Abstract
Summary
Total cholesterol and low-density lipoprotein (LDL) cholesterol exhibit an independent, strong, continuous correlation with cardiovascular events. The effectiveness of hydroxy-3-methylglutaryl coenzyme A reductase inhibitors (statins) in the treatment and prevention of atherosclerosis is well-established. However, despite the lowering of LDL targets and the increased use of statins, patients with type 2 diabetes mellitus (DM) continue to experience a higher proportion of adverse coronary artery disease events. This is as a result of an atherogenic dyslipidaemia, characterized by low levels of high-density lipoprotein and elevated plasma triglyceride concentrations, often with high levels of cholesterol-rich remnant particles. This article will review dyslipidaemia and its role in DM, and will discuss available treatment modalities that address residual cardiovascular risk in this disease.
Introduction
Diabetes mellitus (DM) is characterized by hyperglycaemia and is often associated with dyslipidaemia, hypertension and, in the case of type 2 DM, insulin resistance and abdominal obesity. As a result, atherosclerosis is often premature, more prevalent and extensive in diabetic patients. Figures from the UK prospective diabetes study (UKPDS) indicated that 49% of deaths within 10 years of diagnosis were due to cardiovascular (CV) disease. 1 Indeed, the risk of myocardial infarction (MI) in a diabetic patient with no history of a MI is as high as in a non-diabetic with a history of MI. 2
The current approach to management of the increased CV risk focuses on the maintenance of blood glucose, low-density lipoprotein (LDL) cholesterol and blood pressure within a specified range. In recent years, statin therapy has been the cornerstone in the management of dyslipidaemia. In a meta-analysis of 14 randomized trials which included 18,686 individuals with DM (1466 with type 1 and 17,220 with type 2) treated with statins, there was a significant proportional decrease of 21% in the number of major vascular events per mmol/L reduction in LDL in that study group. 3 An important finding of this study was that one in seven of those patients treated with statins still experienced CV events over 5 years. 3 In particular, diabetic dyslipidaemic patients still develop macrovascular and microvascular complications despite being treated according to an accepted optimal treatment regime. 4 Thus, a ‘residual risk’ of developing these complications remains. This article will review dyslipidaemia in DM, and will discuss available treatment modalities that address residual CV risk in this cohort.
Lipid abnormalities in DM
Lipoproteins are essential in the transport of cholesterol and triglycerides (TG) in the blood. They are composed of a lipid core surrounded by phospholipids and specialized proteins known as apolipoproteins. They are divided into high-density lipoproteins (HDL – which are protective against atherogenesis) and non-HDL cholesterol (which are atherogenic). Non-HDL cholesterol is subdivided into chylomicrons, very-low-density lipoproteins (VLDL), intermediate-density-lipoproteins (IDL) and LDL.
Apolipoproteins are a heterogeneous group of molecules involved in enzymatic processes and particle structure. They are divided in function and structure into different classes. The principal apolipoproteins in terms of CV risk are apolipoprotein A1 (ApoA1), apolipoprotein B (ApoB) and apolipoprotein C-III (ApoC-III). These are the major components of HDL, non-HDL and VLDL, respectively.
Type 2 DM patients have a characteristic ‘mixed dyslipidaemia’ characterized by low levels of HDL and elevated plasma TG concentrations often with high levels of cholesterol-rich remnant particles (ApoB and ApoC-III).
Effect of dyslipidaemia: microvascular and macrovascular complications
The residual CV risk in treated patients with DM is likely attributable to lipoprotein abnormalities resulting in an atherogenic dyslipidaemia. 5 This was highlighted in a recent study where even with LDL levels <1.81 mmol/L, vascular risk remained higher than 40% with HDL levels <0.90 or TG levels >2.26 mmol/L. 6
Elevated TG and low HDL cholesterol have both been shown to be independent predictors of CVD, independent of LDL levels. 5 In the Prospective Cardiovascular Münster study (PROCAM) one in seven patients with a high total/HDL cholesterol ratio experienced a MI. 7
The recent consensus statement for lipoprotein management from the American Diabetes Association and American College of Cardiology (ACC) Foundation outlines the importance of ApoB as a predictor for CVD risk. In several studies, ApoB has been shown to be a better predictor of CV disease risk than LDL, particularly over the on-treatment LDL level. 6 A fasting blood sample is not required for ApoB measurement making it potentially an important clinical tool in the management of dyslipidaemia.
Non-HDL cholesterol has been shown to be a better predictor of CVD risk than LDL, particularly in statin-treated patients, and has been proposed as a secondary goal in therapy after treating LDL levels. 7
ApoC-III has also been shown to be an independent risk factor for CVD. It seems to have a special pathological role in DM, with roles in beta cell dysfunction and microvascular complications. 8
Dyslipidaemia in diabetic patients is also associated with the pathogenesis of microvascular complications. Higher levels of total cholesterol, LDL and TG have been shown to be significant risk factors for diabetic neuropathy after adjustment for glycosylated haemoglobin and duration of DM. 9 There is also a strong relationship between autonomic neuropathy and total cholesterol/HDL cholesterol ratio and fasting TG in patients with type 1 DM. 10
Dyslipidaemia is also implicated in the pathogenesis of diabetic nephropathy. Elevated TG was independently associated with both microalbuminuria and macroalbuminuria in type 2 DM patients in the UKPDS study. 11 Another study found that for every 0.54 mmol/L increase in HDL cholesterol, type 1 diabetic patients were approximately half as likely to have albuminuria. 12
A study looking at the associations of dyslipidaemia and retinopathy in type 1 DM patients revealed a positive association between the severity of the retinopathy and TG levels, and a negative association with HDL cholesterol. 13
Taken together, these data highlight the importance of dyslipidaemia in the pathogenesis of both macro- and microvascular complications in diabetic patients. It is vital, therefore, that it is both recognized and addressed aggressively in diabetic patients.
Therapeutic approaches to dyslipidaemia in DM
Diet
In recent years, the benefits of a healthy diet in improving dyslipidaemia and CV risk have been well publicized. Studies have shown that conformity with the Mediterranean dietary pattern (i.e. a diet consisting of vegetables, legumes, unsaturated fats, whole grain cereals and moderate alcohol intake) is associated with lower mortality. The Mediterranean dietary pattern has also been shown to increase HDL and reduce LDL levels, TG and the total/HDL cholesterol levels. 14 Positive changes were also observed in weight levels, blood insulin and glucose levels.
Physical exercise
The updated ACC guidelines for secondary prevention for patients with coronary and other atherosclerotic vascular disease recommend 30–60 minutes of moderate-intensity aerobic exercise per day for all patients. Physical exercise has been shown to reduce type 2 DM and CV risk by up to 50%, with higher levels of physical activity inversely associated with mortality. 15
While it may only have a minimal effect on total and LDL cholesterol concentrations, physical exercise has been shown to significantly reduce the concentrations of small LDL and LDL particle size, VLDL and TG, and increase LDL particle size and concentrations of HDL cholesterol.
There also appears to be a dose-response relationship between the amount of physical exercise and the improvements in dyslipidaemia, with higher amounts of physical exercise associated with higher HDL levels and lower LDL subparticle size and number, TG and VLDL concentrations, and risk of metabolic syndrome. 16 Overall, it appears that a modest amount of moderate-intensity exercise is adequate to obtain health benefits, by improving insulin sensitivity and lipid profile. Although exercise improves fitness, it is the reduction in total and abdominal adiposity that is more strongly associated with favourable changes in risk factors for CV disease and DM.
Pharmacotherapy
Statin therapy is the cornerstone of the pharmacological treatment of dyslipidaemia in DM. However, with recognition of residual risk of CVD, there has been increased focus on other pharmacological agents in recent years. The potential of these agents, such as niacin, fibrates and omega-3 fatty acids, to reduce this residual risk either independently or when used in combination with statins, is currently being explored.
Niacin
Niacin (nicotinic acid) is a unique form of therapy for dyslipidaemia as it improves all lipid abnormalities. It is the most effective agent currently available for raising HDL cholesterol levels, either as monotherapy or in combination with other agents. It acts by inhibiting the hepatic catabolism of Apo A-I, resulting in longer HDL cholesterol half-life, and higher plasma concentrations. 17 In addition, by inhibiting a hepatic enzyme required for TG synthesis, it lowers plasma TG levels and secretion of LDL and VLDL cholesterol. 17
While niacin monotherapy significantly reduces the incidence of coronary death and non-fatal MI, 18 the use of niacin in combination with statin therapy has been shown to be even more effective in improving dyslipidaemia. Results from the SEACOAST I study showed that niacin extended release and simvastatin combination therapy was more effective than simvastatin monotherapy at decreasing non-HDL cholesterol by 15%. 19 In addition, total/HDL cholesterol ratio was 21% lower than in the simvastatin monotherapy group, and average additional improvements over statin monotherapy in HDL, LDL, and TG were 27%, 23%, and 30%, respectively. 19
In light of these benefits, it is somewhat surprising that niacin is not more frequently used in the treatment of dyslipidaemia. Unfortunately, the relative under-use of niacin is probably attributable to an overly negative perception of its side-effect profile. Flushing is perhaps the most well-known symptom, and is caused by the release of prostaglandin D2 (PGD2). It can be prevented by using extended-release (ER) niacin preparations, titrating doses upwards, taking ER medications at bedtime, and using aspirin or an NSAID 30–60 minutes before niacin ingestion. Since 2008, the combination preparation of nicotinic acid and laropiprant (a PGD2 receptor antagonist) is available. The improvement in tolerability as a result of reduced flushing makes it a more attractive option.
Niacin has also been found to induce insulin resistance, increasing fasting blood glucose levels by up to 5%. However, the benefits of niacin therapy on lipid profile outweigh potential risks. 20 Of note, there is no increased risk of myopathy or rhabdomyolyis when niacin is used in combination with a statin. 20
Fibrates
Fibric acid derivatives (fibrates) have been used for more than two decades in the treatment of dyslipidaemia. Fibrates substantially decrease TG levels, and have more modest improvements on total cholesterol, LDL and HDL levels compared to placebo. 21
The mechanism of action of fibrates involves the activation of specific transcription factors, termed proliferator-activated receptors (PPAR), altering the transcription rate of target genes that play a role in the development of atherosclerosis.
In recent years, several large studies have looked at the effect of fibrate therapy on CV risk. The largest trial to date has been the Fenofibrate Intervention and Event Lowering in DM (FIELD) study, which looked at the effects of fenofibrate on lipid profile in 9795 men and women with Type 2 DM. 22 This study demonstrated a non-significant risk reduction in the primary outcome of non-fatal MI and CV death but a significant reduction in total CV events. 22 A recent post hoc analysis showed that the greatest benefit was derived in those patients with mixed dyslipidaemia where there was a 27% relative risk reduction in CV events. 23 A meta-analysis of the effects of fibrates on CV outcomes indicates that fibrate therapy is associated with a clinically important decrease in non-fatal MI, but has little if any effect on all-cause mortality. 21
The combination of statins with fibrates appears to have additional improvements in overall lipid profile, especially in patients with DM. The Effectiveness and Tolerability of Simvastatin plus Fenofibrate for Combined Hyperlipidaemia (SAFARI) trial showed that combination therapy produced a significant additional improvement in TG and LDL reduction, and an additional elevation in HDL levels when compared with simvastatin monotherapy alone. 24 Reluctance to use fibrates in combination with statins likely relates to concerns about the safety of dual therapy, in particular in relation to the increased incidence of reported rhabdomyolyis. However, the incidence of myopathy and rhabdomyolyis appears to be related to the specific fibrate used. For example, gemfibrozil and statin combination therapy is associated with a higher incidence of myopathy than fenofibrate and statin combination therapy which have a very low incidence of rhabdomyolysis. 25 Indeed, in the FIELD trial there were no reported cases of rhabdomyolysis with fenofibrate use. 22
Overall, addition of fibrates to statin therapy looks promising. However, large trial evidence, e.g. from the Action to Control Cardiovascular Risk in DM (ACCORD) study, is awaited to provide further evidence as to the benefits of combination therapy on CV mortality and morbidity.
Omega-3 fatty acids
Omega-3 fatty acids (OM3-FA) such as eicosapentaenoic acid and docosahexaenoic acid are found naturally in fish oils. Meta-analysis of randomized controlled trials has shown that dietary supplementation with OM3-FA exerts a dose-dependent decrease in serum TG, with greater improvements seen in patients with high baseline serum TG levels. 26 OM3-FA were also found to cause a significant reduction in LDL, and an increase in HDL cholesterol levels. 26
Several studies have demonstrated the efficacy of combination statin and OM3-FA therapy in the treatment of dyslipidaemia. For example, the Japan Eicosapentaenoic Acid Lipid Intervention Study (JELIS) randomized 18,645 patients to receive either 1800 mg of eicosapentaenoic acid plus statin or a statin alone. 27 There was a 19% relative reduction in major coronary events in the combination group, with significant reductions in the incidence of unstable angina and non-fatal coronary events.
The Combination of Prescription Omega-3 with Simvastatin (COMBOS) trial evaluated the efficacy of highly purified OM3-FA (P-OM3) added to stable statin therapy in subjects with persistent hypertriglyceridaemia. 28 The P-OM3 and simvastatin group was associated with significant reductions in TG, VLDL and total cholesterol/HDL cholesterol ratio, and a significant increase in HDL cholesterol. There was no significant difference in the incidence of adverse side-effects between the two groups. However, this trial was not designed to assess CV endpoints. Notably, OM3-FA have not been associated with side-effects such as rhabdomyolysis, hepatic or renal impairment or hyperglycaemia.
Summary
DM is a disease with a rapidly growing prevalence in our society. It is characterized by lipoprotein abnormalities, which put diabetic patients at a significant residual risk of developing macrovascular and microvascular complications despite achieving target levels of LDL on statin therapy. Therefore, the optimal management of dyslipidaemia in DM now involves managing the lipoprotein abnormalities that are implicated in residual vascular risk. The Residual Risk Reduction Initiative (R3i), a body established to address residual risk in diabetic patients, suggests that the first step in management should be early lifestyle modification. Intervention with pharmacotherapy is likely to be required in order to achieve all lipid targets, and combination therapy of niacin, fibrates or OM3-FA with a statin may be effective.
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Acknowledgements
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