Diabetic dyslipidaemia

Abstract

Diabetes mellitus (DM) is an escalating pandemic and an established cardiovascular risk factor. An important aspect of the interaction between DM and atherosclerotic cardiovascular disease (ASCVD) is diabetic dyslipidaemia, an atherogenic dyslipidaemia encompassing quantitative [hypertriglyceridaemia (hyperTG) and decreased high density lipoprotein cholesterol (HDL)] and qualitative [increased small dense low density lipoprotein cholesterol (sdLDL) particles, large very low density lipoprotein cholesterol (VLDL) subfraction (VLDL1) and dysfunctional HDL] modifications in lipoproteins. Much of the pathophysiology linking DM and dyslipidaemia has been elucidated. This paper aims to review the pathophysiology and management of diabetic dyslipidaemia with respect to ASCVD. Briefly, the influence of diabetic kidney disease on lipid profile and lipid changes causing type 2 diabetes mellitus are highlighted. Biomarkers of diabetic dyslipidaemia, including novel markers and clinical trials that have demonstrated that non-lipid and lipid lowering therapies can lower cardiovascular risk in diabetics are discussed. The stands of various international guidelines on lipid management in DM are emphasised. It is important to understand the underlying mechanisms of diabetic dyslipidaemia in order to develop new therapeutic strategies against dyslipidaemia and diabetes. The various international guidelines on lipid management can be used to tailor a holistic approach specific to each patient with diabetic dyslipidaemia.

Keywords: Biomarkers; Cardiovascular disease; Diabetic dyslipidaemia; Guidelines; Insulin resistance; Lipid-lowering therapy.

Fig. 1

Pathogenesis of atherogenic dyslipidaemia in diabetes mellitus. 1. Hypertriglyceridaemia (hyperTG), central to the lipid abnormalities that occur in diabetic dyslipidaemia, is due to both increased production and decreased clearance [22]. 2. Insulin resistance (IR) stimulates hormone-sensitive lipase (HSL)-mediated lipolysis, which releases free fatty acids (FFA) from adipose tissue, increasing hepatic triglyceride (TG) production [24]. 3. The contribution of (i) TRL (TG-rich lipoprotein) remnants [chylomicron (CM) and very low density lipoprotein cholesterol (VLDL) remnants] and (ii) hepatic de novo lipogenesis (DNL) to hepatic TG production is minimal [23]. 4. When hepatic TG is increased, degradation of apolipoprotein (Apo) B is reduced, and VLDL production is facilitated [23]. 5. IR stimulates hepatic microsomal TG transfer protein (MTP) activity and thereby enhances VLDL assembly [23]. 6. When TG > 1.5 mmol/L, large TG-rich VLDL particles (VLDL1) form [34]. 7. In IR, VLDL1 (rich in TG, ApoCIII and ApoE) is preferentially produced compared to VLDL2 (TG-poor) [25]. 8. Cholesteryl ester transfer protein (CETP) facilitates the replacement of cholesteryl ester (CE) in low density lipoprotein cholesterol (LDL) by TG from VLDL1 resulting in TG-rich LDL [35]. 9. Lipoplysis of TG- rich LDL is increased as it is the preferred substrate for hepatic lipase (HL) resulting in small dense LDL (sdLDL) formation [35]. 10. Prolonged circulation time of sdLDL results in several atherogenic modifications of sdLDL particles [oxidised LDL (oxLDL), desialylated LDL, electronegative LDL [LDL(-)] and glycated LDL (gLDL)] in plasma [40]. 11. CETP mediates the replacement of CE in high density lipoprotein (HDL) by TG from VLDL1 to form TG-rich HDL [15]. 12. Being a thermodynamically unstable particle, the catabolism of TG-rich HDL is accelerated by HL resulting in low HDL2 [15]. 13. IR stimulates intestinal MTP activity and thereby increases CM formation [6]. 14. IR diminishes lipoprotein lipase (LPL) activity located in the luminal surface of the capillary endothelium (skeletal and cardiac muscle, adipose tissue and lactating breast) and increases ApoCIII secretion resulting in decreased hydrolysis of CM and VLDL [6]. 15. CM (ApoB48) and VLDL (ApoB100) particles compete for clearance as both are cleared from the circulation by common pathways, further aggravating fasting and postprandial hyperTG [15].