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The European Society of Cardiology

Treating dyslipidaemia in the patient with type 2 diabetes

D.J. Betteridge*

Department of Medicine, University College London Medical School, The Middlesex Hospital, London, UK

* Correspondence: Prof. D.J. Betteridge, Department of Medicine, University College London Medical School, The Middlesex Hospital, Mortimer Street, London W1N 8AA, UK. Tel.: +44-207-679-9444; fax: +44-207-679-9440
j.betteridge{at}ucl.ac.uk

Abstract

Cardiovascular disease (CVD) is a major cause of morbidity and mortality in patients with type 2 diabetes. Individuals with diabetes are at a much greater risk of developing CVD than those without diabetes, and have a much poorer outcome. For any given concentration of plasma cholesterol, the risk of CVD is approximately three times higher in subjects with diabetes, compared with those without the disease. The mechanisms underlying this increase in risk not only involve hyperglycaemia but also other major risk factors, such as dyslipidaemia and hypertension, which are potentially modifiable. The involvement of multiple risk factors in diabetes underlines the fact that it is a vascular disease, requiring total risk factor management. Diabetic dyslipidaemia is characterized by hypertriglyceridaemia, the accumulation of cholesterol-rich remnant particles, small dense low-density lipoprotein (LDL) and low high-density lipoprotein (HDL). Clinical trials have provided unequivocal evidence of the importance of lipid-lowering therapy in the secondary prevention of CVD in patients with diabetes. Lipid-lowering therapy is also beneficial in the primary prevention setting. Further information will become available from ongoing prospective studies in specific lower-risk diabetic populations.

Key Words: Diabetic dyslipidaemia • Hypertriglyceridaemia • Lipid-lowering therapy • Low-density lipoprotein • Type 2 diabetes

Introduction

In his preface to the recent International Diabetes Federation (IDF) publication Diabetes and Cardiovascular Disease: Time to Act,1 entitled `A Time Bomb', the President of the IDF, Sir George Alberti, points to the double jeopardy of diabetes and cardiovascular disease (CVD): `The IDF considers CVD to be one of the most serious problems facing people with diabetes.'

A current estimate puts the number of people in the world with diabetes at 150 million – a figure expected to double in the next 25 years.2 People with diabetes are 2–4 times more likely to develop CVD than the general population, making it the most common diabetic complication.3 The overall decline in coronary heart disease (CHD) mortality rates in developed countries is significantly less apparent in the diabetic population, with even a possible increase in women.4 People with diabetes have approximately the same CHD risk as people without diabetes who have already had a heart attack.5 In a population-based study in Finland, the 7-year incidence of fatal and nonfatal myocardial infarction (MI) among 1373 non-diabetic subjects was compared with the incidence among 1059 diabetic subjects.5 The 7-year incidence rates of MI in subjects without diabetes, with and without prior MI at baseline, were 18.8% and 3.5%, respectively ().5 The 7-year incidence rates of MI in subjects with diabetes, with and without prior MI, were 45.0% and 20.2%, respectively ().5 These data suggest that diabetic patients without previous MI have as high a risk of MI as non-diabetic patients with previous MI. Diabetic patients with acute MI also have a higher case fatality.6 The outcome of patients with diabetes following a revascularization procedure is worse than for patients without diabetes, and diabetes remains an independent risk predictor in patients with heart failure.

Diabetes is a major risk factor for disease outside the coronary vasculature. Stroke (2-fold increase) and transient ischaemic attack (2- to 6-fold increase) are more common in people with diabetes.1 Lower limb amputation is dramatically increased, its incidence in the diabetic population being 15- to 40-fold higher than in the general population.1 Therefore, it behoves physicians and scientists to discover and understand the factors in patients with diabetes that are responsible for their increased risk of atherosclerosis, in order to determine the best methods of intervention.

Diabetes, atherosclerosis and total risk factor management

Professor Bierman outlined putative mechanisms for increased atherosclerosis in the patient with type 2 diabetes in his 1992 George Lyman Duff Memorial Lecture, entitled `Atherogenesis in diabetes'.7 These included not only hyperglycaemia but other risk factors that also cluster in diabetic individuals, such as dyslipidaemia, hypertension, hyperinsulinaemia/insulin resistance, haemostatic abnormalities, advanced glycosylation end-product (AGE) proteins and oxidative stress.7

It is known that hyperglycaemia is a risk factor for microvascular disease, affecting the kidney, the eye and the nerves; in addition, high glucose levels impair beta-cell function and affect insulin sensitivity in the tissues. However, it has also been shown that hyperglycaemia is a CVD risk factor.3

In the United Kingdom Prospective Diabetes Study (UKPDS), more intensive glucose lowering was compared with conventional therapy for the treatment of newly-diagnosed patients with type 2 diabetes over a period of 10 years.8 After this time, haemoglobin A1c was 7.0% (6.2–8.2) in the intensively treated group, compared with 7.9% (6.9–8.8) in the conventionally treated group; intensive therapy resulted in a significant () reduction in diabetes-related events (combined microvascular and macrovascular), compared with conventional therapy.8 However, the significance of this reduction was mainly due to the reduction in microvascular events (): the reduction in MI was only of borderline significance (), the reduction in stroke was insignificant (), and there was no impact on peripheral vascular disease (; Table 1).8 These data indicate that, in order to affect macrovascular disease in the diabetic patient, it is necessary to look beyond glycaemic control. Diabetes is a vascular disease, and hyperglycaemia is just one risk factor among many CVD risk factors. Microvascular complications benefit more substantially than macrovascular complications from a given reduction in glucose. A greater benefit in reducing CVD risk should be achieved by the appropriate management of other risk factors.


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  		Table 1 United Kingdom Prospective Diabetes Study (UKPDS): end-points by glucose treatment group

 
In the 12-year follow-up of approximately 348,000 men who were screened to participate in the Multiple Risk Factor Intervention Trial (MRFIT), 5163 were taking medication for diabetes.9 Data from this follow-up indicated that, across the range of cholesterol levels measured, the risk of cardiovascular mortality was three times greater for diabetic than non-diabetic individuals, and there was a similar trend for cigarette smoking, hypertension and also when the three risk factors were combined (Fig. 1).9 It is therefore clear that a reduction in CVD among diabetic patients will require aggressive and early modification of the major CVD risk factors.



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  		Fig. 1 Diabetes, other risk factors and 12-year cardiovascular mortality for men screened in the Multiple Risk Factor Intervention Trial (MRFIT). Copyright © 1993 American Diabetes Association. From Diabetes Care, Vol. 16; 1993:434–444. Reprinted with permission from The American Diabetes Association.9

 
Diabetes and dyslipidaemia

Dyslipidaemia is common in the diabetic population and is a major risk factor for CHD that is open to therapeutic intervention.10,11 It is present on diagnosis of type 2 diabetes and largely persists despite treatment of hyperglycaemia. It is an integral feature of the insulin-resistance syndrome and correlates strongly with parameters of insulin resistance.

Since studies such as MRFIT have shown that diabetic patients are at a much higher risk of CVD than non-diabetic individuals,9 one might expect low-density lipoprotein (LDL)-cholesterol levels to be elevated in the former, compared with the latter. However, plasma LDL-cholesterol levels are similar in diabetic and non-diabetic individuals. Diabetic dyslipidaemia is, however, characterized by moderately elevated levels of triglycerides (TG), and frequently associated with low levels of high-density lipoprotein (HDL)-cholesterol. This lipid profile was observed in baseline data from the PROspective CArdiovascular Münster (PROCAM) study.12 In this study, LDL-cholesterol levels were similar in the diabetic and non-diabetic patient populations, but TG levels were significantly higher (), and HDL-cholesterol levels significantly lower () in diabetic, compared with non-diabetic, individuals (Fig. 2).12



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  		Fig. 2 Diabetic dyslipidaemia and the PROspective CArdiovascular Münster (PROCAM) study. Assmann G, Schulte H. Identification of individuals at high risk for myocardial infarction. Atherosclerosis 1994; 110:S11–S21. Printed with permission from Elsevier.12

 
LDL atherogenicity
Although diabetic dyslipidaemia is not associated with a quantitative alteration in LDL-cholesterol levels, LDL in type 2 diabetes shows important qualitative changes that increase its atherogenicity. Firstly, the rate of glycation of apolipoprotein (apo) B is increased in diabetic individuals.13 As a result of glycation, LDL is a less efficient ligand for its receptor. This delays LDL clearance from plasma, thereby increasing the likelihood of uptake by macrophages. Cholesterol ester accumulates within macrophages, resulting in the formation of foam cells. Secondly, glycated LDL particles show an increased susceptibility to oxidation, a process that plays a key role in the development and progression of the atherosclerotic plaque. Thirdly, a predominance of smaller, denser LDL particles is an integral feature of diabetic dyslipidaemia. Gel electrophoresis demonstrates two LDL phenotypic patterns, termed A and B.14 Pattern A is comprised predominately of large LDL particles, whereas in pattern B there are more small, dense LDL particles. These small particles are more susceptible to oxidation than the larger particles and are, therefore, potentially more atherogenic. On ultracentrifugation, LDL subdivides into three main subfractions, according to density, which are labelled I, II and III.15 In healthy subjects, LDL-II predominates, whereas LDL-III predominates in the pattern B LDL phenotype. The pattern B phenotype is also associated with moderately elevated levels of plasma TG and low levels of HDL-cholesterol, a combination that has been termed the atherogenic lipoprotein phenotype.16 Patients with type 2 diabetes have this atherogenic lipoprotein phenotype.16 In addition to this, diabetes is associated with increased oxidative stress, as measured by a variety of techniques, including increased concentrations of hydroperoxides.17,18 These abnormalities demonstrate the importance of LDL as a risk factor for CHD in type 2 diabetes, and highlight the need to lower LDL-cholesterol.

Hypertriglyceridaemia
The independent relationship between increasing plasma TG levels and vascular risk has been controversial.19–21 Although a meta-analysis has indicated that the level of TG is an independent CHD risk factor,22 and within diabetic populations their relationship to CHD risk appears stronger than in the non-diabetic population, it is unlikely that epidemiological studies will provide further insight. More is likely to be gained from elucidation of the pathological consequences of hypertriglyceridaemia on lipoprotein metabolism and atherosclerosis. The fasting TG level is a major determinant of the distribution of LDL particles, and approximately 70% of the variability in LDL density is accounted for by plasma TG and HDL-cholesterol levels.23 The proportion of small, dense particles in LDL increases as the level of fasting TG increases, particularly when the TG level is 200 mgdl–1 (2.3 mmoll–1).24 Hypertriglyceridaemia is associated with increased postprandial lipaemia and accumulation of atherogenic remnant particles, and with low HDL-cholesterol concentrations.11,25 In addition, coagulation abnormalities, such as elevation in the level of plasminogen activator inhibitor-1, have a positive correlation with plasma TG.24

Insulin/lipoprotein interactions
Insulin influences several key stages in the metabolism of lipid and lipoprotein. The parameters of diabetic dyslipidaemia show a strong correlation with both insulin resistance and insulin precursor molecules. Therefore, a current hypothesis to explain the pathophysiology of diabetic dyslipidaemia is as follows: in the presence of insulin resistance and hyperinsulinaemia, hepatic very low-density lipoprotein (VLDL) output, particularly large VLDL, is increased. In the postprandial state, hepatic output continues and competes for the hydrolytic activity of lipoprotein lipase with exogenously derived lipid on chylomicrons. Postprandial lipaemia is prolonged, with increased accumulation of remnants. Increased lipid exchange via cholesterol ester transfer protein leads to triglyceride enrichment of LDL and HDL. These particles are substrates for hepatic lipase, which leads to lipid depletion and small dense LDL and HDL. Small dense HDL is catabolized more rapidly, leading to low HDL-cholesterol concentrations.

Lipid lowering and diabetes

Subgroup analyses of secondary prevention trials have demonstrated that diabetic patients benefit from statin therapy to a similar extent as non-diabetic patients.26–28 Indeed, given the higher risk of diabetic patients, the absolute benefit is greater. Less consistent information is available for fibrate therapy. In the Veterans Administration HDL Intervention Trial (VA-HIT) there was a reduction in CHD events with gemfibrozil, and this benefit was also seen in diabetic patients.29 However, in the Bezafibrate Infarction Prevention study no overall benefit was observed with bezafibrate.30

For primary prevention there are little data available from clinical trials. In the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS), a reduction in cardiovascular end-points was demonstrated in the diabetic population, but the number of diabetic subjects was very small, as was the number of events.31 In the GREek Atorvastatin Coronary heart disease Evaluation (GREACE) study, atorvastatin dosage (10–80 mg/day) was titrated to achieve the National Cholesterol Education Program (NCEP) goal for LDL-cholesterol (100 mgdl–1; 2.6 mmoll–1) in an intervention group of CHD patients (), compared with usual care ().32 In the intervention group, the risk ratio for major coronary events was 0.49 (). In a diabetic subgroup (), the risk ratio was 0.42 compared with usual care ().32 In the MRC/BHF Heart Protection Study, 20,536 adults (aged 40–80 years) with coronary disease, other occlusive arterial disease or diabetes were randomized to receive 40 mg simvastatin daily or placebo over a 5-year period, to assess the effects of cholesterol lowering on total mortality and cause-specific mortality in a wide range of patients at high risk of CHD.33 The diabetic cohort consisted of 5963 patients (615 with type 1 diabetes and 5348 with type 2 diabetes), 2913 of whom had no history of vascular disease. On subgroup analysis, the benefits of statin therapy in the diabetic cohort were shown to be similar to those of the population as a whole.

Therefore, the use of statins in the secondary prevention of CVD in patients with diabetes is clear cut: aggressive lipid management is required. Although data from the Heart Protection Study (HPS) is encouraging, further clinical trials are needed to elucidate the role of statin therapy in the primary prevention of CVD in patients with diabetes. In the words of Armitage and Collins:34 `Really reliable evidence about the effects of cholesterol lowering on cause-specific mortality and morbidity in people with diabetes is only likely to emerge from prospectively-planned cholesterol treatment trialists' collaborative meta-analysis of the results of all relevant trials.'

Treatment guidelines
National and international guidelines on overall diabetic management and the prevention of CVD include important targets for lipid management. The guidelines of the American Diabetes Association (ADA)35 and the third Adult Treatment Panel (ATP III) of NCEP36 specify LDL-cholesterol as the primary target for lipid management, with a therapeutic goal 100 mgdl– 1 (2.6 mmoll– 1). Statins are regarded as first-line therapy. In the presence of hypertriglyceridaemia (>=200 mgdl–1 [2.3 mmoll–1]), ATP III recommends a secondary goal for non-HDL-cholesterol of 130 mgdl–1 (3.4 mmoll–1), recognizing the atherogenic potential of remnant lipoproteins. Low HDL-cholesterol (40 mgdl–1 [1.0 mmoll–1]) is recognized as a strong independent predictor of CHD, although ATP III does not specify a goal of therapy for HDL-cholesterol, since evidence from clinical trials of the benefit of increasing HDL-cholesterol is considered insufficient. In patients with low HDL-cholesterol, the primary target for lipid management is LDL-cholesterol. When LDL-cholesterol is to goal, the secondary target is non-HDL-cholesterol when hypertriglyceridaemia is present. The joint European guidelines have a less stringent goal of therapy for LDL-cholesterol of 115 mgdl–1 [3.0 mmoll–1].37

For primary prevention, ATP III has advocated that diabetes should be regarded as a CHD risk equivalent (i.e., diabetic patients should be treated as if they already have CHD). This recommendation is based on studies showing that patients with diabetes, but without previous MI, have an equal risk of MI as non-diabetic patients who have had a previous MI.5 This has major implications in terms of compliance with multiple drug therapy and economic considerations. However, in the author's opinion, this is likely to represent a major clinical advance in CHD prevention.

In Europe, clinicians are likely to continue using risk charts, usually based on the Framingham model, to calculate individual CHD risk.37 Many diabetic patients will fulfil the absolute risk requirements (20% in 10 years) to justify statin therapy for primary prevention. However, the recently-published results of a cross-sectional and a cohort study, carried out in Tayside, Scotland, in a population of over 263,000 patients, demonstrated that patients with type 2 diabetes were at a lower risk of cardiovascular outcome than patients with established CHD.38 In the cross-sectional study, the adjusted risk ratio for death from all causes was 2.27 (95% confidence interval [CI] 1.82–2.83) for patients who had had an MI, compared with those with diabetes, and the risk ratio for hospital admission for MI was 1.33 (1.14–1.55).38 In the cohort study, patients who had just had an MI had a higher risk of death from all causes (adjusted risk ratio: 1.35; 95% CI 1.25–1.44), cardiovascular death (2.93; 2.54–3.41), and hospital admission for MI (3.10; 2.57–3.73; Fig. 3).38 European guidelines are, therefore, unlikely to adopt the American view of diabetes as a CHD risk equivalent until this issue is clarified when primary prevention trials in diabetic populations have been reported.



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  		Fig. 3 Death from any cause: patients with newly-diagnosed type 2 diabetes versus patients with previous MI. Scottish cohort. Printed with permission from the BMJ Publishing Group 2002; 324:939–42.38

 
Trials in progress
Two ongoing large-scale trials with atorvastatin have been designed to determine the efficacy of lipid-lowering therapy for the primary prevention of CHD in patients with type 2 diabetes. The Collaborative Atorvastatin Diabetes Study (CARDS) in the United Kingdom is a multi-centre, randomized, placebo-controlled, double-blind trial of atorvastatin 10 mg/day versus placebo in patients with type 2 diabetes, aged 40–75 years, without symptomatic CHD, but with at least one other risk factor, including current smoking, hypertension, retinopathy and albuminuria.39 Over 4000 people have been screened for CARDS, 3257 entered at baseline, and there are currently 2838 participating, 908 of whom are women. The last person to enter the trial was randomized in June 2001. In order to be considered for randomization, patients had LDL-cholesterol levels <=160 mgdl–1 (<=4.1 mmoll–1) and TG levels <=600 mgdl–1 (<=6.8 mmoll–1). Patients will be followed for a minimum of 4 years, and primary end-point is time to a first major cardiovascular event (CHD death, nonfatal MI, unstable angina, nonfatal stroke, cerebrovascular death, coronary artery bypass graft [CABG] surgery or other revascularization procedure). The trial is events-driven and requires a total of 304 events to complete. As of February 2002, there were 129 events.

In the Atorvastatin Study for the Prevention of coronary heart disease Endpoints in NIDDM (ASPEN) in the United States, a total of 2421 patients with type 2 diabetes, 75% of whom have had no prior MI, have been randomized to receive either atorvastatin 10 mg/day or placebo for 4 years.40 To enter the study, patients without prior MI had LDL-cholesterol levels <=160 mgdl–1 (<=4.1 mmoll–1) and TG levels <=600 mgdl–1 (<=6.8 mmoll–1); patients with diagnosed CHD had LDL-cholesterol levels <=140 mgdl–1 (<=3.6 mmoll–1) and TG levels <=140 mgdl–1 (<=1.6 mmoll–1). The primary end-point is time to a cardiovascular event (CHD death, nonfatal MI, congestive heart failure, recanalization, CABG surgery or stroke), and results are expected in 2003. It is hoped that it will be possible to pool the data from CARDS and ASPEN.

In addition to these two statin trials, the Fenofibrate Intervention and Event Lowering in Diabetes (FIELD) trial in Australia is underway, and will assess the effect of fenofibrate therapy on CHD risk and mortality reduction in patients with type 2 diabetes. FIELD is expected to report in 2005.

Conclusion

The objective of managing the patient with diabetes is to alleviate their symptoms and improve their quality of life. Treatment should not only address glycaemic control in order to reduce microvascular risk, but also focus on major risk factors for macrovascular disease including dyslipidaemia, hypertension and smoking. For the patient with diabetes, LDL-cholesterol is the major therapeutic target, with a secondary target of non-HDL-cholesterol for some patients. For the majority of patients, treatment with a statin is the preferred lipid-lowering therapy.

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