Department of Medicine - DIMED, MD, PhD, Professor
Elevated levels of blood lipids are one of the major risk factors for cardiovascular (CV) disease in patients with type 2 diabetes mellitus. Diabetic dyslipidaemia is characterised by the presence of potentially atherogenic lipids, including high levels of plasma triglycerides (TGs), mild-to-moderately elevated levels of low-density lipoprotein cholesterol (LDL-C), and low levels of high-density lipoprotein cholesterol (HDL-C). Statin therapy to reduce LDL-C levels is the mainstay of treatment practice to reduce CV risk. However, despite achieving targets for LDL-C, patients with diabetic dyslipidaemia remain at a high risk of residual CV events. Hence there is a need to target other components (i.e. elevated TGs) of the atherogenic dyslipidaemia that are not affected by treatment with statins. This review highlights the clinical benefits of using non-HDL-C, a single marker that includes all atherogenic lipoproteins, as a leading treatment target to reduce the residual CV risk.
Повышенный уровень липидов в крови является одним из основных факторов риска развития сердечно-сосудистых заболеваний (ССЗ) у пациентов с сахарным диабетом 2 типа (СД2). Дислипидемия на фоне СД характеризуется наличием потенциально атерогенных липидов, включая высокие уровни триглицеридов (ТГ) в плазме, умеренно повышенным уровнем холестерина липопротеинов низкой плотности (ХС ЛПНП) и низким уровнем холестерина липопротеинов высокой плотности (ХС ЛПВП). Терапия статинами, направленная на снижение уровня ХС ЛПНП, является основным методом лечения с целью снижения риска развития ССЗ, обусловленных атеросклерозом. Однако, несмотря на достижение целевых уровней ХС ЛПНП, у пациентов с дислипидемией на фоне СД сохраняется высокий риск развития остаточных нежелательных явлений, связанных с заболеваниями сердечно-сосудистой системы. Следовательно, существует необходимость обращать внимание на другие компоненты (например, повышенные уровни ТГ) атерогенной дислипидемии, на которые не влияет терапия статинами. В этом обзоре подчеркнуты клинические преимущества использования уровня ХС не-ЛПВП как единственного маркера, который включает все атерогенные липопротеины, в качестве основной цели терапии, направленной на снижение риска развития остаточных явлений, связанных с заболеваниями сердечно-сосудистой системы.
A major risk factor contributing to an increased risk of cardiovascular (CV) disease and CV mortality in patients with type 2 diabetes mellitus (T2DM) is dyslipidaemia [
The therapeutic choice for treating diabetic dyslipidaemia is primarily aimed at reducing the large burden of associated CV risk [
However, it is now known that even if the recommended LDL-C targets are met, a considerable residual CV risk remains [
Table 1: Residual CV risk in patients with and without diabetes treated with lipid-lowering agents
Study name, Reference | Treatment | Events | Event ratewithout diabetes (%) | Event ratewith diabetes (%) | ||
Statin | Placebo | Statin | Placebo | |||
HPS [5] | Simvastatin | CHD death, nonfatal MI, stroke, and revascularisation | 19.8 | 25.7 | 33.4 | 37.8 |
CARE [7] | Pravastatin | CHD death, nonfatal MI, CABG, and PTCA | 19.0 | 25.0 | 29.0 | 37.0 |
LIPID [14] | Pravastatin | CHD death and nonfatal MI | 12.0 | 15.0 | 19.0 | 23.0 |
PROSPER [15] | Pravastatin | CHD death, nonfatal MI, and stroke | 13.1 | 16.0 | 23.1 | 18.4 |
ASCOT-LLA [16] | Atorvastatin | CHD death and nonfatal MI | 4.9 | 8.7 | 9.6 | 11.4 |
IMPROVE-IT [17] | Statin + Ezetimibe | CV death, nonfatal MI, unstable angina requiring rehospitalisation, revascularisation, and stroke | 30.2 | 30.8 | 40.0 | 45.5 |
FOURIER [18] | Statin + Evolocumab | 11.4 | 13.0 | 14.4 | 17.1 |
Notes: ASCOT-LLA, Anglo-Scandinavian Cardiac Outcomes Trial—Lipid Lowering Arm; CABG, coronary-artery bypass grafting; CARE, The Cholesterol and Recurrent Events; CHD, coronary heart disease; CV, cardiovascular; FOURIER, Further Cardiovascular Outcomes Research with PCSK9 Inhibition in Subjects with Elevated Risk; HPS, Heart Protection Study; IMPROVE-IT, The Improved Reduction of Outcomes: Vytorin Efficacy International Trial; LIPID, The Long-term Intervention with Pravastatin in Ischaemic Disease; MI, myocardial infarction; PROSPER, Prospective Study of Pravastatin in the Elderly at Risk; PTCA, percutaneous transluminal coronary angioplasty
The IMPROVE-IT trial showed that ezetimibe added to simvastatin resulted in an incremental decrease in LDL-C levels and improved CV outcomes in patients with diabetes, compared with those on simvastatin alone. However, despite having LDL-C levels at 1.4 mmol/L, treatment with simvastatin plus ezetimibe revealed a CV event rate of 30% at 5 years [
The results from the ACCORD-Lipid study substantiated the effect of atherogenic dyslipidaemia on residual CV risk, where patients treated with simvastatin with controlled LDL-C levels had a >70% higher risk of CV events when the TG and HDL-C levels were not targeted [19, 20]. Genetic studies have also shown that elevated levels of TG-rich lipoproteins and remnant cholesterol (calculated as the difference of LDL-C plus HDL-C from total cholesterol [TC]) led to an increased risk of CV events and all-cause mortality. [21, 22] Hence, optimising secondary targets should be considered a top priority in patients at high CV risk despite achieving LDL-C targets [
Besides the simplicity of including all atherogenic lipoproteins into a single marker, the use of non-HDL-C is also more practical as it can be easily calculated (TC minus HDL-C) without the need for fasting samples and with no additional costs [
As aforementioned, the LDL-C component of non-HDL-C in high-risk patients can be treated with the highest tolerated dose of a statin or a statin plus ezetimibe (or a PCSK-9 inhibitor) combination [5, 17, 18]. The most commonly used therapies to target the remaining lipid components of the non-HDL-C focus mainly on TGs and include omega-3 fatty acids and fibrates [
Omega-3 fatty acids
Omega-3 fatty acids, such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), have been used to lower TG levels in patients with hypertriglyceridaemia. They act by reducing the production of hepatic VLDL and by increasing postprandial lipoprotein lipase levels [
A recent study, REDUCE-IT, evaluated if highly purified EPA reduces ischaemic events in statin-treated patients with hypertriglyceridemia (1.52 to 5.63 mmol/L) and high CV risk. This double-blind, randomised, placebo-controlled trial enrolled >8000 patients who were followed-up for a median of 4.9 years. A 25% reduction in CV death, nonfatal myocardial infarction (MI), stroke, revascularisation, or unstable angina was seen in patients treated with EPA (2 mg twice daily)-statin therapy compared with those on placebo-statin therapy (P<0.001). A similar benefit was seen in patients with and without diabetes who constituted approximately 58% of the enrolled patients in each treatment arm. A 19.7% greater median reduction in TG levels from baseline was seen in the EPA group compared with the placebo group (P<0.001) [
Fibrates
Fibrates are agonists of the peroxisome proliferator-activated receptor-α, which act via transcription factors to control lipid metabolism and arterial function. Fibrates are highly effective in reducing plasma TGs and moderately increasing HDL-C levels [
Two prospective RCTs, ACCORD and FIELD, studied the clinical effects of fenofibrate in patients with diabetes. In the ACCORD study, a subgroup of patients (n=5518) on statin therapy were randomised to receive either fenofibrate or placebo. Although the primary endpoint (composite of nonfatal MI, nonfatal stroke, or death from CV causes) was not met, the clinical benefit of adding fenofibrate to statin therapy was evident in a prespecified subgroup of patients with atherogenic dyslipidaemia (high TG [≥2.3 mmol/L] and low HDL-C [≤0.9 mmol/L] levels). A 31% risk reduction in CV events was demonstrated with the combination therapy compared with statin monotherapy in patients with atherogenic dyslipidaemia, who constituted 17% of the overall study population [
The AACE guidelines therefore recommend the use of fibrates or omega-3 fatty acids (2–4 mg per day) in patients with severe hypertriglyceridaemia (TG >500 mg/dL) and to further reduce CV outcomes in patients with TG concentrations ≥200 mg/dL and HDL-C <40 mg/dL, on a background of optimised statin therapy [
Statins are recommended as the first-line lipid-lowering therapy in combination with lifestyle modifications in patients with diabetes to reduce the risk of CV events. However, despite aggressive LDL-C lowering with statin therapy (±ezetimibe and PCSK9 inhibitors), a considerable residual CV risk remains specifically in patients with T2DM. Hence, there is a need for optimising secondary targets in patients who are at high CV risk despite achieving LDL-C goals. Non-HDL-C, a single marker that includes all atherogenic lipoproteins, has been recommended for use as a secondary target in high-risk individuals, as it provides a better measure of CV risk compared with LDL-C alone. Clinical benefits of using omega-3 fatty acids and fenofibrate in reducing the CV risk in patients with atherogenic dyslipidaemia has been well established. Therefore, the key to reducing CV risk in patients with diabetes is to use a comprehensive CV risk reduction approach of lifestyle optimisation, LDL-C management and treatment of all the atherogenic lipoproteins by targeting non-HDL-C (Figure 1).
Figure 1: Treatment considerations to reduce CV risk in patients with diabetes: CV, cardiovascular; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; PCSK-9, proprotein convertase subtilisin/kexin type 9; TG, triglycerides; TC, total cholesterol
Disclosures. AZ has received honoraria for lectures at national and international meeting from Amgen, Sanofi, Servier, Chiesi, Alfasigma, Abbott, Mylan, and Novartis.
Acknowledgements. The article is based on the presentation by the author at Diabetes Scientific School “T2D patients’ journey: holistic approach and quality of life” held in Moscow (11–12 April 2019). The author meets the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this manuscript, take responsibility for the integrity of the work as a whole, and has given final approval to the version to be published. The author acknowledges Nihal Ganesh Maremanda, PhD of Novartis Healthcare Private Limited, India for medical writing support which was funded by Novartis Pharma AG, Basel, Switzerland, in accordance with good publication practice (GPP3) guidelines (
© Endocrinology Research Centre, 2020
The authors declare that there are no conflicts of interest present.