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© The European Society of Cardiology 2006. All rights reserved. For Permissions, please e-mail: journals.permissions@oxfordjournals.org

Diabetic dyslipidaemia: the triad

Anthony S. Wierzbicki

St Thomas’ Hospital, Lambeth Palace Road, London SE1 7EH, UK

Correspondnig author. Tel: +44 20 7188 1256; fax: +44 20 7928 4226. E-mail address: anthony.wierzbicki{at}kcl.ac.uk


   Abstract
Top
 Abstract
Acknowledgements
 References
 
The lipid changes of diabetes and the metabolic syndrome are characterized by a biochemical lipid triad of low HDL-cholesterol, raised triglycerides, and small, dense low-density lipoprotein (LDL) particles. This triad is caused by the processes changing the size of lipoprotein particles, which result in the presence of atherogenic small, dense LDL-C and also rapidly cleared small, dense HDL-cholesterol. Low HDL-cholesterol is a powerful cardiovascular risk factor that is common in patients with diabetes. Analysis of available evidence suggests that raising HDL-cholesterol by 1% reduces cardiovascular events by 2–3%. Statin trials have shown that the excess risk associated with low HDL-cholesterol is not abrogated by the statin therapy. Fibrates, which do not alter LDL-cholesterol, can reduce cardiovascular events as can nicotinic acid, which raises HDL-cholesterol, alters lipoprotein sizes, and also lowers LDL-cholesterol. Specific interventions targeted at raising HDL-cholesterol and changing the size of lipoprotein particles are likely to have additional beneficial effects over and above reducing LDL-cholesterol.

Key Words: Diabetes • Dyslipidaemia • HDL-cholesterol • Cardiovascular risk • Coronary heart disease

Diabetes is well known as a cardiovascular risk factor. Its importance was recognized in the Framingham study and subsequently confirmed in numerous other epidemiological studies. The Framingham and Münster studies, which included few patients with diabetes, showed that the ratio of total cholesterol:HDL-cholesterol is a strong determinant of cardiovascular risk and its significance increases with age.1–3 Risk is further increased by elevated triglycerides and in patients with diabetes.4,5 The InterHEART study shows that the apolipoprotein (apo) analogue of total cholesterol:HDL-cholesterol ratio (apo B:A-I ratio) is a 3.25-fold risk factor for coronary heart disease (CHD) and that diabetes increases CHD risk by 2.4-fold.6 These factors account for 49.2% and 9.9% of population-attributable risk for CHD, respectively.

Recently, following on a comparison in a Finnish study, patients with diabetes have been accepted as having equivalent CHD risk to normoglycaemic patients with CHD in the US and UK guidelines.7,8 This equivalence has not been confirmed in subsequent studies where patients with diabetes have been shown to have 70% of the risk of those with CHD.9 Thus, although not a CHD risk equivalent, patients with diabetes are at high risk for cardiovascular disease (CVD) events and deserve aggressive therapy, as CVD accounts for 70–80% of deaths in diabetes. CVD imposes a large burden of morbidity because of stroke, peripheral vascular disease, renal artery stenosis, and CHD, and data from the UK Progression of Diabetes Study (UKPDS) showed that although tight glycaemic and blood pressure control reduced CVD, significant excess CVD risk remained.10 Neither of these interventions had a significant effect on lipid profiles in these patients, and no specific lipid intervention was performed as part of the UKPDS protocol. However, analysis of the UKPDS showed that low-density lipoprotein (LDL)-cholesterol was the strongest risk factor for CHD in this population and HDL-cholesterol was the second strongest. It suggested that a 1% rise in HDL-C would reduce CHD risk by ~3%, i.e. that a 0.1 mmol/L increase in HDL-C would reduce CHD risk by 15%.10 Thus, for many years, the benefits of intervention on lipoproteins as cardiovascular risk factors in diabetes were uncertain. Recently, data from the Heart Protection Study11 and the Collaborative Atorvastatin Diabetes Study12 have confirmed the benefits of LDL-cholesterol reduction in diabetes. Statins are now acknowledged as first-line therapy for dyslipidaemia in diabetes.13

The incidence of type 2 diabetes is rising in parallel with that of the metabolic syndrome and obesity, and the lipid profiles seen in patients with metabolic syndrome or obesity are not always associated with high levels of LDL-cholesterol. Similarly, rates of type 1 diabetes are increasing. Both conditions are associated with an increased prevalence of cardiovascular risk factors. In type 2 diabetes, the atherogenic lipid changes commonly include the classical triad of low HDL-cholesterol, high triglycerides, and increased quantities of small, dense LDL particles (i.e. elevated levels of apolipoprotein B). In type 1 diabetes, lipid values appear superficially normal when glycaemic control is achieved, and the lipid triad is absent but all lipoproteins are glycated and thus handled differently by lipoprotein receptors, particularly of the scavenger group, and thus promote atherogenesis.

Type 2 diabetes and the metabolic syndrome are extremely common and the lipid triad is a feature of both conditions. Other features include hyper-apobetalipoproteinaemia, and an excess of triglyceride-rich remnants distinguished by the presence of apoC-III and a general shift of all lipoprotein particle types to a smaller and denser pattern.14–16 The presence of small, dense LDL particles, whose presence correlates with hypertriglyceridaemia, waist circumference, and plasma insulin levels, has been proven to be associated with an excess risk of CVD events in the Quebec Cardiovascular Study.17 This complicated dyslipidaemia arises as a consequence of changes in liver, adipose tissue, and muscle lipid metabolism. Many patients with diabetes have central obesity, which increases free fatty acid flux to the liver and consequently increases production of LDL particles containing apolipoprotein B. Insulin resistance results in a reduction in lipoprotein lipase activity, allowing more particles to remain triglyceride rich. This excess triglyceride is exchanged for cholesterol esters from HDL by the activity of cholesterol ester transfer protein (CETP).18,19 The resulting cholesterol-enriched apolipoprotein B particles are a suitable substrate for hepatic lipase, which generates small, dense LDL particles, which are poor ligands for the apoB/E(LDL) receptor. These particles have a longer plasma residence time and are thus more prone to oxidation and thus to promote atherosclerosis. Similarly, triglyceride-rich HDL is a substrate for hepatic lipase and the resulting small HDL particles are degraded rather than re-circulating like normal HDL. This imbalance in lipid transport results in an acceleration of atherosclerosis.

Studies of fibrates and nicotinic acid show consistent effects in increasing lipoprotein particle sizes. A few studies have addressed combination therapy with statins on lipoprotein size, and both fibrates and nicotinic acid have been shown to have additive effects to statins on particle size and number.20,21

Clinical studies have confirmed that intervention on the dyslipidaemia of the lipid triad without affecting LDL-cholesterol can reduce rates of CVD. There is evidence with the fibrate, gemfibrozil, that in patients with low LDL-cholesterol (3.0 mmol/L) and low HDL-cholesterol (0.9 mmol/L) recruited to the Veterans Administration HDL Intervention Trial reduced events by 22–30% with a number need to treat of 23.22,23 This benefit occurred in patients, one-third of whom were type 2 diabetic, despite relatively small changes in HDL-cholesterol (8%) and no change in LDL-cholesterol (0%). The principal effect of the fibrate was a 31% reduction in triglycerides actually reflecting large changes in particle sizes. In a subgroup of the primary prevention Helsinki Heart Study examining patients with mild obesity (BMI>26 kg/m2), low HDL-cholesterol (<1 mmol/L) and high triglycerides (>2.25 mmol/L) gemfibrozil reduced cardiovascular events by 78%.24

Nicotinic acid raises HDL-cholesterol more than fibrates and has similar effects on triglycerides and more effect on reducing LDL-cholesterol. There are less data on nicotinic acid, as the monotherapy endpoint trial of niacin, Coronary Drug Project (CDP), was conducted at a time when the significance of HDL-cholesterol and triglycerides had not been so clearly recognized. Nicotinic acid reduced coronary events by 20–25% at 6 and 15 years in CDP,25 but because of the lack of lipid subfraction data, it is impossible to ascribe the benefits of nicotinic acid to its relative effects on HDL as opposed to LDL-cholesterol. In addition, a post hoc re-analysis of the group of patients with glucose >7 mmol/L, i.e. those now classified as having diabetes by current criteria, showed an event reduction of 56%.26 A number of early small-scale studies raised concerns about hyperglycaemia induced by high-dose nicotinic acid.27 In the Arterial Disease Multiple Intervention Trial (ADMIT) of 173 patients with type 2 diabetes using up to 2500 mg of immediate release nicotinic acid, little effect was seen on plasma glucose in patients with or without diabetes.28 This finding has recently been re-investigated with the prolonged-release form of nicotinic acid (Niaspan). In the Assessment of Diabetes Control and Evaluation of the Efficacy of Niaspan Trial study of 146 patients with type 2 diabetes using Niaspan 1500 mg, a transient small effect was seen on blood glucose at 4 weeks, later evident in HbA1C levels at 16 weeks, but resolved on continuing treatment.29 Thus, the effects of nicotinic acid on blood glucose may have been overstated, be easily managed by adjustment of hypoglycaemic therapies, and may not apply as obviously to newer formulations.

The lipid changes in diabetes suggest that to successfully treat the process behind atherosclerosis in diabetes, intervention on both the LDL and HDL sides of the equation is required. The number of apolipoprotein B particles produced needs to be reduced and their clearance improved. Similarly, interventions are required to correct the size changes in the lipoproteins and by increasing the activity of lipoprotein lipase, reducing the activity of the CETP shuttle, and the excess activity of hepatic lipase. Correction of the size changes also results in additional improvement in the clearance patterns of apolipoprotein B and A-I, further lowering the levels of LDL-cholesterol meantime raising the levels of HDL-cholesterol. The effects of lipid-lowering drugs on LDL particle sizes have been investigated, and it has been shown that statins reduce the numbers of particles but have relatively little effect on their size. In contrast, fibrates or nicotinic acid increases particle size and reduces the proportion of small, dense LDL while having lesser effects on particle numbers. Thus, there is potential for additive action of these classes of drugs.

When the initial statin studies were performed, benefits were seen in the small subgroups with diabetes recruited to the Scandinavian Simvastatin Survival Study (4S), Cholesterol and Recurrent Events (CARE), and Long-term Intervention with Pravastatin in Ischemic Disease (LIPID) studies. Detailed analysis showed that the benefits of statin therapy related to baseline LDL-cholesterol in all groups. However, in an analysis of patients with low LDL-cholesterol recruited to CARE and LIPID, it was noticed that the effects of statins were independent of HDL-cholesterol and that statins did not reduce the excess risk associated with low HDL-cholesterol.30 The data from large-scale clinical trials of statins have recently been meta-analysed in the Cholesterol Treatment Triallists’ Collaboration and this supposition has been confirmed.31 Thus, a therapeutic gap exists in patients with diabetes in that their CVD risk associated with the lipid triad is not resolved with statin therapy alone. In addition, angiographic data suggest that progression of atherosclerosis measured by carotid intima-media thickness or on angiography is not halted, unless very high doses of statins are used. In patients with diabetes, even these doses may not be sufficient to induce cessation of progression. Both fibrates and nicotinic acid reduce progression of atherosclerosis either in monotherapy or in combination therapy in normoglycaemic patients32–34 and data from the Diabetes Atherosclerosis Intervention Study with fenofibrate monotherapy show a reduction in progression in diabetes.35 Few trials have assessed the effect of nicotinic acid added to baseline statin or other therapies in line with modern guidelines specifically in patients with diabetes, although data for beneficial effects exist in normoglycaemic populations.32,33,36,37

The dyslipidaemia of diabetes and the metabolic syndrome is associated with the reduced HDL-cholesterol, elevated triglycerides, and small, dense particles. Although statins reduce LDL-cholesterol and particle numbers and are very successful therapies for cardiovascular risk in diabetes, they do not affect the excess risk due to low HDL-cholesterol. The future of lipid-modulating therapy in diabetes is likely to include interventions to raise HDL-cholesterol and alter lipoprotein particle size as well as lower LDL-cholesterol. Nicotinic acid, which raises HDL-cholesterol more than a fibrate, changes particles sizes, reduces C-reactive protein, and can safely be added to statin therapy, which is thus a good potential agent for combination therapy in these patients.


   Acknowledgements
Top
 Abstract
 Acknowledgements
References
 
A.S.W. has received honoraria for lectures and advisory boards as well as travel and research grants from Astra-Zeneca, Bristol-Myers-Squibb, GlaxoSmithKline, Merck kGA, Merck, Sharp & Dohme, Novartis, Pfizer, Sanofi-Aventis, Schering-Plough, Solvay-Fournier and Takeda.

Conflict of interest: none declared.


   References
Top
 Abstract
 Acknowledgements
 References
 

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