(BQ) Part 2 book “Managing cardiovascular complications in diabetes” has contents: Dyslipidemia and its management in type 2 diabetes, thrombosis in diabetes and its clinical management, management of acute coronary syndrome, management of peripheral arterial disease,… and other contents.
CHAPTER Dyslipidemia and Its Management in Type Diabetes D John Betteridge University College London Hospital, London, UK Key Points • Dyslipidemia is an integral component of metabolic syndrome and type diabetes • Dyslipidemia involves both quantitative and qualitative lipid and lipoprotein abnormalities: moderate hypertriglyceridemia, low HDL-cholesterol, small dense LDL particles, and accumulation of cholesterol-rich remnant particles • Dyslipidemia is a major independent risk predictor for atherosclerosis-related disease • Increasing LDL-cholesterol concentrations and decreasing HDL-cholesterol concentrations were the strongest risk predictors for myocardial infarction observed in UKPDS • Patients with type diabetes are at high risk of CVD events and the majority will fulfill criteria for pharmacotherapy to lower LDL-cholesterol • Statins are the cornerstone of therapy and their use is based on a wealth of data from well-conducted robust RCT • Some patients are statin intolerant and other drug classes such as ezetimibe, fibrates, nicotinic acid, and colesevalam may be required • New LDL-cholesterol-lowering strategies are in development that should ensure, if proved to be effective and safe, that more patients achieve LDL-cholesterol goals • Low HDL-cholesterol remains a significant risk predictor even when low LDL-cholesterol levels are achieved in the statin trials • To date no evidence is available from RCT to support measures to increase HDLcholesterol to lower CVD events • Intensive management of dyslipidemia should be part of a global approach to CVD risk reduction in the diabetic population Introduction Atherosclerosis-related disease, coronary heart disease (CHD), peripheral vascular disease (PVD), and thrombotic stroke are major complications in Managing Cardiovascular Complications in Diabetes, First Edition Edited by D John Betteridge and Stephen Nicholls © 2014 John Wiley & Sons, Ltd Published 2014 by John Wiley & Sons, Ltd 165 166 Managing Cardiovascular Complications in Diabetes people with type diabetes mellitus [1] A recent meta-analysis of 102 prospective studies demonstrated a hazard ratio of for coronary death and non-fatal myocardial infarction (MI) and 2.5 for ischemic stroke [2] In the United Kingdom Prospective Diabetes Study (UKPDS), for each 1% increase in HbA1c there was a 28% inc rease in PVD [3] The main focus for CVD risk management relates to patients with type diabetes, but the increased lifetime risk for those with type diabetes should be remembered when considering lipid lowering, particularly those with albuminuria, hypertension, and chronic kidney disease [4] The pathogenesis of atherosclerosis in diabetes is multifactorial and the task for the physician is to manage all modifiable risk factors to prevent CVD events However, it is clear from prospective studies that plasma cholesterol and low-density lipoprotein (LDL)-cholesterol in particular are major independent risk factors In the United Kingdom Prospective Diabetes Study (UKPDS) of newly presenting patients with type diabetes, LDL-cholesterol was the strongest predictor of MI The second strongest predictor of MI was low levels of high-density lipoprotein (HDL)-cholesterol ahead of glycated hemoglobin, systolic blood pressure, and cigarette smoking [5] Diabetic Dyslipidemia The dyslipidemia of metabolic syndrome, insulin resistance, and type diabetes consists of both quantitative and qualitative lipid and lipoprotein abnormalities [6] Moderate hypertriglyceridemia is accompanied by low levels of HDL-cholesterol and an increase in cholesterol-rich remnant particles of chylomicrons and very low-density lipoprotein (VLDL) metabolism LDL-cholesterol concentrations reflect those of the background population However, important qualitative changes are present in the LDL particle distribution, with the accumulation of smaller, denser particles that are thought to be more atherogenic [7] This complex phenotype is present at the time of diabetes diagnosis as it is part of the metabolic syndrome and prediabetes In an individual patient it will be influenced by gender and lifestyle factors, particularly central obesity, the degree of physical activity, poor glycemic control, cigarette smoking, and alcohol intake In addition, other secondary causes including renal and hepatic dysfunction, hypothyroidism, and concurrent medication may have a significant effect Concurrent primary dyslipidemias such as familial hypercholesterolemia, familial combined hyperlipidemia, and type III dyslipidemia should be identified and managed appropriately Although understanding of the impact of insulin resistance on lipid and lipoprotein metabolism has increased enormously, much remains to be Dyslipidemia and Its Management in Type Diabetes 167 learned A basic abnormality is the overproduction of large VLDL from the liver, partly as a result of an increased flux of fatty acids from adipose tissue combined with lack of inhibition of VLDL assembly [8] In the postprandial state, hepatic VLDL production is not suppressed and this, together with exogenous fat absorbed in the form of chylomicrons, saturates activity of the enzyme lipoprotein lipase (LPL) LPL activity itself can also be reduced by increased levels of apoprotein C-III, apoprotein A-V, excess levels of fatty acids, low adiponectin levels, and insulin resistance Prolongation of the postprandial phase of lipid metabolism is associated with increased cholesterol and triglyceride exchange through the activity of cholesterol ester transport protein (CETP) CETP facilitates a mole-for-mole transfer of cholesterol esters from HDL to VLDL, IDL and chylomicron remnants, and LDL in exchange for triglycerides As a result, LDL and HDL are triglyceride enriched and become substrates for the enzyme hepatic lipase, the activity of which is increased in diabetes As a result of the triglyceride hydrolysis by this enzyme, LDL and HDL become smaller and denser Smaller, denser HDL particles are cleared more rapidly, contributing to the low plasma levels observed [7, 9] Dyslipidemia and CVD Risk It is those patients with diabetes and concomitant metabolic syndrome including dyslipidemia that are at highest risk In the National Health and Nutrition Examination (NHANES III) performed in the USA, the prevalence of metabolic syndrome in diabetes was 86% The prevalence of CHD in this group was 19.2% In those with diabetes and no evidence of metabolic syndrome, CHD prevalence was 7.5%, which is comparable to those without diabetes or metabolic syndrome [10] Many studies in different populations have confirmed that dyslipidemia is a common finding in type diabetes The prevalence of low HDL-cholesterol (