Non-HDL cholesterol goal attainment and its relationship with triglyceride concentrations among diabetic subjects with cardiovascular disease: A nationwide survey of 2674 individuals in Hungary

doi:10.1016/j.atherosclerosis.2015.04.810

Atherosclerosis

Volume 241, Issue 1, July 2015, Pages 62-68

https://doi.org/10.1016/j.atherosclerosis.2015.04.810 Get rights and content

Highlights

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Nationwide population-based study involving 2674 patients with DM and CVD.
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LDL-C and Non-HDL-C goals attainment improved over time but remain suboptimal.
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Non-HDL-C goal attainment was inversely and continuously related to TG, unlike LDL-C.
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At higher TG, Non-HDL-C rising levels are related to TRL-C (but not HDL-C or LDL-C).
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TG, nonspecialist care and uncontrolled BP were inversely related to goal attainment.

Abstract

Aims

Non-HDL cholesterol represents the pro-atherogenic, apo-B-containing lipoprotein fraction of circulating lipids, and represents a secondary target for CVD prevention in people with diabetes. We therefore assessed the proportion of individuals with diabetes and CVD who attain a non-HDL-C goal of <2.6 mmol/L, the extent to which triglycerides influence this goal attainment, and their relationship with HDL-C and triglyceride-rich lipoproteins (TRL).

Methods and results

Of 2674 diabetic subjects with baseline CVD in the Hungarian MULTI-GAP programme (mean age 64.8 years, mean HbA1c 7.2%), an LDL-C goal <1.8 and non-HDL-C goal <2.6 mmol/L was attained in 13.5% and 17.7% individuals, respectively. Non-HDL-C goal attainment declined at higher triglyceride concentrations; and graphically this relationship appeared to be continuously and inversely associated with triglyceride concentrations. In contrast, the relationship between LDL-C goal attainment was inversely and continuously associated with triglyceride levels up to about 2.5 mmol/L, after which the graphical appearance plateaued such that no further difference in LDL-C were observed beyond triglyceride levels of 2.5 mmol/L. With increasing triglyceride concentrations, non-HDL-C increased continuously, HDL-C decreased initially but later plateaued (at 1.5-2.0 [men] or 2.0–2.5 mmol/L [women]), LDL-C levels plateaued at about 2.0–2.5 mmol/L, and TRL-cholesterol (non-HDL-C minus LDL-C) rose continuously. In multivariable-adjusted models, elevated triglyceride concentrations, non-specialist care and uncontrolled blood pressure were inversely associated with non-HDL-C goal attainment. Triglyceride levels were more strongly associated with non-HDL-C than with LDL-C goal attainment (ORs per 1-SD increase in log-triglycerides was 0.74, 95% CI 0.61–0.89, for LDL-C goal attainment, and 0.49, 95% CI 0.38–0.61, for non-HDL-C goal attainment).

Conclusion

Non-HDL-C goal attainment was suboptimal in people with diabetes and co-existing CVD. This was most marked at higher triglyceride levels, possibly due to higher levels of TRL.

Introduction

Diabetes mellitus is known to approximately double the risk of coronary heart disease (CHD), stroke, other vascular events, and overall mortality [1]. While cardiovascular (CV) mortality has declined in developed countries over the last decade for individuals both with and without diabetes [2], the comparable age- and sex-adjusted mortality still remains higher for people with diabetes, especially among those with co-existing cardiovascular disease (CVD) [2], [3]. As a result, most international guidelines now recommend stringent low-density lipoprotein cholesterol (LDL-C) targets in this high-risk population [3], [4], [5], even though treatment-to-targets remains controversial [6].

Furthermore, while the current ESC/EAS guidelines [4] and previous NCEP-ATP-III guidelines [7] recommend LDL-C as the principal target for informing clinical decision-making in those with diabetes, both these guidelines equally recognise the importance of other apo-B-containing atherogenic lipoproteins. Therefore, they recommend non-high-density lipoprotein cholesterol (non-HDL-C) as a secondary treatment target in people with high triglyceride (TG) concentrations [4], [7]. While previous studies evaluating reasons for deviation from guideline-based goal attainment of lipid levels focused either on the uptake rates of lipid-lowering therapy (LLT) or the attainment of LDL-C goals among high risk patients, it remains unclear what proportion of individuals with diabetes meet non-HDL-C goals and what factors determine the satisfactory attainment of these goals.

Hence, we set out to estimate the proportion of individuals with diabetes at very high CV risk [4], [5] who achieve the optional non-HDL-C goal of 2.6 mmol/L, using data from a subgroup of patients with diabetes and co-existing CVD in the Hungarian Multi-Goal Attainment Problem (MULTI-GAP) programme. Our secondary aim was to assess the extent to which TG concentrations influence non-HDL-C goal attainment and whether this is due to the inverse relationship with HDL-C or increased production of triglyceride-rich lipoprotein cholesterol (TRL-C).

Section snippets

Methods

Briefly, the MULTI-GAP programme (described elsewhere [8], [9], [10]) investigated trends in lipid goal attainment (and thereby gaps in guideline-based recommendations for LLT in clinical practice) in people with high CV risk. MULTI-GAP consisted of a series of surveys conducted annually since 2007 involving individuals at high CV risk, who were seen by general practitioners (GP) or specialists throughout Hungary using structured questionnaires that focused on the reporting of lipid levels and

Results

Participant characteristics have been reported in Table 1 and Supplementary Table S1. The average age of the participants was 64.8 years, 58% were male and roughly two thirds were treated by GPs or Internists. The median duration of diabetes was 61.8 months (IQR 26.2–120.0), and mean HbA_1c in the overall study population was 7.2%. Approximately half of the individuals had HbA_1c ≥ 7%, though the proportion of such individuals decreased from 2009 to 2011 (from 57.5% to 49.6%, p = 0.008). The

Discussion

Despite a significant improvement of about 7–9% in lipid goals attainment over the three year study period, our results from this large nationwide sample of very high-risk diabetic individuals with pre-existing CVD show an overall low attainment of lipid goals, with about four-fifths of participants not meeting their LDL-C or non-HDL-C targets, and only 13% of subjects meeting both targets in 2011. These findings are in general agreement with previous data from Hungary [8], [9], [12]. By

Conclusions

In a large contemporary sample of individuals with diabetes and co-existing CVD from Hungary, we found that attainment of recommended lipid goals was suboptimal, likely due to a combination of factors. The attainment of non-HDL-C goals correlated most strongly with TRL. Attempts to attain non-HDL-C goals may require additional treatments that target TG rich particles.

Conflicts of interest

L.M.: advisory boards and/or lectures fees from Hungarian branches of Abbott, Sandoz, Amgen and MSD. A.J.V.V.: none. I.R.: honoraria for advisory boards or lectures from Hungarian branches of Abbott, Amgen and MSD. G.P.: none. S.R.K.S.: consultancy fees from Amgen; unrestricted educational grant support (to group) from Kowa. K.K.R.: advisory boards and/or lecture fees from Pfizer, BMS, Astra Zeneca, MSD, Kowa, Abbott, Roche, Regeneron, Sanofi, Amgen, Aegerion, Lilly, Novartis, Novo Nordisk,

Funding

None.

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Cited by (22)

2019 ESC/EAS guidelines for the management of dyslipidaemias: Lipid modification to reduce cardiovascular risk
2019, Atherosclerosis
Non-HDL-C goals based on the distribution of population percentiles in ELSA-Brasil: Is it time to change?
2018, Atherosclerosis
Citation Excerpt :
We showed that the higher the TG levels were, more pronounced was the non-HDL-C based reclassification to a higher category. This could be explained because non-HDL-C concentrations increases steadily with TG levels, and from a certain level of TG, this increase is determined primarily due to an increase in TRL, and not due to higher LDL-C or lower HDL-C concentration [27]. The strategy of estimating the non-HDL-C reference values based on the distribution of population percentiles seems to be reproducible.
Non–high-density lipoprotein cholesterol (non-HDL-C) goals are defined as 30 mg/dL (0.78 mmol/L) higher than the respective low-density lipoprotein cholesterol (LDL-C) goals. This definition, however, do not consider the population distribution of non-HDL-C, which could represent a more appropriate individual goal when both markers are discordant. The aim of this study is to establish non-HDL-C goals at the same population percentiles of LDL-C.
Non-HDL-C values were assigned at the same percentiles correspondent to the LDL-C treatment goals for 14,837 participants from the Longitudinal Study of Adult Health (ELSA-Brasil) with triglycerides levels ≤ 400 mg/dL (4.52 mmol/L). We also assessed the frequency of reclassification, defined as the number of subjects with LDL-C levels in the recommended therapeutic category, but with non-HDL-C levels above or below the category.
The non-HDL-C values, based on correspondent LDL-C population percentiles, were 92 (2.38), 122 (3.16), 156 (4.04), 191 (4.95), and 223 mg/dL (5.78 mmol/L). Among participants with LDL-C <70 mg/dL (1.81 mmol/L), 22.8% were reclassified in a higher category according to the guidelines-based non-HDL-C cut-off and 30.1% according to the population percentile-based cut-off; 25.6% and 64.1%, respectively, if triglycerides concurrently 150–199 mg/dL (1.69–2.25 mmol/L).
Our results demonstrated that non-HDL-C percentiles-based goals were up to 8 mg/dL (0.21 mmol/L) lower than the guidelines recommended goal and had a profound impact on the reclassification of participants, notably when LDL-C was <100 mg/dL (2.56 mmol/L), the treatment goal for high risk patients. Therefore, non-HDL-C goals should be changed for reduction of residual risk.
Discovery of pentacyclic triterpene 3β-ester derivatives as a new class of cholesterol ester transfer protein inhibitors
2017, European Journal of Medicinal Chemistry
Citation Excerpt :
Torcetrapib, as the first CETP inhibitor tested in a long-term outcomes clinical trial, discontinued in 2006 due to the elevation of blood pressure and aldosterone levels [12]. In 2015 Evacetrapib's phase III trials was terminated because of the lack of sufficiently clinical efficacy for patients with ‘high-risk’ coronary disease [13]. However, the Dal-GenE randomized trial is currently being conducted in patients with a recent acute coronary syndrome to evaluate the effects of Dalcetrapib on cardiovascular risk in a genetically defined population [14].
A series of pentacyclic triterpene 3β-ester derivatives were designed, synthesized and evaluated as a new class of cholesteryl ester transfer protein (CETP) inhibitors for the treatment of dyslipidemia. In vitro screening assay showed that 5 out of 30 compounds displayed moderate inhibiting human CETP activity with IC₅₀s less than 10 μM. Among them, compound 20 (IC₅₀ = 2.3 μM) had the most potent biological activity, and effectively ameliorated plasma lipid levels of human adipose tissue specific CETP transgenic (ap2-CETPTg) mice and guinea pigs. Additional safety evaluation (no blood pressure elevation in guinea pigs) and pharmacokinetics studies indicated that the potential druggability for compound 20 which is a promising lead for development of a new class of CETP inhibitors for the treatment of dyslipidemia.
Effect of glycemic and lipid achievements on clinical outcomes type 2 diabetic, Chinese patients with stable coronary artery disease
2016, Journal of Diabetes and its Complications
Citation Excerpt :
More than half of the type 2 diabetic patients with stable CAD did not meet each HbA1C and lipid goals, and only 12.9% of the patients met dual-goals of HbA1C and LDL-C. These findings were in general agreement with previous studies (Mark et al., 2015; Shi et al., 2013). A nationwide survey in Hungary investigated the qualitatively trend of the achievement for LDL-C, NHDL-C and HbA1C from 2009 to 2011, they showed about four-fifths of diabetic patients with CAD not meeting their lipid goals, and half of the patients not meeting the HbA1C goals (Mark et al., 2015).
To describe the effect of glycemic and lipid achievements and their joint roles in future major adverse cardiovascular events (MACEs) prediction.
One thousand two hundred sixty consecutive, type 2 diabetic patients with stable coronary artery disease (CAD) were identified, they were followed up a median of 24.07 months.
At baseline, 85.4% of patients with blood pressure less than 140/90 mmHg, while only a minority of patients met guideline-recommended hemoglobin A1C (HbA1C) (44.2%), low-density lipoprotein cholesterol (LDL-C) (24.7%), non high-density lipoprotein cholesterol (NHDL-C) (36.3%), or apolipoprotein B (apoB) levels (38.6%). After follow-up, patients achieving either glycemic or lipid goals experienced a lower rate of future events (HbA1C 35.4%, LDL-C 19.3%, NHDL-C 30.4%, apoB 26.7%). Dual-goal achievements of HbA1C and lipids showed the lowest event risk (adjusted relative risk, RR: HbA1C, 0.92 vs. LDL-C 0.75 vs. dual 0.27; HbA1C, 0.86 vs. NHDL-C 0.59 vs. dual 0.44; HbA1C, 0.74 vs. apoB 0.64 vs. dual 0.55). Patients with suboptimal goals (LDL-C 1.8–2.5 mmol/L, NHDL-C 2.5–3.4 mmol/L, or apoB 0.8–1.0 g/L) were at risk when compared to those with guideline-recommended goals.
Dual-achievement of glycemic and lipid goals based on a relative well-controlled condition of blood pressure conferred a better prognosis in type 2 diabetic patients with CAD.
World Heart Federation Cholesterol Roadmap 2022
2022, Global Heart
Comparison of low-density lipoprotein cholesterol level calculated using the modified Martin/Hopkins estimation or the Friedewald formula with direct homogeneous assay measured low-density lipoprotein cholesterol
2022, Archives of Medical Science

View all citing articles on Scopus

¹: Joint first authors (these authors contributed equally to this work).

View full text

Non-HDL cholesterol goal attainment and its relationship with triglyceride concentrations among diabetic subjects with cardiovascular disease: A nationwide survey of 2674 individuals in Hungary

Highlights

Abstract

Aims

Methods and results

Conclusion

Introduction

Section snippets

Methods

Results

Discussion

Conclusions

Conflicts of interest

Funding

Pharmacol. Ther.

Lancet

Atherosclerosis

Clin. Ther.

J. Am. Coll. Cardiol.

J. Am. Coll. Cardiol.

Vasc. Pharmacol.

Diabetes mellitus, fasting glucose, and risk of cause-Specific Death

N. Engl. J. Med.

European Guidelines on cardiovascular disease prevention in clinical practice (version 2012)

Eur. Heart J.

ESC/EAS guidelines for the management of dyslipidaemias

Eur. Heart J.

ESC guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD

Eur. Heart J.

The ACC/AHA 2013 guideline on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular disease risk in adults: the good the bad and the uncertain: a comparison with ESC/EAS guidelines for the management of dyslipidaemias 2011

Eur. Heart J.