Hypertriglyceridemia and residual dyslipidemia in statin-treated, patients with diabetes at the highest risk for cardiovascular disease and achieving very-low low-density lipoprotein-cholesterol levels

Journal of Clinical Lipidology (2012) 6, 434–442

Hypertriglyceridemia and residual dyslipidemia in statin-treated, patients with diabetes at the highest risk for cardiovascular disease and achieving very-low low-density lipoprotein-cholesterol levels Laurent Querton, MD, Martin Buysschaert, MD, PhD, Michel P. Hermans, MD, PhD* Service d’Endocrinologie et Nutrition, Cliniques Universitaires St–Luc, Universit
e Catholique de Louvain, Avenue Hippocrate UCL 54.74. B–1200 Brussels, Belgium KEYWORDS: Apolipoprotein B100; Atherogenic dyslipidemia; Diabetes; LDL-C; Non-HDL-C; Statins; Triglycerides

BACKGROUND: As the result of the high prevalence of comorbidities and conventional risk factors among patients with type 2 diabetes (T2DM), most patients belong to the highest cardiovascular disease risk category, and have a target low-density lipoprotein cholesterol (LDL-C) of ,70 mg/dL. Because substantial residual risk persists at LDL-C ,70 mg/dL, a more comprehensive control of non-LDL-C and particles was recommended in the joint 2008 American Diabetes Association/ American College of Cardiology Consensus. OBJECTIVE: To ascertain, in statin-treated T2DM patients belonging to this greatest-risk group, with on-statin LDL-C ,70 mg/dL, (1) the proportion of patients meeting all three critical levels (LDL-C ,70 mg/dL, non-high-density lipoprotein cholesterol [HDL-C] ,100 mg/dL, apoB ,80 mg/dL) and (2) the variables associated with target attainment versus nonattainment. PATIENTS AND METHODS: Among 675 unselected patients with T2DM, 367 were both at very high cardiometabolic risk and taking statins; 118 of these patient had LDL-C levels ,70 mg/dL. Patients meeting all three criteria (LDL-C, non-HDL-C, and apoB; n 5 79; all three at goal group) were compared with those only reaching LDL-C (n 5 49; only LDL-C at goal group). RESULTS: LDL-C was 54 (12) for the all three at goal group versus 57 (10) mg/dL for the only LDL-C at goal group (NS). The two groups were similar regarding age, gender, diabetes duration, body mass index, waist circumference, blood pressure, renal function and micro-/macroangiopathy prevalence. A statin plus fibrate was given to 16% of patients in the all three at goal group and 32% in the only LDL-C at goal group. The two groups did not differ in baseline (prestatin) LDL-C, HDL-C, and non-HDL-C, except for pre-/postlipid-lowering drug(s) triglycerides (TG): 177 (95)/118 (56) for all three at goal versus 279 (134)/ 241 (103) mg/dL for only LDL-C at goal (P 5.0230 and P 5.0001). The only LDL-C at goal group had lower HDL-C (vs. all three at goal): 41 (12) vs. 47 (14) mg/dL (P 5.0237), with atherogenic dyslipidemia [hypo-HDL-C 1 hyper-TG] prevalence of 35% in the all three at goal versus 56% in the only LDL-C at goal group (P , .0001). log(TG)/HDL-C was 0.049 (0.021) for all three at goal versus 0.063 (0.021) for only LDL-C at goal (P , .0001). The LDL-C/apoB ratio was 0.92 (0.24) for all three at goal vs. 0.67 (0.18) for only LDL-C at goal (P , .0001), suggestive of smaller/denser LDL. CONCLUSION: The presence of atherogenic dyslipidemia was associated with a failure to meet all three critical modifiable targets for hypercholesterolemia, such a nonachievement being found in a large

* Corresponding author. E-mail address: [email protected]

Submitted November 28, 2011. Accepted for publication April 4, 2012.

1933-2874/$ - see front matter Ó 2012 National Lipid Association. All rights reserved. doi:10.1016/j.jacl.2012.04.002

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proportion (one-third) of very-high risk T2DM patients with very-low on-statin LDL-C. Attainment of all three targets will require (1) titration/permutation of statins, (2) lifestyle (re)inforcement; and/or (3) statinfibrate bitherapy. Ó 2012 National Lipid Association. All rights reserved.

Standards of care in type 2 diabetes mellitus (T2DM) management include optimization of modifiables risk factors (RFs) to prevent new-onset or progression of microand macroangiopathies. Reducing macrovascular disease risk requires a multifactorial intervention that targets multiple RFs, such as hypertension, hypercholesterolemia, sedentary lifestyle, obesity, or smoking. In addition to Therapeutic Lifestyle Changes (TLC), standards of care recommend that major critical modifiable RFs (hyperglycemia [HbA1c as surrogate]), systolic blood pressure, and low-density lipoprotein cholesterol [LDL-C]) should be brought to or below consensual thresholds, although for RFs with a continuous distribution, residual vascular risk (RVR) may persist even when RFs are deemed satisfactory.1–9 Among lipid-related RFs in T2DM, the reduction of LDL-C, usually via the use of statins as preferred first agent, is highly effective in reducing the risk of cardiovascular disease (CVD), both in primary or secondary prevention, as confirmed from landmark statins trials and meta-analyses of statins trials. Because of the effectiveness of LDL-C lowering with statins, the administration of this class of lipid-lowering drugs (LLDs) is considered beneficial to most patients with T2DM either because (1) baseline LDL-C values are elevated, (2) estimated CVD risk is high, or (3) regardless of baseline lipids, patients with the common form of T2DM are considered secondary prevention-equivalent with a high risk of new-onset CVD in the absence of CVD.1–4,6–8,10–13 Yet, even with LDL-C at target, a solely LDL-C–based approach will leave a substantial component of lipid-related RVR unaltered, all the more so that poststatin RVR is rarely quantified in routine practice. Achieving low levels of LDL-C (,70 mg/dL), on the other hand, does not imply that all the CVD risk associated with non-LDL dyslipidemia will be under control, as shown by clinical trials in which investigators demonstrated greater CV residual risk when high-density lipoprotein cholesterol (HDL-C) was low (,40 mg/dL).14–19 A recent joint consensus statement from the American Diabetes Association and the American College of Cardiology Foundation recommends two sets of targets goals for LDL-C, non-HDL-C, and apoB for patients with cardiometabolic risk, such as those with atherogenic dyslipidemia (AD), the hallmark of which is increased levels of triglycerides (TG) and low HDL-C. Accordingly, LDL-C, non-HDLC and apolipoprotein B100 (apoB) levels ,100 mg/dL, ,130 mg/dL, and ,90 mg/dL, respectively, are recommended for patients without diabetes or known CVD but with

$2 additional major CVD RFs, or with diabetes and without major CVD RFs. LDL-C, non-HDL-C, and apoB levels ,70 mg/dL, ,100 mg/dL, and ,80 mg/dL, respectively, are recommended for patients at the greatest risk of CVD, ie, known CVD or diabetes plus $1 additional major CVD RFs.2 Because of the high prevalence of MetS, CV comorbidities, and conventional RFs among T2DM, 80% to 90% of them qualify as being at the greatest risk for CVD.2,9 The aim of the present study was to ascertain, in statin-treated T2DM patients belonging to this greatest-risk group, and with on-statin LDL-C ,70 mg/dL: (1) the proportion of patients meeting all three critical targets, namely non-HDL-C ,100 mg/dL and apoB ,80 mg/dL in addition to LDL-C ,70 mg/dL and (2) the variables associated with attainment versus nonattainment of those three critical modifiable targets.

Patients and methods The study design was cross-sectional. We evaluated 675 consecutive adult outpatients with T2DM who were followed at the diabetes center of a tertiary academic hospital in Brussels, Belgium, between October 2009 and October 2010. Sixty-percent (n 5 407) were treated with statins, among whom 367 (90%) were classified as ‘‘very high-cardiometabolic risk’’ according to the 2008 Joint ADA-ACC Consensus statement.2 When we considered achieved poststatin LDL-C values, we found that 249 (68%) patients from this very high-risk group did not reach LDL-C target ($70 mg/dL) and were excluded from this analysis, whereas the remaining 118 (32%), at LDL-C goal ,70 mg/dL, represent the population of interest for this study. These 118 patients were split into two groups, analyzed in parallel, according to whether they also met additional lipid targets as regards non-HDL-C and/or apoB levels. Thus, patients meeting all three criteria (LDL-C, non-HDL-C, and apoB; n 5 79; thereafter described as [all three at goal]) were compared with those only reaching LDL-C without meeting non-HDL-C and/or apoB targets (n 5 39; [only LDL-C at goal] group). The following sociodemographic and clinical variables were recorded: age, gender, achieved educational level, age at diabetes diagnosis, diabetes duration, familial history (premature-onset cardiovascular disease, diabetes mellitus), current medications (oral antidiabetic drugs, insulin, bloodpressure [BP]-lowering drugs, aspirin, lipid-lowering drugs

436 [LLDs]), weight, height, body mass index (BMI), waist circumference and total body fat (four-limbs BodyFat Analyser, Omron BF 500, Omron Healthcare Europe B.V., Hoofddorp, The Netherlands). The presence of hypertension was defined as systolic BP $140 mmHg and/or diastolic BP $90 mmHg and/or current treatment with BP-lowering drug(s) prescribed for treating high BP. The presence of a metabolic syndrome (MetS) was defined according to the harmonized IDF/NHLBI/AHA/ WHF/IAS/IASO consensus definition.20 Each subject underwent noninvasive assessment of insulin sensitivity and b-cell function using the Homeostasis Model Assessment computer-based version (http://www.dtu.ox.ac.uk) as previously described.21,22 Ultrasonographic evidence of fatty liver was considered in the presence of hyperreflectivity and in the absence of other etiological factors known to be associated with liver steatosis, including excess ethanol intake. As regards macroangiopathy, coronary artery disease (CAD) was retrospectively inferred from medical history (myocardial infarction, angioplasty, stenting, revascularization surgery and/or significant coronary stenosis confirmed by angiography) and systematic review of all procedures, screening (exercise testing, echocardiography). Stroke was defined according to the UK Prospective Diabetes Study (UKPDS) criteria.23,24 Peripheral artery disease (PAD) was defined by a well-documented medical history of lowerlimb(s) claudication and/or clinical or imaging evidence for ischemic diabetic foot, angioplasty, stenting, revascularization surgery and/or significant lower-limb artery stenosis at Doppler ultrasonography and/or angiography. Diabetic retinopathy was diagnosed following dilated fundus examination, with fluoangiography performed when deemed necessary by an in-house ophthalmologist. The presence of a peripheral neuropathy was based on clinical examination (knee and ankle reflexes, Semmes-Weinstein 5.07 monofilament test) and/or 4-limbs electromyography. The following biologic variables were recorded: current glycated hemoglobin (HbA1c), current and prelipid-loweringdrug(s) (pre-LLDs), fasting lipids (total cholesterol [C], highdensity lipoprotein cholesterol [HDL-C], TG). Total C and TGs were determined by the use of the SYNCHRON system (Beckman Coulter Inc., Brea, CA). HDL-C was determined with the ULTRA-N-geneous reagent (Genzyme Corporation, Cambridge, MA). Apolipoprotein A-I (apoA-I) and apolipoprotein B100 (apoB) were determined with immunonephelometry on BNII Analyzer (Siemens Healthcare Products GmbH, Marburg, Germany). The within-subject coefficients of variation were as follows: 6.9% (apoB), 6.5% (apoA-I), 5.4% (total C), and 7.1% (HDL-C). LDL-C was computed with Friedewald’s formula25 and non-HDL-C by subtracting HDL-C from total C. The size of LDL particles was estimated using the ratio of LDL-C to apoB.7,9,26 TG-rich lipoprotein-C was estimated by subtracting LDL-C from non-HDL-C, a value that equates, as per Friedewald’s formula, with fasting TG/5. AD was diagnosed and quantified in a two-fold manner: (1) as dichotomous state, using baseline lipid values (ie, before any

Journal of Clinical Lipidology, Vol 6, No 5, October 2012 LLD(s) in treated patients), with AD being considered in case of concurrent low HDL-C (,40 [males] or ,50 mg/ dL [females]) plus elevated fasting TG ($150 mg/dL); (2) as continuous variable, by computing the ratio log(TG)/ HDL-C,7,9 without sex-dichotomy.26 As for nonlipid cardiometabolic markers, levels of highsensitivity C-reactive protein, uric acid, fibrinogen, leucocytes count, liver enzymes (aspartate aminotransferase, alanine aminotransferase, g-glutamyl transpeptidase), homocysteine, folic acid, and vitamin B12 were determined by routine laboratory methods. Normo, microalbuminuria, and macroalbuminuria were defined as urinary albumin excretion ,30 (normo-), 30 to 299 (micro-) and $300 mg.mg creatinine21.1.73 m2 (macro-) from first-morning urine sample. Glomerular filtration rate was estimated using the Modified Diet in Renal Disease formula.27 The study was performed in accordance with the institutional review board of St-Luc Academic Hospital.

Statistical methods Results are presented as means 61 SD or proportions (%). The significance of differences between means was assessed by Student’s t test or by alternate Welch’s test for data sets with significant differences in SDs, and by the Fisher’s exact test for differences in proportions. Results were considered significant or nonsignificant for P , .05 or $.05, respectively.

Results In the study population with LDL-C ,70 mg/dL (n 5 118), mean (1 SD) age was 68 (9) years, diabetes duration 16 (10) years, and the male/female ratio 73:27%. Mean BMI was 29.7 (5.5) kg.m22, waist circumference was 107 (13) and 105 (13) cm in males (n 5 86) and females (n 5 32), respectively. Ninety-one percent of patients had a MetS phenotype. Mean HbA1c was 7.48% (1.31). In addition to statins, 21% of patients were on dual LLD therapy with peroxisome proliferator-activated receptor-a agonist fenofibrate, whereas 5% were treated with dual LLD therapy statin plus ezetimibe, and 2% were on triple LLD therapy (statin plus ezetimibe plus fibrate). Baseline lipid values (before the administration of any LLD) were characteristic of the common form of T2DM associated with features of the MetS: HDL-C 46 (13) mg/dL, fasting TG 192 (109) mg/dL, TG-rich lipoprotein cholesterol 31 (18) mg/dL, with elevated prevalence of AD (42%). As for current lipids, mean total cholesterol was 131 (23), LDL-C 55 (12), non-HDL-C 87 (20), apoB 69 (18), TG 159 (94), HDL-C 45 (14), and apoA-I 145 (32) mg.dL21. Mean log(TG)/HDL-C was 0.053 (0.022). In the whole population, macroangiopathy prevalence, and the proportion of patients in true secondary prevention as a result, was 48%, with CAD in 37%; PAD in 8% and/or transient ischemic attack/stroke in 13%.

Querton et al

Residual dyslipidemia in statin-treated T2DM with low LDL-C

The characteristics of the 79 subjects belonging to the all three at goal subgroup were compared with those of the 39 subjects from the only LDL-C at goal group. There were no significant differences between groups as regards age, gender, diabetes duration, glucose-lowering therapies, HbA1c, BMI, waist circumference, fat mass, insulin sensitivity (decreased in both groups), MetS prevalence, liver steatosis, prevalence of hypertension, and BP values, kidney function, or albuminuria nor regarding the frequency of micro- or macroangiopathy. Diabetes and/or CVD familial histories were not different between groups, nor were socioeducational level, smoking history, ethanol intake, leisure-time physical activity duration, and time spent watching television and/or reading off computer screens. There were no significant differences between groups regarding the prevalence of diabetic retinopathy, lower-limb polyneuropathy, overall macroangiopathy, PAD, CAD and/or transient ischemic attack/stroke (Table 1). There were no significant differences in highsensitivity C-reactive protein, fibrinogen, urate, leucocytes, homocysteine, TSH, free T4, liver enzymes, folates, and vitamin B12. UKPDS Risk Engine 10-year absolute CV risk was also not different between groups (not shown).

Table 1

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Although all patients were treated with statins as per protocol, there were twice as many patients taking fibrates in only LDL-C at goal group compared with the all three at goal group, although the difference (32% vs. 16%) did not reach statistical significance. Baseline lipid values were not different between patients in the only LDL-C at goal and all three at goal group except for fasting TG values and AD prevalence, which was significantly greater by a mean 102 mg/dL (158%) for the former and by a relative 160% for the latter in the only LDL-C at goal group (P 5 .0230 and P 5 .0469, respectively; Table 2). Within statins drugs, usage of simvastatin was significantly greater (185%) in the all three at goal patients, with no significant differences regarding other statins. Average dose of statin was 80.0 mg (fluvastatin); 40.0 mg (pravastatin); 23.1 mg (simvastatin); 27.1 mg (atorvastatin); and 12.6 mg (rosuvastatin) in the only LDL-C at goal group versus 20.0 mg (pravastatin); 30.0 mg (simvastatin); 22.9 mg (atorvastatin); and 9.3 mg (rosuvastatin) in the all three at goal group, without significant differences in dosages between groups. Mean absolute and relative decreases in LDL-C following statins, although substantial in both groups, were

Patients’ characteristics

n Age, yr Sex ratio (M/F) % Diabetes duration, yr Glucose-lowering drug(s), % Metformin b-cell stimulant Incretin-based therapy Thiazolidinedione Insulin HbA1c, % BMI, kg.m-2 Waist circumference, cm Fat mass, % HOMA S, % Metabolic syndrome, % Liver steatosis, % Hypertension, % Systolic BP, mm Hg Diastolic BP, mm Hg eGFR, mL.min-1.1.73 m2 Albuminuria, mg.mg creatinine-1 Retinopathy, % PNP, % Macroangiopathy, % PAD, % TIA/stroke, % CAD, %

All three at goal

Only LDL-C at goal

P

79 69 (9) 72:28 17 (10)

39 66 (11) 74:26 15 (10)

NS NS NS

69 49 5 6 52 7.4 29.6 106 31.7 54 87 70 97 138 75 69 183 36 28 48 9 14 38

77 56 10 5 54 7.7 30.0 107 31.4 46 97 84 97 137 75 72 160 22 14 44 5 10 36

NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS NS

(1.2) (5.5) (13) (9.3) (35)

(20) (9) (29) (552)

(1.5) (5.6) (13) (7.5) (37)

(15) (10) (31) (336)

BMI, body mass (Quetelet’s) index; BP, blood pressure; CAD, coronary artery disease; eGFR, estimated glomerular filtration rate (MDRD formula); F, female; HOMA, homeostatic model assessment; HOMA-S, insulin sensitivity from HOMA; M, male; PAD, peripheral artery disease; PNP, lower-limb diabetic polyneuropathy; TIA, transient ischaemic attack; NS, non-significant. Results are expressed as means (1 SD) or proportions (%).

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Table 2

Baseline lipid values, ongoing LLD, and LDL-C changes after LLD All three at goal

n Baseline (pre-LLD) lipids Total cholesterol (C), mg.dL-1 Non-HDL-C, mg.dL-1 ApoB100*, mg.dL-1 LDL-C, mg.dL-1 HDL-C, mg.dL-1 Triglycerides, mg.dL-1 Atherogenic dyslipidemia, % Fluvastatin, % Pravastatin, % Simvastatin, % Atorvastatin, % Rosuvastatin, % Statin 1 ezetimibe, % Fenofibrate, % Post-LLD LDL-C change, mg.dL-1 Post-LLD LDL-C change, %

79 216 170 117 135 46 177 35 1.3 1.3 50.0 16.7 25.6 5.1 16.0 282 258

Only LDL-C at goal

P w

39 (39) (39) (25) (32) (13) (95)

(36) (15)

229 182 125 141 44 233 56 0.0 8.1 27.0 18.9 43.2 2.7 32.0 283 257

(33) (31) (20) (26) (15) (134)

NS NS NS NS NS .0230 .0469 NS NS .0293 NS NS NS NS NS NS

(27) (10)

HDL, high-density lipoprotein; LDL, low-density lipoprotein; LLD, lipid-lowering drug; NS, non-significant. Results are expressed as means (1 SD) or proportions (%). *Computed from the unbiased equivalence equation: [apoB 10050.65 ! (non-HDL-C) 1 6.3 mg/dL](Hermans et al. Cardiovasc Diabetol 2011).

not significantly different between only LDL-C at goal and all three at goal patients (Table 2). Post-LLD lipids and lipoproteins values are described in Table 3. Mean total cholesterol was significantly lower (by a mean relative 214%) in all three at goal patients (P , .0001). Mean LDL-C was markedly below the 70 mg/dl target, without significant differences between groups: 54 (12) mg/dL in all three at goal versus 57 (10) mg/dL in only LDL-C at goal. Non-HDL-C was greater, by a mean

Table 3

relative 133%, in only LDL-C at goal patients and at 104 (20) versus 78 (13) mg/dL in all three at goal patients. A mere 28% of only LDL-C at goal patients attained the ,100 mg/dL target for non-HDL-C. TG-rich lipoprotein cholesterol was more than two times greater (mean relative increase 1104%) in only LDL-C at goal patients (P , .0001). ApoB was higher, by a mean relative 147%, in only LDL-C at goal: 88 (17) mg/dL versus 60 (11) mg/ dL in all three at goal.

Lipids and lipoproteins

n Total cholesterol (C), mg.dl-1 LDL-C, mg.dl-1 HDL-C, mg.dl-1 Non-HDL-C, mg.dl-1 non-HDL-C , 100 mg.dl-1, % TG-rich lipoproteins-C, mg.dL-1 apoB100, mg.dL-1 apoB 100 , 80 mg.dL-1, % apoA1, mg.dL-1 apoB100 . apoA1-1 triglycerides, mg.dL-1 triglycerides , 150 mg.dl-1, % log (TG).HDL-C-1 total-C . HDL-C-1 non-HDL-C . HDL-C-1 LDL-C . apoB100-1

All three at goal

Only LDL-C at goal

P

79 124 54 47 78 100 23 60 100 146 0.43 118 80 0.049 2.83 1.83 0.92

39 145 57 41 104 28 47 88 26 141 0.64 241 21 0.063 3.80 2.80 0.67

w ,.0001 NS .0237 w w ,.0001 w w NS ,.0001 ,.0001 ,.0001 .0009 ,.0001 ,.0001 ,.0001

(20) (12) (14) (13) (11) (11) (29) (0.13) (56) (0.021) (0.67) (0.67) (0.24)

(23) (10) (12) (20) (19) (17) (38) (0.20) (103) (0.021) (1.09) (1.09) (0.18)

Apo, apolipoprotein; HDL, high-density lipoprotein; LDL, low-density lipoprotein; TG, triglycerides; NS, non-significant. Results are expressed as means (1 SD) or proportions (%).

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Residual dyslipidemia in statin-treated T2DM with low LDL-C

HDL-C was significantly greater (by a mean relative 1 15%) in all three at goal patients: 47 (14) mg/dL versus 41 (12) mg/dL in only LDL-C at goal. ApoA-I was not significantly different between groups: 146 (29) mg/dL in all three at goal versus 141 (38) mg/dL in only LDL-C at goal. Mean TG were markedly greater (absolute/relative difference 1123 mg/dl/1104%) in only LDL-C at goal patients, a mere 21% of whom attained target TG levels ,150 mg/dL (vs. 80% in all three at goal; P , .0001; Table 3). True underlying AD prevalence, estimated from baseline lipids was 35% in all three at goal versus 56% in only LDL-C at goal (P 5 .0469; Table 2). Concerning atherogenic ratios, total C/HDL-C was greater (134%) in only LDL-C at goal (P , .0001), as was non-HDL-C/HDL-C, higher (153%) in only LDL-C at goal (P , .0001). ApoB/ApoA-I was also greater (149%) in only LDL-C at goal (P , .0001). LDL/apoB was lower (227%) in only LDL-C at goal (P , .0001). The AD ratio log(TG)/HDL-C was greater (129%) in only LDL-C at goal (P , .0001), as was the atherogenic index of plasma [log (TG/HDL-C)]: 0.38 (0.28) in all three at goal versus 0.74 (0.28) in only LDL-C at goal (P , .0001; Table 3).

Discussion The main findings of the present study are threefold. First, in statin-treated patients with T2DM who achieved the strictest LDL-C target (,70 mg/dL), as is recommended for patients with the greatest cardiometabolic risk,2 one-third of patients still did not attain the two other critical lipid targets represented by non-HDL-C and apoB, respectively. On the positive side, a sizeable two-thirds’ majority of patients achieving LDL-C target also achieved nonHDL-C and apoB targets. In the remaining one-third, nonattainment was observed despite achieving a marked decrease in LDL-C, with mean on-statin LDL-C at 57 mg/dL, as a result of a substantial average decrement in baseline (pre-LLD) LDL-C of 83 mg/dL (ie, 57%). Second, not attaining the target was unrelated to baseline levels of LDL-C, non-HDL-C, or apoB but was significantly associated with baseline as well as current TG levels and also with the presence of AD. Third, failure to attain the target was not related to differences in absolute/relative LDL-C decrement after LLD. As the result of protocol, the T2DM patients in this study, with on-statin LDL-C ,70 mg/dL, may represent a selected population of statin-tolerant, LLD-compliant patients who responded well to LLD. A marked response to statin therapy may ensue from intrinsic effective hepatic response to the drug, from limited enterocytic cholesterol compensatory reabsorption, and/or from other pharmacogenomic idiosyncrasies.8,9,28–31 As regards nonlipid parameters, there were no significant differences between attainers and nonattainers in sociodemographics, anthropometrics, cardiometabolic profile (eg, waist circumference,

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insulin sensitivity, MetS prevalence, hypertension and presence of fatty liver), glucose homeostasis determinants and degree of diabetes control, non-lipid therapies (antidiabetic, BP-lowering), nonlipid parameters (eg, subclinical inflammatory markers), nor in micro- or macroangiopathies frequency. Among numerous lipid and lipoproteins variables significantly associated with target attainment, the majority related to abnormalities in TG-rich lipoproteins synthesis or metabolism and/or AD. The latter was 60% more prevalent in nonattainers, who also had significantly greater TG levels (both baseline and post-LLD), despite a nonsignificantly greater use of fibrates. AD is frequently observed in conditions in which LDL-C is only marginally elevated because of a preponderance of small-dense LDL, which belies the absolute increase in LDL particles number. AD is driven by protracted insulin signaling in a setting of insulin resistance/compensatory hyperinsulinemia. AD is initiated by hepatic overproduction of apoB-containing, TG-rich VLDL. These VLDL are the major source of hypertriglyceridemia in AD states. TG transfer from VLDL to LDL and to HDL, in exchange for cholesteryl esters, with TG-rich LDL and TG-rich HDL undergoing further TG removal by hepatic lipase, rendering them smaller and denser, less atheroprotective, functionally impaired and shorter-lived (in the case of HDL), or more atherogenic due their increased number or oxidation-prone behavior (in the case of LDL).2–4,7,9,26,32–39 The present data suggest that hypertriglyceridemia, as the result of TG-rich lipoproteins overproduction and/or decreased catabolism, is a major factor associated with lack of goals attainment. On the basis of pre-LLD baseline values and with both patient groups attaining LDL-C ,70 mg/dl, clearance of LDL via the LDL-receptor is allegedly active, and expression/function of LDL-receptor not a rate-limiting step. On the other hand, large-size TG-rich lipoproteins do not associate efficiently with lipoprotein receptors. Partial hydrolysis of their TG by lipoprotein lipase (LpL), which markedly reduces their size, is a prerequisite for catabolism. Enrichment in apoB may therefore closely associate with reduced LpL activity. Because of the central role of LpL in the conversion of VLDL into LDL, it is possible that the reduced LDL-C levels in the [only LDL-C goal] group could reflect reduced LpL activity, the latter emerging as a pivotal candidate underlying lack of attainment of all three targets. Although our data suggest that nonattainment was associated with the enrichment in TG-rich lipoproteins, it is also the outcome of a combination of reduced LDL particles size with increased LDL particles number. Although LDL particle size and number were not directly assessed in the present study, the LDL-C/apoB ratio, a surrogate for LDL size, was markedly lower in the only LDL-C at goal group. Moreover, TG-rich lipoprotein enrichment is almost invariably associated with decreased LDL size and increased LDL number. Although the equivalence of baseline levels of LDL-C, non-HDL-C, and apoB is congruent with the American College of Cardiology/American Diabetes Association

440 consensus, the three parameters will not de facto exhibit parallel shifts after LLD. Thus, statin therapy alters the relationship between apoB and LDL-C or non-HDL-C. Preferential removal of large, buoyant LDL by statin- and/ or ezetimibe-upregulated hepatic LDL receptors was proposed as potential explanation, although not on the basis of mechanistic studies.30,40–44 Our results suggest that nonattainment was essentially associated with enrichment in TG-rich lipoproteins, rather than the outcome of a combination of reduced LDL particles size with increased LDL particles number. If such were the case, all measures of AD, including TG levels and those of TG-rich-lipoprotein-C would have been similar in attainers and non-attainers, and in addition, non-attainment would differently impact apoB and non-HDL-C levels.2,7,35,38,44–50 Post-LLD lipid-related RvR may relate to various atherogenic aspects of on-statin lipids and lipoproteins. First, the lack of strict target attainment for all atherogenic variables of the LDL pathway (LDL-C, non-HDL-C, and/or apoB) is linearly related to the amount of above-target cholesterol in atherogenic particles and their numbers. Another component of post-statin lipid abnormalities results from abnormal levels of TG-rich lipoproteins, of their remnants and from decreased number and/or functionality of HDL. This substantial modifiable RvR component pertains to AD, a unique non-LDL dyslipidemia, the hallmark of which is decreased HDL-C coupled with increased TG. AD is causally associated with insulinstimulated hepatic VLDL overproduction, together with reduced reverse cholesterol transport by HDL, is little affected by statin monotherapy, and is on the rise worldwide in the aftermath of the global pandemics of obesity and MetS.7,9,26,39,51,52 At present, TLC reinforcement and/or dual LLD therapy are the usual options to improve target attainment, with either a fibrate or ezetimibe.7,18,19,30,33,36,37,43,53–57 Patients with T2DM benefit at least as much, and sometimes more, that nondiabetic patients, in achieving combined targets attainment with simvastatin-ezetimibe bitherapy versus statin alone for LDL-C, non-HDL-C, and apoB.30 This study has several limitations. First, the crosssectional design does not allow us to draw inferences regarding the directionality-causality of the observed associations. Second, neither were direct LDL-C nor LDL particles number/size measurements available, nor were data available on LpL activity or levels of LpL modulators, such as apoE, apoCI, apoCII, and apoCIII. Third, the present study emanates from a single-centre, academic setting from a mostly white Caucasian population. Finally, we did not investigate the various dynamic aspects of lipoprotein metabolism, including the postprandial state in attainers versus non-attainers. In conclusion, we found a high prevalence of nonachievement of key modifiable lipid and lipoprotein among very-high risk T2DM patients who nevertheless reached very-low on-statin LDL-C levels. This result represents a substantial component of residual risk, which remains

Journal of Clinical Lipidology, Vol 6, No 5, October 2012 addressable by more aggressive interventions. Underachievement was significantly associated with AD rather than use of different statins or greater baseline cholesterol and apoB levels. In practice, attainment of all three targets in patients with T2DM at greatest risk will require: (1) titration/permutation of statins, (2) TLC (re)inforcement; and/or (3) statin-fibrate bitherapy.

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