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............................................................................................................................................................................. the clearance of both TRLs and remnants, resulting in prolonged residence times of these particles in the circulation.413,414 In fact, the defective catabolism of TRLs seems to be a more important contributor to the elevation of plasma TGs than the increased production rate leading to an excess of remnant particles. Together, TRL remnants, small dense LDL, and small dense HDL comprise the atherogenic lipid profile, which is also characterized by an increase in ApoB concentration due to an increased number of ApoB-containing particles. Importantly, TRLs—including chylomicrons, VLDL, and their remnants—carry a single ApoB molecule, also like LDL particles. Therefore, the malignant nature of diabetic dyslipidaemia is not always revealed by the lipid measures used in clinical practice, as LDL-C levels may remain within the normal range. It may be better revealed by non-HDL-C levels.415

Elevation of TGs or low HDL-C levels in the fasting or post-prandial state is seen in about one-half of all people with T2DM,416,417 and is also often present in people with abdominal adiposity, insulin resistance or impaired glucose tolerance.413

Box 7 summarizes dyslipidaemia in MetS and T2DM.

9.4.2 Evidence for lipid-lowering therapy 9.4.2.1 Low-density lipoprotein cholesterol. LDL-C is the primary target of lipid-lowering therapy in patients with DM. Trials specifically performed in people with T2DM, as well as subsets of individuals with DM in major statin trials, have consistently demonstrated significant benefits of statin therapy on CVD events in people with T2DM.418 Statin therapy reduces the 5 year incidence of major CVD events by 23% per 1 mmol/L reduction in LDL-C, regardless of the initial LDL- C level or other baseline characteristics based on meta-analysis.418 The CTT meta-analysis further indicates that people with T2DM will have a relative risk reduction that is comparable to that seen in nondiabetic patients; however, being at higher absolute risk, the absolute benefit will be greater, resulting in a lower number needed to treat (NNT). Thus, statin therapy is the first-line treatment for LDL-C lowering and for the reduction of CVD burden.419 Ezetimibe lowers LDL-C by 24% and, when added to statin therapy, decreases the risk of major vascular events.33 The relative risk reduction in major vascular events is proportional to the absolute degree of LDL-C lowering and consistent with the relationship seen for statins. The subset of patients with DM in IMPROVE-IT had, as expected, a higher rate of major vascular events than patients without DM (46 vs. 31% 7 year KaplanMeier rate in the placebo arm). Ezetimibe appeared particularly efficacious in patients with DM, with a relative risk reduction of 15% (95% CI 622%) and an absolute risk reduction of 5.5%.299

The mAb PCSK9 inhibitors evolocumab and alirocumab lower LDL-C levels by 60% and, when added to statin therapy, decrease the risk of major vascular events.119 In the FOURIER study, the relative risk reduction for major vascular events was similar in patients with and without DM; however, given the higher baseline risk in patients with DM, the absolute risk reductions tended to be greater in patients with DM (2.7% absolute decrease in major vascular events over 3 years).297 Of note, the achieved LDL-C in the evolocumab arm was 0.8 mmol/L. The same benefits were also recently demonstrated for diabetic patients after ACS in the ODYSSEY trial.420 Recent studies have suggested an increased incidence of DM in patients treated with statins.247 These observations have been seen in Mendelian randomization studies and in clinical trials, although the effect appears greatest in patients already at high risk for DM (e.g. those with pre-diabetes). These observations should not lessen our attention to the treatment of patients, as the overall benefits in CV event reduction remain and greatly outweigh the increased incidence of DM. In RCTs, neither ezetimibe nor the PCSK9 inhibitors have been reported to increase the risk of DM.297

9.4.2.2 Triglycerides and high-density lipoprotein cholesterol. Lifestyle modification provides the first option to improve atherogenic dyslipidaemia due to its multifaceted effects. Weight loss is, in most cases, the most effective measure since it is associated with very pronounced effects on plasma TG and HDL levels, together with a modest decrease in TC and LDL-C levels. Moderate-to-heavy aerobic exercise is also associated with improvement of the plasma lipid profile by reducing TG levels and increasing HDL-C concentrations. In relation to diet composition, besides the need to eliminate trans fat, the available evidence supports the reduction of saturated fat intake and its substitution with unsaturated fat, as well as the replacement of a major proportion of refined starchy foods and simple sugars with fibre-rich foods like fruits, vegetables, and wholegrains.179 The clinical benefits achieved by the treatment of high TG and low HDL-C levels (frequently seen with DM) are still a matter of debate, as the effects of fenofibrate therapy on the major outcome (MACE) remained negative in both the FIELD and the ACCORD studies performed in T2DM cohorts.306,307 In a post hoc analysis of the FIELD study, fenofibrate reduced CVD events by 27% in those with elevated TGs [2.3 mmol/L (200 mg/dL)] and increased HDL-C levels (NNT = 23).416 The ACCORD trial confirmed the following: patients who had both TG levels in the higher third [2.3 mmol/L (200 mg/dL)] and an HDL-C level in the lower third [<_0.4 mmol/L (<_34 mg/dL)], representing 17% of all participants, appeared to benefit from the addition of fenofibrate to simvastatin.306 Recently, post-trial follow-up of the ACCORD lipid trial participants reported the beneficial effect of fenofibrate in people with

Box 7 Summary of dyslipidaemia in metabolic syndrome and type 2 diabetes mellitus

Dyslipidaemia represents a cluster of lipid and lipoprotein abnormalities, including elevation of both fasting and post-prandial TG, ApoB, and small dense LDL, and low HDL-C and ApoA1 levels. Non-HDL-C or ApoB are good markers of TRLs and remnants, and are a secondary objective of therapy. Non-HDL-C <2.6 mmol/L (<100 mg/dL) and ApoB <80 mg/dL are desirable in those at high-risk, and non-HDL-C <2.2 mmol/L (<85 mg/dL) and ApoB <65 mg/dL in those at very highrisk. For those at very high-risk with recurrent ASCVD events, a goal of non-HDL-C <1.8 mmol/L (<70 mg/dL) and ApoB <55 mg/dL may be considered. Atherogenic dyslipidaemia is one of the major risk factors for CVD in people with type 2 diabetes, and in people with abdominal obesity and insulin resistance or impaired glucose tolerance. Apo = apolipoprotein; ASCVD = atherosclerotic cardiovascular disease; CVD = cardiovascular disease; HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol; TG = triglyceride; TRLs = triglyceride-rich lipoproteins. Downloaded from academic.oup.com/eurheartj/article/41/1/111/5556353 by guest on 07 October 2026