIII and the National Cholesterol Education Program as the primary target of lipid-lowering therapy [1]. Though it is indisputable that the focus on LDL-C has been strongly validated by recent clinical trials, which demonstrate that LDL-lowering therapy reduces the risk for coronary heart disease (CHD), in this review, we examine the basis for LDL-C target-based treatment recommendations.

LDL-C treatment targets

The concept of adopting LDL-C targets is based on evidence that indicates a near absence of clinical CHD in populations with LDL-C <100 mg/dl [2]. Thus, LDL-C <100 mg/dl was deemed optimal. Moreover, the log-linear relationship between serum cholesterol or LDL-C and CHD risk serves as the basis for further classifying patients with LDL-C above the optimal level into near-optimal (100–129 mg/dl), borderline high (130–159 mg/dl), high (9160–189 mg/dl) and very high (≥190 mg/dl) groups [1]. Further, treating patients with nonoptimal LDL-C levels, especially with statins, has provided strong evidence for reduction in CHD events, CHD mortality and even overall mortality [3]. There is also a great harmony between the findings from clinical trials of LDL-C reduction and projections based on large-scale epidemiological studies [4]. Together, these data have traditionally supported the idea of serum LDL-C lowering to a target level based on estimated risk of CHD and have found place in current ATPIII recommendations. Table 1 summarizes the current ATPIII LDL-C treatment targets. The simplicity of this concept has also struck a cord with practitioners and healthcare providers across specialties and has seen widespread acceptance and adoption. Faced with this practice paradigm, we ask two questions: is a target-based LDL-C-lowering therapy recommendation truly evidence based? And should there be a lower limit for LDL-C?

Table 1. Third adult treatment panel low-density lipoprotein cholesterol treatment targets.

Risk level	LDL-C target (mg/dl)
Patients at high risk	≤70
CHD and CHD risk equivalent	<100
Multiple (2+) risk factors	<130^†
0–1 risk factor	<160

^†LDL-C goal for multiple risk factors and 10-year risk >20% is <100 mg/dl.

CHD: Coronary heart disease; LDL-C: Low-density lipoprotein cholesterol.

The dogma of treating specific at-risk patients to a predefined LDL-C target level may be questionable and unsupported by large-scale randomized clinical strategy trials [5]. Though most trials have used fixed-dose regimens of LDL-C-lowering drugs with disconcordant clinical results, despite a lowering of LDL-C effect, this approach also disregards the heterogeneity of the LDL-C molecule itself [6]. Statins lower LDL-C level and CHD risk, torcetrabib lowers LDL-C, but not CHD risk. Thus, most of the evidence for LDL-C lowering is based on statin use. In both primary and secondary prevention statin trials, a single, fixed-dose regime has been tested and, although the magnitude of clinical benefit has been more robust and early inpatients achieving very low levels of LDL-C, this evidence certainly cannot be used to advocate a LDL-C target-based approach [6]. It is also important to recognize that the ability to estimate CHD risk based on LDL-C levels is limited and the clinical benefits of LDL-C lowering are often independent of its pretreatment levels [7]. The use of LDL-C targets may be one of the key factors that has led to the introduction of numerous LDL-C-lowering drugs in addition to statins and has led to multiplicity of concomitant drug therapies. The safety of this approach and its overall efficacy in reducing CHD risk remains ambiguous; however, the use of target-based treatment approach tends to fuel the use of such combination drugs. While pointing to the limitations of the target-based approach for LDL-C reduction, it is important to acknowledge that this approach, while based on extrapolations of clinical trial data, is both in line with our understanding of the mechanism of atherosclerosis and has great intuitive appeal. Therefore, it has had remarkable success in bringing lipid management to the forefront of preventing and treating cardiovascular disease. If we are to accept a target-based LDL-C reduction as the established current paradigm, should there be a lower limit to its reduction?

Lower limit for LDL-C reduction

It is now well established that lowering plasma LDL-C to reduce the risk of CHD and secondary event rates is safe and effective. However, whether there is a lower threshold level of safety and efficacy for plasma LDL-C remains undefined [8].

Based on a meta-analysis of 58 clinical trials, a 38.7 mg/dl reduction in LDL-C is associated with a 36% reduction in coronary events over a 5-year follow-up period [9]. The ATPIII recommends considering statin therapy in patients with overt CHD and/or patients with a 10-year CHD risk of >20% to achieve LDL-C reduction below 100 mg/dl and even 70 mg/dl [1]. Thus, super-intensive LDL-C-lowering statin interventions have been advocated for patients with acute coronary syndrome or cerebrovascular disease. A meta-analysis of 26 statin trials with over 170,000 patients demonstrated a 20% reduction in the combined incidence of major coronary events, coronary revascularizations and stroke over a 5-year period for every 38.67 mg/dl reduction in LDL-C [10]. An additional 19.33 mg/dl lowering of LDL-C was associated with an additional 15% reduction in the risk of major cardiovascular events (4.5% intensive therapy vs 5.3% standard therapy; p < 0.0001), an effect independent of baseline LDL-C.

Evidences from human and primate studies indicate that a very low LDL-C may be an evolutionary norm for humans and other mammals. The optimal affinity of the LDL-C receptor for LDL-C at plasma levels of 25 mg/dl may be enough for all cholesterol-related cellular metabolic and synthetic functions [11]. The evidence from studies of genetically very low LDL suggests that, as long as a bare minimum level of lipoprotein secretion is maintained, very low levels of plasma LDL are sufficient for normal metabolic function. Moreover, newborns often have a plasma LDL-C levels ≤50 mg/dl and primates with the affinity of the LDL-C receptor for LDL-C similar to humans maintain a LDL-C level ≤80 mg/dl [12]. Despite the evidence cited above, the safety of extremely low LDL-C together with the use of high-dose statins remains. These safety concerns have been raised on the basis of isolated reports that link statin use and/or low LDL-C with cancer, myopathies and liver dysfunction. In Table 2, we provide a summary of evidence for safety of intensive LDL-C lowering with respect to cancer, liver function test abnormalities and muscle-related symptoms and conditions in patients enrolled in primary and secondary prevention statin trials with LDL-C levels <100 mg/dl. Concerns regarding an increased risk of death due to cancer, respiratory disease, hemorrhagic stroke and other nonmedical conditions have been dispelled by data from multiple large-scale randomized statin trials included in Table 2 [13,14]. Questions regarding elevated serum levels of alanine transaminase, liver damage, myopathy and rhabdomyolysis have been far more difficult to address. With low dose (20–40 mg) of simvastatin daily, the risk of myopathy is low (∼1/10,000 patients per annum), but it increases 10-fold with 80 mg simvastatin daily to 1/1,000 patients per annum [15]. Atorvastatin at 80 mg dose does not appear to be associated with markedly increased rate of myopathy or a rise in creatine kinase levels in randomized trials as is 20 mg rosuvastatin [16,17]. The risk of myopathy and rise in creatine kinase increases at higher doses (80 mg) of rosuvastatin [17].

Table 2. Safety of statins in selected randomized trials, which achieved plasma low-density lipoprotein cholesterol <100 mg/dl.

Primary prevention trials
Trial name	AURORA [22]	JUPITER [23]	CARDS [24]	ASPEN [25]	GISSI-HF [26]	4D [27]	ASCOT LLA [28]
Population	HD	High CRP	DM	DM	CHF	DM, HD	HTN
Subjects (n)	2776	17,802	2838	2410	4631	1255	19,342
Active arm	Rosuvastatin 10 mg	Rosuvastatin 20 mg	Atorvastatin 10 mg	Atorvastatin 10 mg	Rosuvastatin 10 mg	Atorvastatin 20 mg	Atorvastatin 10 mg
Control	Placebo	Placebo	Placebo	Placebo	Placebo	Placebo	Placebo
LDL at 1 year	61.5	62.3	73.1	75	82.8	91.3	91.6
Overall death	636/660 (NS)	198/247 (0.02)	82/61 (NS)	NS	657/644 (NS)	297/320 (NS)	185/212 (NS)
New cancer	107/118 (NS)	298/314 (NS)	X	X	X	44/39	X
Cancer death	25/27 (NS)	35/58 (0.02)	20/30 (NS)	X	81/75	17/19	X
New diabetes	10/14 (NS)^†	270/216 (0.01)^‡	X	X	X	X	154/134 (NS)^†
Abnormal LFT	5/6 (NS)^§	23/17 (NS)^¶	17/144	1.4%/1.2%^†	26/12^†	5/13	X
Muscle symptoms	310/343 (NS)^††	1421/1375 (NS)^‡‡	61/72^§§	3%/1.6%^§§	23/21^†	7/5 (NS)	X
Myopathy	X	10/9 (NS)^†	1/1^†	X	X		X
Abnormal CK	10/9 (NS)^†††		2/10^‡‡‡		9/2^§§§	12/4^†††
Rhabdomyolysis	3/2 (NS)^†	1/0^†	0/0	1/1^†	0/0	0/0	1/0
Secondary prevention trials
Trial name	A to Z [29]	TNT [30]	PROVE-IT [31]	HPS [32]	IDEAL [33]	SEARCH [34]	LIPS [35]
Population	ACS	Stable CHD	ACS	CHD/DM	Prior MI	Prior MI	Post-PCI
Subjects (N)	4,497	10,001	4,162	20,536	8,888	12,064	1,677
Active arm	Simvastatin 80 mg^¶¶¶	Atorvastatin 80 mg	Atorvastatin 80 mg	Simvastatin 40 mg	Atorvastatin 80 mg	Atorvastatin 80 mg	Fluvastatin 80 mg
Control	Simvastatin 20 mg	Atorvastatin 10 mg	Pravastatin 40 mg	Placebo	Simvastatin 20 mg	Simvastatin 20 mg	Placebo
LDL at 1 year	69.2	73.5	76.2	80.8	80.8	81.6	96.7
Overall death	104/130 (NS)	284/282 (NS)	1.9%/2.2% (NS)	1328/1507 (0.0003)	366/374 (NS)	964/970	36/49 (NS)
New cancer	X	X	X	814/803 (NS)	X	640/677	46/49
Cancer death	X	85/75 (NS)	X	359/345 (NS)	99/112 (NS)	246/266 (NS)	14/18
New diabetes	X	X	X	X	X	625/587 (NS)^†	X
Abnormal LFT	19/8^¶	60/9 (<0.001)^#	3.3%/1.1% (<0.001)^¶	43/32^§	61/7 (<0.001)^#	51/40^§	10/3^#
Muscle symptoms	41/34 (NS)^¶¶	241/234 (NS)^§§	3.3%/2.7% (NS)^§§	32.9%/33.2% (NS)^§§	97/51 (<0.001)^§§	7%/7% (NS)^§§	X
Myopathy	9/1 (0.02)^##	X	X	5/1^##	6/11 (NS)^‡	53/2^†	X
Abnormal CK	X					145/43^§§§	0/3^‡‡‡
Rhabdomyolysis	X	2/3^‡	0/0	5/3	3/2^‡	7/0	0/0

^†Not defined; ^‡Physician reported; ^§ALT > 4X ULN; ^¶ALT > 3X ULN; ^#ALT and/or AST > 3X ULN; ^††Muscle spasm, pain and/or weakness; ^‡‡Muscular weakness, stiffness or pain; ^§§Myalgia; ^¶¶Muscle-related adverse event; ^##Muscle-related symptoms with CK >10X; ^†††CK > 3X ULN; ^‡‡‡CK > 10X ULN; ^§§§CK > 5X ULN; ^¶¶¶Currently unapproved dose by US FDA.

4D: Deutsche diabetes dialyze studies; A–Z: AGGRASTAT to ZOCOR; ACS: Acute coronary syndrome; ASCOT-LLA: Anglo-Scandinavian cardiac outcomes trial – lipid-lowering arm; ASPEN: Atorvastatin study for prevention of coronary heart disease endpoints in noninsulin-dependent diabetes mellitus; CARDS: Collaborative atorvastatin diabetes study; CHD: Coronary heart disease; CRP: C-related protein; DM: Diabetes mellitus; GISSI-HF: Gruppo Italiano per lo Studio della Sopravvivenza nell'insufficienza Cardiaca; HD: Hemodialysis; HPS: Heart protection study; HTN: Hypertension; IDEAL: Incremental decrease in clinical endpoints through aggressive lipid lowering; JUPITER: Justification for the use of statins in primary prevention: an intervention trial evaluating rosuvastatin; LIPS: Lescol intervention prevention study; MI: Myocardial infarction; PCI: Percutaneous coronary intervention; AURORA: A study to evaluate the use of rosuvastatin in subjects on regular hemodialysis: an assessment of survival and cardiovascular events; PROVE-IT: Pravastatin or Atorvastatin evaluation and infection therapy; SEARCH: Study of the effectiveness of additional reductions in cholesterol and homocysteine; TNT: Treating to new targets.

Early evidence with the approach to target the inhibition of proprotein convertase subtilisin/kexin type 9 responsible for increased hepatic degradation of LDL receptors, suggests a significant reduction in plasma LDL cholesterol levels [18]. When use in concert with statin therapy, this novel approach provides an additional ≥60% reduction in LDL-C compared with statins alone. Extremely low LDL-C levels with proprotein convertase subtilisin/kexin type 9 inhibition have not been associated with increased risk of cancer or myopathies. Significant LDL-C lowering without safety signals has also been reported with an apo-B synthesis inhibitor, mipomersen [19]. The Veterans Affairs US FDA investigational device exemption trial, Plaque Regression and Progenitor Cell Mobilization with Intensive Lipid Elimination Regimen Trial is currently testing the hypothesis of whether the most intensive LDL-lowering therapy with LDL apheresis could lead to a rapid and detectable reduction in coronary atheroma volume, along with a more robust EPC mobilization compared with standard statin therapy in acute coronary syndrome patients without familial hyperlipidemia (ClinicalTrials.gov identifier: NCT01004406) [20].

The evidence presented here argues for a nontarget-based approach to LDL-C management, unless a treatment to a target strategy is tested in a large-scale clinical trial. Further, greater reductions of plasma LDL-C than current guideline targets are likely to safely reduce cardiovascular event rates using both traditional and novel LDL-C-lowering therapies. The most recent ACC/AHA guideline recommendation for the first time has clearly articulated the fact that there are no randomized controlled trials to support LDL-C treatment targets [21].

Financial & competing interests disclosure

S Banerjee has received research grants from Boston Scientific; consultant/speaker honoraria from Medtronic, Covidien; ownership: Mdcare Global (spouse); intellectual property: HygeiaTel. ES Brilakis has received research grants and consulting fees/speaker honoraria from St Jude Medical, Boston Scientific, Asahi, Janssen, Sanofi, Abbott Vascular and Terumo; research support from Guerbet; spouse is an employee of Medtronic. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.