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Nicotinic Acid in the Management of Dyslipidaemia Associated With Diabetes and Metabolic Syndrome: a Position Paper Developed By a European Consensus Panel

Posted on: Saturday, 11 June 2005, 03:00 CDT

Key words: Cardiovascular disease - Dyslipidaemia - Metabolic syndrome - Nicotinic acid - Type 2 diabetes

ABSTRACT

Individuals with type 2 diabetes and metabolic syndrome are at markedly increased risk of cardiovascular morbidity and mortality. The increasing prevalence of both conditions poses a major challenge for clinicians in the 21st century. Both diabetes and metabolic syndrome are associated with a clustering of cardiovascular risk factors. In particular, dyslipidaemia characterised by low plasma levels of high-density lipoprotein cholesterol (HDL-C), elevated triglycerides and an increase in small, dense low-density lipoprotein (LDL) particles (the lipid triad), has been established as the most important modifiable risk factor for coronary heart disease (CHD).

Current treatment guidelines recognise the increased CHD risk associated with diabetes and metabolic syndrome and focus on LDL-C lowering with statin treatment, in addition to dietary and lifestyle modification, as the primary lipid-modifying therapy. However, while there is no doubt that statin therapy significantly reduces CHD risk in these patients, their residual absolute risk remains higher than in individuals without diabetes or metabolic syndrome. Thus, there is a clear need to target other aspects of lipoprotein metabolism, notably low HDL-C and hypertriglyceridaemia, to further reduce CHD risk. Combining statin therapy (targeting LDL-C) with interventions that also modify low HDL-C and elevated triglycerides could be a useful strategy to optimise CHD risk reduction. Cautious combination of a fibrate or nicotinic acid with a statin is useful for the management of combined dyslipidaemia. Nicotinic acid is the more potent agent for raising HDL-C (by up to 29% at clinically recommended doses). It also substantially reduces triglycerides and LDL-C, and promotes a shift from small, dense LDL to larger, more buoyant LDL particles. Preliminary clinical data suggest that combining nicotinic acid with a statin will produce a greater reduction in cardiovascular risk in patients with diabetes and metabolic syndrome than statin monotherapy alone. Nicotinic acid is also safe for use in patients with diabetes, with no evidence of clinically relevant deterioration in glycaemic control at recommended doses (≤ 2g/day). On review of the available evidence, this European Consensus Panel recommends the combination of nicotinic acid and a statin, together with lifestyle modification, as a useful strategy to lower CHD risk in patients with diabetes and metabolic syndrome. Prolonged-release nicotinic acid with improved tolerability compared with previous formulations may have obvious advantages for use in this setting.

Introduction

Individuals with type 2 diabetes or the metabolic syndrome are at markedly increased risk of cardiovascular disease.

Cardiovascular mortality rates are more than two-fold higher in diabetic than non-diabetic individuals1,2, coronary heart disease (CHD) being the main cause of death3. The risk of any cardiovascular event, not infrequently in younger patients, is up to four times greater among diabetics and is also associated with greater mortality4. Moreover, there is evidence that individuals with diabetes and no history of myocardial infarction (MI) have the same risk of a major coronary event as non-diabetic individuals with a history of MI5, although this was not confirmed in all populations6,7.

There is also clear evidence that the presence of metabolic syndrome itself confers an increased risk for development of diabetes, CHD and for cardiovascular morbidity and mortality8-13. Patients with the metabolic syndrome are nearly twice as likely to die from cardiovascular disease, and their risk of MI and stroke is three-fold higher than normal14,15. Data from the Scandinavian Simvastatin Survival Study (4S)16, the Air Force/Texas Coronary Atherosclerosis Prevention Study (AFCAPS/TexCAPS)16, as well as the West of Scotland Coronary Prevention Study (WOSCOPS)17 show that placebo-treated non-diabetic patients with characteristics of the metabolic syndrome had an increased risk of CHD of between 1.5- and 3.7-fold compared with patients who did not have the metabolic syndrome. Even individuals with only one or two characteristics associated with the metabolic syndrome were at significantly greater risk of CHD compared with unaffected individuals (hazard ratios 1.79 and 2.25, respectively)17. Data from WOSCOPS17 also showed that the presence of characteristics of the metabolic syndrome was associated with a 24.5-fold increased risk for diabetes compared with men with none. Additionally, the presence of elevated C-reactive protein (CRP)17 and raised alanine aminotransferase levels18 were associated with an increased likelihood of CHD.

Data from myocardial perfusion imaging studies, such as the Detection of Ischemia in Asymptomatic Diabetics (DIAD) study19, showed that 20-30% of asymptomatic diabetic individuals had abnormal coronary perfusion studies indicative of silent ischaemia, thereby providing further evidence of the high cardiovascular risk associated with diabetes.

Current treatment guidelines recognise the higher cardiovascular risk associated with type 2 diabetes and the metabolic syndrome. The National Cholesterol Education Program Adult Treatment Panel III Guidelines (NCEP ATPIII)20 identify diabetes as a CHD risk equivalent that warrants intensive risk factor management. In the European Guidelines on cardiovascular disease prevention21, diabetes is a multiplier of risk score by two-fold in men and four-fold in women. The International Atherosclerosis Society (IAS) Harmonized Clinical Guidelines22 recognise that diabetes is associated with a constellation of risk factors, all requiring attention. Furthermore, the NCEP ATPIII20 recognises the metabolic syndrome as a secondary target for risk reduction after lowering of low-density lipoprotein cholesterol (LDL-C).

Visceral (or intra-abdominal) adiposity i.e., increased accumulation of fat in the abdominal cavity, plays a major role in the development of both type 2 diabetes and metabolic syndrome and is associated with increased cardiovascular risk23. Thus, in the NCEP ATPIII criteria20 for metabolic syndrome obesity is based on assessment of waist circumference as this more closely reflects visceral adiposity than body mass index (BMI).

Because of our increasingly sedentary lifestyle, the prevalence of visceral obesity has escalated markedly. As a result, both type 2 diabetes and metabolic syndrome have increased dramatically and will continue to do so in the 21st century. Currently, it is estimated that over 150 million people in the world have diabetes, with type 2 diabetes accounting for more than 90% of cases. This figure is expected to double by 202524. Surveys (based on data collected nearly 10 years ago) report that the metabolic syndrome typically affects about 20-30% of middle-aged adults in the USA14,25, and 15% of asymptomatic non-diabetic adults in Europe26; prevalence rates are higher in individuals with clinical vascular disease27, as well as in older women28. In WOSCOPS, 26% of enrolled patients had the metabolic syndrome at baseline17. Hyperglycaemia is a key factor associated with the increased cardiovascular risk in both type 2 diabetes and metabolic syndrome17.

Thus, there is a clear consensus that clinicians are facing a pandemic of cardiovascular disease, due to the increasing prevalence of diabetes and metabolic syndrome, with serious implications for public health. Clearly, there is a need for comprehensive and aggressive clinical management. This consensus paper, authored by a panel of key opinion leaders in Europe, reviews evidence relating to cardiovascular risk associated with diabetes and metabolic syndrome, and, arising from this, provides recommendations for new treatment strategies that may further reduce vascular risk in these patient groups.

Diabetes and metabolic syndrome: clustering of cardiovascular risk factors

Despite evidence from epidemiological studies that population hyperglycaemia corresponds with increased vascular risk29, elevated glucose and insulin concentrations are not the only or even main factors driving this phenomenon. While anti-diabetic treatment does reduce microvascular, and (for metformin), macrovascular complications, the burden of cardiovascular disease in diabetic patients remains high, even when they manage to achieve good glycaemic control30.

Both type 2 diabetes and metabolic syndrome are typically characterised by a clustering of cardiovascular risk factors including visceral obesity, dyslipidaemia, hypertension, impaired glucose tolerance (in metabolic syndrome) and other cardiovascular abnormalities that promote CHD. The most widely adopted criteria for metabolic syndrome, published as part of the NCEP ATPIII guidelines20, highlight the association of abdominal obesity, elevated triglycerides, low levels of high-density lipoprotein cholesterol (HDL-C) and elevated blood pressure together with hyperglycaemia (see Table 1). The World Health Organization criteria for metabolic syndrome differ slightly by requiring obvious insulin resistance and microalbuminuria in association with other metabolic factors (see Table 1)31,32. A \unifying definition of the metabolic syndrome will be published jointly by the International Diabetes Federation and NCEP later this year.

Irrespective of which criteria are used, it is clear that individuals with metabolic syndrome have higher levels of most cardiovascular risk factors and are at greater risk of CHD than unaffected individuals". Moreover, this risk factor clustering predicts CHD, cardiovascular disease and total mortality more strongly than the sum of the individual elements12,15. Risk is therefore multiplicative rather than additive.

Data from the EUROASPIRE II survey demonstrate the significance of CHD risk factor clustering in diabetic patients, specifically highlighting the association between obesity, in particular visceral obesity, elevated blood pressure and dyslipidaemia33. The aggregation of risk factors associated with the metabolic syndrome also increases the prevalence of macrovascular complications in patients with type 2 diabetes. In a cross-sectional study34, diabetic patients with metabolic syndrome had a higher prevalence of peripheral and coronary artery disease than those without these features. Moreover, an increase in the number of risk factors diagnostic of the metabolic syndrome resulted in a substantial increase in the proportion of patients with diabetic complications; in patients with none/one, two, three or four risk factors, the proportions with CHD were 36%, 44%, 52% and 60%, respectively. The co-existence of a number of cardiovascular risk factors implies the need for integrated cardiovascular risk management guidelines and screening to identify higher risk patients.

Table 1. Definition of the metabolic syndrome

Dyslipidaemia is now clearly established as the most important modifiable risk factor for CHD common to patients with diabetes and the metabolic syndrome. Analysis of data from the United Kingdom Prospective Diabetes Study (UKPDS)35 involving 2693 patients with newly diagnosed type 2 diabetes who were followed for a median of 7.9 years, identified LDL-C and HDL-C as the most important modifiable risk factors for cardiovascular disease, more so than glycated haemoglobin (HbA^sup 1c^, a measure of glycaemic control), systolic blood pressure and smoking. Epidemiological data from the USA show that 80% of the adult population with diabetes have dyslipidaemia, as reflected by high levels of triglycerides (36%), low HDL-C (21%) and/or elevated LDL-C (59%)14.

Common pattern of dyslipidaemia in diabetes and metabolic syndrome

The dyslipidaemia common to both diabetes and metabolic syndrome is characterised by low plasma levels of HDL-C and elevated triglycerides. In the Botnia study15, which included 4483 men and women aged 35-70 years, (1697 with diabetes, 798 with abnormal fasting glucose and 1988 with normal glucose tolerance), the prevalence of low HDL-C (< 35 mg/dL [0.9 mmol/L] in men and < 40 mg/ dL [1.0 mmol/L] in women) and/or elevated plasma triglycerides (≥ 150 mg/dL [1.7 mmol/L]) was substantially higher in individuals with diabetes (by up to three-fold) and abnormal fasting glucose (by up to two-fold), than in those with normal glucose tolerance (Figure 1). Dyslipidaemia was also more pronounced in women than in men.

Data from the Prospective Cardiovascular Munster (PROCAM) Study and the UKPDS are consistent with these findings. Analysis of PROCAM data, including 3737 men aged 36-60 years, of whom 200 developed diabetes within the 4-10 year follow-up period, showed that diabetic men had 35% higher median triglyceride values, as well as 7% lower mean HDL-C levels compared with non-diabetic men (p < 0.001)36. Similarly, data from the UKPDS demonstrated that patients with type 2 diabetes had significantly lower plasma levels of HDL-C and elevated triglycerides at diagnosis, compared with a control group37. In the UKPDS, a reduced plasma HDL-C level was the second strongest cardiovascular risk factor after LDL-C35. There is also evidence of a change in HDL subfraction composition, specifically an increase in small, dense HDL, that has been shown to have impaired antioxidative activity38 as well as increased renal clearance.

Figure 1. Prevalence of dyslipidaemia in adults with diabetes, impaired glucose tolerance and normal glucose tolerance. Data from the Botnia Study15. Dyslipidaemia was defined as high-density lipoprotein cholesterol < 35mg/dL [0.9 mmol/L] in men and < 40 mg/ dL [1.0 mmol/L] in women and/or plasma triglycerides ≥ 150 mg/ dL [1.1 mmol/L]

Figure 2. Mechanism of atheroprotective action of high-density lipoprotein (HDL). Reproduced with permission from Barter (1999)43. LDL = low-density lipoprotein; MCP-1 = macrophage chemoattractant protein-1

Although plasma levels of LDL-C in patients with diabetes and metabolic syndrome are either normal or only modestly elevated, there is an increase in the number of small, dense LDL particles whose apolipoprotein B-100/LDL-C ratio is increased39-41. These small, dense LDL particles are thought to be highly atherogenic because of their increased susceptibility to oxidation and their greater ability to penetrate the arterial wall42. Together this dyslipidaemic profile - elevated triglycerides, low HDL-C and an increase in small, dense LDL particles - is referred to as the 'lipid triad.'

Why is the lipid triad associated with an increased risk of atherosclerosis?

The risk of atherosclerosis is reflected in the balance between apolipoprotein B (apo B), the major protein component of cholesterol- rich LDL and very low-density lipoprotein [VLDL] particles, and apolipoprotein A-I (apo A-I), the main constituent of HDL. Apo B is linked to the transfer of cholesterol to the peripheral tissues, and is also associated with the assembly of triglycride- and cholesterol- rich lipoprotein particles. By contrast, apo A-I-containing HDL particles promote cholesterol efflux from peripheral cells and facilitate its transport to the liver for excretion. In addition, HDL may be atheroprotective because of its anti-inflammatory and anti-oxidant actions and its ability to normalise impaired endothelial function43 (Figure 2). Intravenous infusion of HDL has been shown to restore endothelial function in hypercholesterolaemic men44. Furthermore, direct infusion of recombinant apo A-I^sub Milano^ phospholipid liposomes into patients with acute coronary syndromes induced a reduction of 4.2% in atheroma volume within 5 weeks45 (compared with a reduction of 0.9% after 18 months intensive atorvastatin therapy in the Reversal of Atherosclerosis with Aggressive Lipid Lowering [REVERSAL] study46).

Data from the Apolipoprotein-related Mortality Risk (AMORIS) study47 were among the very first to highlight the relative importance of apo B/apo A for identification of MI risk. Subsequently, the INTERHEART Study48, which assessed the relative importance of different risk factors for CHD in 52 countries worldwide, identified abnormal lipids - specifically the imbalance between atherogenic lipids (reflected in apo B) and atheroprotective lipids (as measured by apo A-I) - as the most important potentially modifiable predictors of MI.

In patients with type 2 diabetes and metabolic syndrome, insulin resistance - a core feature of both conditions - increases breakdown of triglycrides in the fat cells, leading to increased plasma free fatty acid levels. This increased supply of free fatty acids to the liver raises triglyceride synthesis, promotes the secretion of large VLDL particles (mainly VLDL^sub 1^ particles)49 and may be a primary event in the development of visceral obesity, leading to hepatic insulin resistance50.

The increased secretion of VLDL in turn leads to a rise in fasting and postprandial triglycerides and drives the transfer of triglyceride from VLDL to HDL in exchange for cholesteryl esters via the action of cholesteryl ester transfer protein (CETP)49. As a result, VLDL becomes more cholesterol-rich while HDL gains triglyceride and becomes susceptible to the lipolytic action of hepatic lipase, which turns it into smaller, denser particles38,49 less able to accept cholesterol for transfer to the liver and excretion from the body. These smaller particles are more rapidly catabolised and cleared by the kidney, further reducing plasma levels of HDL-C. The key action of CETP as a major determinant of the atherogenic lipoprotein profile in type 2 diabetes has been confirmed by ex vivo studies involving measurement of interlipoprotein cholesteryl ester flux41.

CETP may also promote the transfer of triglycerides from VLDL to LDL in exchange for cholesteryl ester49; these triglyceride-rich cholesteryl ester-depleted LDL subsequently undergo lipolytic hydrolysis resulting in small, dense LDL particles, which are highly atherogenic because they are more liable to oxidation and more readily adhere to and subsequently invade the arterial wall. In addition, the reduced affinity of these small, dense LDL particles for the LDL receptor extends their lifetime in the plasma, again facilitating their likelihood of infiltrating the arterial wall and becoming deposited there. Similar processes occur with chylomicron remnants containing apo B-48; increased plasma accumulation of triglyceriderich remnants and exaggerated postprandial lipaemia are common features of patients with metabolic syndrome51. Together with the increased susceptibility of small, dense LDL to oxidation, these processes contribute to plaque formation. Thus, abnormalities in fat metabolism in patients with diabetes and metabolic syndrome lead to elevated triglycerides and low plasma levels of HDL-C, as well as increased atherogenicity of the circulating LDL particles. The co- existence of these three factors aggravates lipid accumulation in the arterial wall and the development of plaques.

The endothelium plays a crucial role in the maintenance of normal cardiovascular system function52. Damage to the endothelium, such as that causedby oxidised LDL52,53, is one of the earliest processes in the development of atherosclerotic plaque. Chronic postprandial hypertriglyceridaemia and hyperglycaemia - as in type 2 diabetes and metabolic syndrome - as well as age per se, induce endothelial damage, with oxidative stress the common mediator of this effect52,54,55. In addition, in type 2 diabetes, endothelial insulin resistance is a pathogenetic factor for premature atherosclerosis and promotion of expression of adhesion molecules. Moreover, the close association between endothelial dysfunction and inflammation perpetuates this process. Pro-inflammatory cytokines increase the binding of LDL to the endothelium56 and its subsequent translocation to the subendothelial space where it is taken up by macrophages to form foam cells. At the same time, oxidised LDL stimulates these foam cells to increase production of pro-inflammatory cytokines57. In addition, inflammation increases the secretion by macrophages of anti-fibrinolytic factors such as plasminogen activator inhibitor-1 (PAI-1)58-60, which in turn increase the extent and severity of cardiovascular events61.

Implications for treatment of dyslipidaemia associated with diabetes and metabolic syndrome

Current treatment recommendations for the management of the dyslipidaemia associated with diabetes and metabolic syndrome focus on statin therapy, in addition to dietary and lifestyle adaptation, even though plasma levels of LDL-C may be only slightly elevated in such patients20-22. The NCEP ATPIII20 recommends LDL-C lowering in addition to lifestyle changes, such as dietary modification (reduced intake of saturated fats and cholesterol, use of plant stanols and sterols), weight reduction and increased physical activity. Moderate weight loss (by 5-10%) combined with exercise significantly decreases triglyceride levels and increases HDL-C, and has beneficial effects on cardiovascular risk factors62.

Recommendations for statin therapy are based on data from major intervention studies, which showed that LDL-C lowering with a statin was effective in reducing CHD risk in patients with diabetes in both primary and secondary settings (Table 2)63-74. In fact, the Collaborative Atorvastatin Diabetes Study (CARDS)64, which specifically recruited patients with type 2 diabetes without high LDL-C (≤ 160 mg/dL [4.1 mmol/L]) or history of CHD, demonstrated a 37% reduction in the risk of major cardiovascular events with statin therapy.

Table 2. Reduction in relative coronary heart disease (CHD) risk for all patients (diabetic and non-diabetic) and for diabetic patients treated with statins in major intervention trials

Data from these studies consistently show that statin therapy gives a similar relative CHD risk reduction in diabetic patients as in the overall study populations. The absolute reduction in CHD risk was greater in patients at higher baseline cardiovascular risk, such as in 4S (60-70% of patients had a history of MI and baseline LDL-C was 186-189mg/dL [4.8-4.9 mmol/L])67-69, than in those with a lower baseline risk, such as in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT-LLT)73, the Heart Protection Study (HPS)72 and CARDS64.

Aggressive statin therapy, in addition to lifestyle modification, may provide early benefit in patients with diabetes. Subgroup analysis of the GREak Atorvastatin and CHD Evaluation Study (GREACE)75 involving 313 diabetic patients, showed that treatment with atorvastatin (mean daily dose 23.7 mg) in addition to usual clinical care reduced all-cause and CHD mortality and CHD morbidity by more than 50% compared with a control group (usual clinical care alone). Clinical benefits manifested as early as within 6 months of initiating treatment.

Although there are few published data relating to the effect of statins on CHD risk in patients with characteristics of the metabolic syndrome, the available evidence from the Cholesterol and Recurrent Events (CARE) trial66 and the 4 S study69,76 shows a reduction in CHD risk at least comparable to that observed overall in these studies. In the CARE study66 in 342 patients without a history of diabetes who had an entry fasting glucose of 110-125 mg/ dL (6.1-7.0 mmol/L); treatment with pravastatin led to a 23% reduction in major coronary events, the same as in the overall study population and comparable with that observed in patients with diabetes. However, this same risk reduction translated into a greater number of events avoided as a consequence of higher baseline risk. In a recently published subgroup analysis of the 4S study76, LDL-C lowering with simvastatin reduced the relative risk of a major CHD event by 41% in patients with metabolic syndrome compared with 29% in patients without metabolic syndrome.

There is no doubt that statin therapy significantly reduces CHD risk in patients with diabetes (and metabolic syndrome)64,72. Nevertheless, although diabetic patients gained as much relative benefit from statins as non-diabetic patients, treatment did not reduce their absolute risk to the same value as in non-diabetics. For example, subgroup analyses from the Heart Protection Study71,72 showed that the residual risk of a coronary event in diabetic patients remained twice that observed in non-diabetic patients treated with statins (1.48 vs. 0.75) (Table 3). These findings were consistent across all statin intervention studies irrespective of the nature of the statin.

Importance of targeting other lipids

The high level of residual risk in patients with diabetes and metabolic syndrome treated with statins highlights the need to target other lipids, specifically low HDL-C and elevated triglycerides77 characteristic of the atherogenic dyslipidaemia associated with both conditions. The NCEP ATPIII identifies non-HDL- C (LDL + VLDL cholesterol) as a secondary target for therapy in patients with high triglycerides (≥ 200 mg/dL [2.3 mmol/ L])20, and both the NCEP ATPIII guidelines20 and the American Diabetes Association (ADA) recommendations78 recognise HDL-C as a strong predictor of CHD risk. Therapeutic lipid goals in patients with diabetes and metabolic syndrome, based on these guidelines and modified in accordance with recent trial evidence79, are summarised in Table 4.

Table 3. Risk of a major coronary event; subgroup analysis in patients with coronary heart disease (CHD) alone and CHD and diabetes based on data from the Heart Protection Study71,72

Table 4. Therapeutic lipid goals (mg/dL [mmol/L]) based on the National Cholesterol Education Program Adult Treatment Panel IIP20 and recommendations of the American Diabetes Association78, modified in accordance with recent trial experience79

While statins are effective in reducing plasma levels of LDL-C, they have only modest effects on reducing triglycerides (by 15-35%) and raising HDL-C (typically by less than 10%)20, even with aggressive statin therapy46,80. The Steno type 2 (Steno-2) study81 used a combination of lifestyle intervention and multiple targeted and individually-tailored drug therapy, including intensive statin treatment, to reduce cardiovascular risk. While there was a 53% reduction in the relative risk of cardiovascular events, as well as a significant increase in the proportion of diabetic patients who achieved LDL-C treatment goals (70% vs. 20% in patients treated with conventional therapy, p < 0.001], there was little change in the proportion of patients who achieved triglyceride treatment goals (58% vs. 43%, p = 0.19). Clearly there is a need to target low HDL- C and elevated triglycerides, both of which are usually inadequately managed by statins.

HDL-C is clearly established as an independent and predictive risk factor for CHD in both diabetic and non-diabetic individuals82. Data from the UKPDS35 and other observational studies demonstrate that HDL-C is a major component of cardiovascular risk in diabetic patients and could even be the most consistent predictor of CHD in patients with type 2 diabetes. The beneficial effect of raising HDL- C on clinical outcome has already been demonstrated by a number of studies including the Veterans Affairs HDL Intervention Trial (VA- HIT)83 and the Helsinki Heart Study84. Analysis of data from VA-HIT showed that the reduction in coronary events with gemfibrozil was greater in patients with insulin resistance (both diabetic and non- diabetic) than in those without insulin resistance85. Moreover, the benefit of HDL-C raising associated with gemfibrozil treatment in VA- HIT83 compared favourably with that observed in primary and secondary prevention studies involving statin therapy63-65,67,70,86 (Figure 3).

Older data from a subgroup of patients in the Helsinki Heart Study with many features of the metabolic syndrome (BMI > 26 kg/ m^sup 2^, high triglycerides > 220 mg/dL [2.5 mmol/L] and low HDL- C) showed that gemfibrozil reduced cardiovascular events by 55% compared with placebo87.

The results of a recent study88 investigating the atherogenicity of LDL-C, HDL-C and triglycerides in 750 CHD patients (with normal fasting glucose [n = 272], impaired fasting glucose [n = 314] or type 2 diabetes [n = 164]) are consistent with findings from VA-HIT and further highlight the importance of raising HDL-C in patients with type 2 diabetes and related metabolic disorders. Factor analysis again identified HDL as the key player in generating vascular risk. Overall, the HDL-factor (HDL-C, apo A-I and LDL particle diameter) but not the LDL-factor (total cholesterol, LDL- C, apo B-100) was associated with the presence of significant coronary stenosis. These data highlight the importance of low HDL-C (and to a lesser extent the lipid triad) in the development of coronary atherosclerosis in patients with insulin resistance as in type 2 diabetes. Raising HDL-C is important in increasing reverse cholesterol transport; lowering triglycerides and increasing LDL particle size may also \be as important to reduce cardiovascular risk in patients with diabetes.

Figure 3. Clinical benefit associated with raising high-density lipoprotein cholesterol (HDL-C) in major statin intervention studies63-65,67,70,86 compared with the Veterans Affairs HDL Intervention Trial (VA-HIT)83

Taken together, the available data suggest that a combination of lipid-modifying therapy aimed at LDL-C reduction (with a statin), as well as raising HDL-C and reducing triglycerides, is an important strategy to further reduce cardiovascular risk in patients with diabetes and metabolic syndrome.

Alternative treatments for raising HDL-C and reducing triglycerides

There is consensus20,22,89-91 that the minimum HDL-C goal in patients at high cardiovascular risk should be 40 mg/dL (1.0 mmol/ L); recent guidelines recommend that target levels should be at least 10 mg/dL (0.26 mmol/L) higher in women78,92. Many physicians would aspire to an even higher target since these two goals barely represent the HDL-C value of the average population14.

Lifestyle modification such as losing weight and physical exercise is important93. The effect of these interventions is well established, and more pronounced in individuals with elevated triglycerides and low levels of HDL-C (as in the metabolic syndrome and type 2 diabetes). Weight loss, in particular, is an effective intervention for raising HDL-C in overweight/obese individuals, including those with characteristics of the metabolic syndrome94,95, and should be encouraged and sustained.

However, in order to achieve the required HDL-C targets in patients with diabetes and metabolic syndrome and low plasma levels of HDL-C, therapeutic agents capable of raising HDL-C by 20-30%, in addition to lifestyle intervention, are frequently required. There are a number of agents that both raise HDL-C and lower triglycrides, which could potentially be used in combination with a statin. These include the peroxisome proliferator-activated receptor (PPAR) agonists (α and γ] and nicotinic acid. Other agents that act specifically to lower triglycerides (such as ezetimibe or omega 3 fatty acids) or raise HDL-C (such as CETP inhibitors, currently undergoing preliminary clinical investigation), but do not act on both HDL-C and triglycerides, are beyond the focus of this paper.

PPARα agonists

Fibrates, the progenitor PPARα agonist, have been shown to reduce serum triglycerides by 20-50% and LDL-C by 5-20%96 although effects on raising HDL-C are more modest, typically in the region of 10-15%97, depending on lipid phenotype and baseline concentration96. Findings from a recent meta-analysis including data from 53 trials using fibrates are consistent with these findings, reporting an increase in HDL-C of 10% and reduction in triglycerides and LDL-C of 36% and 8%, respectively98. There is some evidence that fibrates may decrease plasma lipoprotein(a) (Lp(a)) levels in nondiabetic patients with hypercholesterolaemia99, although further data are needed to confirm this finding. Recent data from the Bezafibrate Infarct Prevention Study show that this fibrate prevents the development of type 2 diabetes; however, data from other agents are currently lacking100.

The clinical benefits of raising HDL-C and lowering triglycerides with fibrate therapy in patients with diabetes have been established in VA-HIT83,85 and the Diabetes Atherosclerosis Intervention Study (DAIS)101; furthermore, fibrates may have a potential role in the treatment of metabolic syndrome102. Patients included in VA-HIT had a high prevalence of characteristics of the metabolic syndrome; 50% had high triglycerides (> 150 mg/dL [1.7 mmol/L]), 75% had low HDL- C (< 35 mg/dL [0.9 mmol/L]), 57% had hypertension, 25% had diabetes and 13% had impaired fasting glucose103. Treatment with gemfibrozil for 5 years reduced non-fatal MI and CHD death by 22% (p = 0.006); moreover, treatment was more effective in patients with hyperinsulinaemia and diabetes85. In DAIS, patients with type 2 diabetes treated with fenofibrate for 3 years exhibited reduced angiographic progression of localised coronary stenoses and also tended to have fewer cardiovascular events101. Recent meta-analysis (including studies in patients with type 2 diabetes as well as patients with a range of dyslipidaemias), has demonstrated that fibrates reduce the risk for major coronary events by 25%98.

However, there are limited clinical data relating to the combination of a fibrate and a statin. In one study, the combination of rosuvastatin and fenofibrate produced significantly greater reduction in triglycerides than either agent alone, although there was no additive benefit in HDL-C raising with the combination104. In contrast, other studies showed a beneficial effect of statin- fibrate combination therapy105, although as yet there are no published outcome data. Side effects associated with the combination of gemfibrozil and a statin may be a particular issue105,106, although fenofibrate and bezafibrate do not appear to carry this concern. Additionally, whether the fibrates have any effect on glycaemic control has yet to be established (although clinical experience shows that reducing levels of serum fatty acids reduces insulin resistance and in turn improves glycaemic control).

PPARγ agonists

PPARγ agonists such as the thiazolidinediones rosiglitazone and pioglitazone are oral anti-diabetic drugs, and offer potential for the treatment of abnormalities in both glucose and lipid metabolism. These agents improve insulin sensitivity and blood glucose levels in patients with type 2 diabetes, as well as having variable effects on the lipid profile. Summary analysis based on data from 19 placebo-controlled studies showed that treatment with pioglitazone was associated with 18.7% reduction in triglycerides and 9.9% increase in HDL-C, although rosiglitazone produced an overall increase in triglycerides (by 4.4%) and only raised HDL-C by 5.2%107. There is also a frequent tendency for PPARα agonists to induce an increase in LDL-C93,96. Newer glitazones such as ragaglitazar may have greater efficacy in raising HDL-C and reducing triglycerides108.

Additionally, the thiazolidinediones have a range of anti- inflammatory properties that may contribute to an improved cardiovascular risk profile in patients with type 2 diabetes and potentially oppose the progression of atherosclerosis109. For example, treatment with rosiglitazone for 26 weeks has been shown to reduce plasma levels of CRP in patients with type 2 diabetes, as well as reducing levels of matrix metalloproteinase (MMP) 9, suggesting that treatment may help to stabilise atherosclerotic plaques from rupture, as well as countering the inflammatory processes associated with the early stages of atherosclerosis110. In addition, thiazolidinedione treatment can suppress the production of pro-inflammatory cytokines in obese, non-diabetic individuals111. Thus, binding to the PPARγ receptor, which is found in fat and muscle tissue, not only mediates the anti-diabetic effects of the thiazolidinediones but is also implicated in the anti-inflammatory actions of these agents109.

Although the thiazolidinediones may offer potential for preventing the progression of type 2 diabetes and its complications, the extent to which these putative benefits can translate into improved outcome for patients has yet to be established. Finally, the safety and tolerability of these agents in combination with a statin have yet to be evaluated.

Nicotinic acid

Nicotinic acid is the most potent agent available for raising plasma levels of HDL-C [by up to 29% at clinically recommended doses112), as well as substantially lowering triglycerides and LDL- C. In a recent meta-analysis98, the extent of HDL-C raising with nicotinic acid (all formulations] was 1.6-fold that reported for fibrates. Nicotinic acid was also slightly more effective in reducing LDL-C and slightly less effective in lowering triglycerides than fibrates98. In addition, nicotinic acid favourably alters the LDL composition, shifting the subclass distribution of LDL from small, dense particles to larger, more buoyant (and potentially less atherogenic) particles, as well as enhancing the cardioprotective larger HDL particles113-116. Nicotinic acid is also the most potent lipid-lowering agent available that reduces Lp(a)115-117, an independent marker of cardiovascular risk118.

Recent research has established the mechanism of action of nicotinic acid on HDL-C and other plasma lipoproteins119-121. Nicotinic acid inhibits catabolism of apo A-I in the liver while preserving uptake and transport of cholesterol esters in the liver, thereby prolonging the half-life of HDL particles. In addition, nicotinic acid inhibits lipolysis in adipocytes and triglyceride synthesis. These effects lead to a decrease in output of triglyceriderich lipoproteins by the liver as well as an increase in HDL-C122. Experimental studies123,124 have shown that the anti- lipolytic effects of nicotinic acid appear to be mediated by a nicotinic acid receptor in vivo, which may potentially represent a new therapeutic target in the future125. Nicotinic acid also inhibits oxidation of LDL-C, one of the critical early steps contributing to atherosclerosis, as well as reducing vascular inflammation (as indicated by a reduction in CRP levels), thereby improving endothelial function126. Studies have shown that nicotinic acid appears to activate nuclear transcription factors such as PPARγ, possibly via prostaglandin metabolism, and this may in part explain its anti-inflammatory effects127. Furthermore, treatment with nicotinic acid has been shown to reduce plasma fibrinogen levels113,128 (an independent risk factor for cardiovascular events) and potentiate fibrinolysis, as shown by a reduction in PAI-1 activity129 and expression130.

Meta-analysis based on data from 30 studies using a range of differe\nt nicotinic acid formulations demonstrated an overall 27% reduction in the risk of major coronary events98. Clinical outcome data have also demonstrated the benefits of nicotinic acid therapy in patients with type 2 diabetes and impaired glucose tolerance. The Coronary Drug Project was a prospective study that evaluated the effect of five different lipidmodifying regimens on the primary endpoint of all-cause mortality in 8341 men with previous MI. Treatment with nicotinic acid (average daily dose 2g) for 6 years reduced total cholesterol by 10% and triglycerides by 26% (HDL-C was not measured). These changes were associated with reductions in non- fatal MI and cerebrovascular events of 26% (p < 0.005) and 24% (p < 0.05) compared with placebo131. Follow-up 9 years after the end of the study demonstrated a significant absolute reduction in mortality in patients treated with nicotinic acid (11% vs. placebo, p < 0.001)132. Furthermore, recently published data suggested a greater reduction in non-fatal MI (by 57%) in patients with the highest fasting blood glucose (≥ 126 mg/dL [7.0 mmol/L])133 (Figure 4). Additional data from the Coronary Drug Project suggest that the clinical benefits of nicotinic acid in patients with the metabolic syndrome were at least similar to those in patients without the metabolic syndrome134, although further details of this analysis are required.

Clinical studies have investigated the potential of nicotinic acid in combination with clofibrate, colestipol and statin therapy. In the Stockholm Ischaemic Heart Disease Secondary Prevention Study135 in 555 post-infarct patients, combination treatment with nicotinic acid and clofibrate reduced total cholesterol by 13% and triglycerides by 19% (HDL-C was not measured) and significantly reduced total and CHD mortality by 26% (p < 0.05) and 36% (p < 0.01), respectively, compared with a control group. In the Familial Atherosclerosis Treatment Study (FATS)136 in 120 patients with established CHD and apo B levels ≥ 125 mg/dL, combination drug therapy (nicotinic acid and colestipol, a bile acid sequestrant) plus dietary counselling for 2.5 years was associated with a 43% increase in HDL-C and a 32% decrease in LDL-C, compared with only negligible lipid changes in the conventional treatment group (dietary counselling and placebo or use of colestipol). This combination also produced atherosclerotic regression in a significantly higher proportion of patients compared with conventional treatment (39% vs. 11%, p < 0.005), and, although not powered to compare clinical outcome, led to a 73% reduction in event rates (death, MI or revascularisation for worsening symptoms).

Figure 4. In the Coronary Drug Project, the greatest reduction in non-fatal myocardial infarction (MI) with nicotinic acid was associated with increased fasting blood glucose. Adapted with permission from Canner et al. (2005)133

Combination nicotinic acid/statin therapy

Combining nicotinic acid and a statin would be a logical approach to therapy as it addresses the metabolic abnormalities associated with diabetes and metabolic syndrome89; nicotinic acid raises HDL-C by about 25% at clinically recommended doses114, as well as substantially reducing triglycerides, and the statin effectively lowers LDL-C. Studies have shown that addition of nicotinic acid (1- 2 g daily) to primary statin therapy produces additional lipid- modifying benefit137,138. In a recently published study, the combination of prolonged-release nicotinic acid and lovastatin (1 g/ 20mg) produced LDL-C lowering of 32% as well as HDL-C raising of 17%; moreover, nicotinic acid 2 g (the maximum clinically recommended dose) and lovastatin 20 mg gave LDL-C lowering of 39% and HDL-C raising of 25% (Figure 5)139.

Figure 5. Changes in low-density lipoprotein cholesterol (LDL-C) and high-density lipoprotein cholesterol (HDL-C) with the combination of prolonged-release nicotinic acid and lovastatin. Data from Insull et al. (2004)139

The clinical benefits of nicotinic acid/statin combination therapy are indicated by the HDL-Atherosclerosis Treatment Study (HATS)140. Treatment with simvastatin (mean daily dose 13 6 mg) and nicotinic acid (mean daily dose (2.4 2.0 g) led to a 26% increase in HDL-C, 38% reduction in triglycerides and 42% reduction in LDL- C. These lipid changes were associated with a 90% fall in the frequency of major coronary events compared with placebo (p = 0.03) in patients with CHD, as well as significant angiographie regression of stenosis by 0.4% on average, compared with progression of 3.9% on placebo (p < 0.001).

Recently reported results from the Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER 2) study141, the first atherosclerosis progression study performed with prolonged-release nicotinic acid, provide further support for the atheroprotective effect of the combination of prolonged-release nicotinic acid (final daily dose 1 g) and an efficacious dose of simvastatin in 167 patients with established CHD and low HDL-C (< 45 mg/dL [1.2 mmol/L]), 27% of whom had type 2 diabetes and over 50% of whom had features of the metabolic syndrome. In this double-blind, randomised study, patients were allocated to treatment with nicotinic acid or placebo in addition to background statin therapy. The primary endpoint of the study was the change in carotid intima-media thickness (CIMT), as assessed by B- mode ultrasonography, a recognised and valid surrogate cardiovascular endpoint142.

After 12 months, patients treated with nicotinic acid in addition to a statin had a 21% increase in HDL-C and a 13% decrease in triglycerides, and these lipid changes arrested the progression of carotid intima-media thickening (CIMT change 0.014 0.104, p = 0.23). By contrast, patients treated with statin and placebo had no change in HDL-C and a 5% decrease in triglycerides, associated with a statistically significant increase in mean CIMT (0.044 0.100 mm, p < 0.001), indicative of marked progression of atherosclerosis (Figure 6). Although the study was not powered to evaluate treatment effects on clinical outcomes, clinical cardiovascular events occurred in 3.8% of patients treated with the combination of nicotinic acid and a statin compared with 9.6% of patients treated with statin alone (p = 0.20)141.

A further study143 demonstrated the potential for further impact on progression of coronary stenosis with more aggressive raising of HDL-C levels. In this small study (n = 143), patients with CHD and low plasma levels of HDL-C (< 35mg/dL [0.9 mmol/L]) were treated with nicotinic acid (mean daily dose 2.5 1.0g) in combination with gemfibrozil 600 mg daily and cholestyramine (mean daily dose 8.4 6.2 g) (in addition to intensive dietary and lifestyle intervention). After 30 months, this combination treatment led to a 36% increase in HDL-C and decreases of 50% in triglycerides and 26% in LDL-C, and was associated with reduction in angiographic coronary stenosis (by 0.8%) compared with an increase of 1.4% in the control group (no drug therapy) (p < 0.05). Although conclusive evidence of the benefit of raising HDL-C with nicotinic acid in addition to a statin will have to await an adequately powered, large outcome study, data from these studies140,141,143 are very encouraging preliminary data for the validity of such an approach to cardiovascular prevention.

Figure 6. Treatment with prolonged-release (PR) nicotinic acid (1 g daily) in combination with a statin produced significant slowing of progression of atherosclerosis, as assessed by carotid intima- media thickness (CIMT), in the Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol (ARBITER) 2 study. Data are given as mean (standard error of the mean [SEM]). Reproduced with permission from Taylor et al. (2004)141

Currently, there is no clear consensus as to which is the most appropriate statin for use in combination with nicotinic acid. It is worth noting that a fixed combination tablet of prolonged-release nicotinic acid and lovastatin (available in doses of 500/20 mg and 1000/20 mg) is now available in the USA; however, as lovastatin is not universally available, simvastatin may be a more appropriate choice for combination with nicotinic acid.

Is nicotinic acid safe in diabetic patients?

Given the potential for complementary therapeutic benefit, the opinion of this Panel is that the addition of nicotinic acid to primary statin therapy would be a useful strategy in patients with type 2 diabetes and/or the metabolic syndrome. However, until recently, there has been caution about the use of nicotinic acid in diabetic patients in clinical practice due to perceptions that treatment may potentially worsen glycaemic control144.

Data from two recent studies have clarified this issue. The Arterial Disease Multiple Intervention Trial (ADMIT)112, which included a subgroup of 125 patients with diabetes (as defined by a history of diabetes treated by diet or medication, or HbA^sub 1c^ > 7%), showed that crystalline (immediate-release) nicotinic acid 2-3 g daily significantly improved diabetic dyslipidaemia (increasing HDL-C by 29% and decreasing triglycerides and LDL-C by 23% and 8%, respectively) without any significant deterioration in glycaemic control. Additionally, there was no significant change in the use of insulin and antidiabetic agents during the study in patients treated with nicotinic acid compared with placebo.

More recently, data from the Assessment of Diabetes Control and Evaluation of the Efficacy of Niaspan Trial (ADVENT)145, involving 97 patients with stable type 2 diabetes (mean baseline HbA^sub 1c^ 7.2% and fasting glucose 138 mg/dL [7.7 mmol/L]) treated with prolongedrelease nicotinic acid 1 g or 1.5 g daily for 16 weeks, confirmed these findings. Treatment with nicotinic acid led to dose- related increases in HDL-C (13-19% with 1 g and 22-24% with 1\.5 g) and decreases in triglycerides (by up to 36% with 1.5 g). At the end of the study, there were no differences between the treatment groups with respect to mean fasting glucose levels, no clinically relevant changes in HbA^sub 1c^ and no significant differences among the groups in the percentage of patients requiring adjustment of the dose of insulin and/or oral antidiabetic medication.

Furthermore, analysis of data from the Coronary Drug Project, involving patients with a fasting plasma glucose level > 100 mg/dL (5.5mmol/L) (about 40% of the study population), showed that although fasting and 1-hour glucose increased slightly but statistically significantly in patients treated with nicotinic acid compared with the placebo group, there were no statistically significant differences at the end of the study in the percentage of patients who were newly prescribed insulin (1.3% vs. 0.9% on placebo) or oral hypoglycaemic agents (4.3% vs. 4.6% on placebo)133.

Although the number of patients included in both studies was limited, the available evidence relating to the use of nicotinic acid in diabetic patients is reassuring. Consequently, in view of these data, the 2004 ADA recommendations for dyslipidaemia management in adults with diabetes, emphasise that: 'Low doses of nicotinic acid (≤ 2g/day) may not have much of a detrimental effect on glycaemic control; and any deterioration may be easily remediable by adjustment of hypoglycaemic medications78.' Thus, the overall consensus of this Panel, based on the available data, is that nicotinic acid at clinically recommended doses (≤ 2g/ day) is an acceptable treatment option in patients with type 2 diabetes, as well as in patients with metabolic syndrome at high CHD risk.

Formulation changes improve tolerability

Flushing is one of the most common side effects with nicotinic acid therapy, occurring in up to 70-80% of patients. This effect is attributable to the metabolism of nicotinic acid via the conjugation pathway, resulting in nicotinuric acid, which is associated with prostaglandinmediated vasodilation115. As the immediate-release formulation of nicotinic acid is predominantly metabolised via this pathway, this treatment is associated with a high rate of flushing. Conversely, sustainedrelease nicotinic acid is preferentially metabolised via the nicotinamide pathway, and is associated with significantly increased risk of hepatotoxicity115.

The availability of a once-daily prolonged-release formulation of nicotinic acid, in which nicotinic acid is absorbed over an 8-12 hour period leading to more balanced metabolism, offers safety and tolerability advantages over earlier nicotinic acid formulations, as discussed extensively in a previous position paper8'1, as well as in recent reviews93,134. While flushing is still the major side effect of treatment, data from a head-to-head comparison of prolonged- release and immediate-release nicotinic acid showed that there were significantly fewer flushing episodes per patient with the prolonged- release preparation compared with the immediate-release preparation146. Moreover, with time, tolerance to this effect does develop98. To further minimise the risk of flushing, clinicians should advise their patients to take their treatment after a low- fat snack at bedtime and to avoid hot drinks, spicy food and alcohol prior to dosing. The possibility of taking aspirin or a non- steroidal antiinflammatory drug to attenuate flushing has also been suggested93.

Considerable elevation of liver function enzymes is also avoided with prolonged-release nicotinic acid. An overview of data from clinical trials, as well as postmarketing experience, indicate a very low incidence of elevated liver function enzymes with prolonged- release nicotinic acid, either alone or in combination with a statin (< 1%)134, and no increase in the incidence of myopathy (when used in combination with a statin) compared with statin therapy alone134. In HATS, patients who received the combination of immediaterelease nicotinic acid and simvastatin (mean daily doses 2.4 g and 13 mg, respectively) for 3 years, showed no significant difference in the frequency of clinical or laboratory side effects compared with placebo147. Nevertheless, clinicians are advised to monitor for evidence of skeletal muscle myopathy, as well as for changes in liver function, measuring liver transaminases and alkaline phosphatase at initiation, after 6 weeks of therapy and every 4-6 months thereafter93. Increases in uric acid and/or precipitation of gout have been reported with some nicotinic acid formulations134; however, data from the ADVENT study145 showed no significant differences in uric acid levels between patients treated with prolonged-release nicotinic acid 1-1.5 g daily or placebo at any time point during the study. As a precaution, however, uric acid levels should be monitored at regular intervals in patients treated with prolonged-release nicotinic acid, particularly in patients with gout. Readers are referred to the manufacturer's product information for complete information relating to contraindications and precautions for use of prolonged-release nicotinic acid.

Recommendations for potential new treatment strategies

Compelling data show that the prevalence of diabetes and metabolic syndrome is escalating dramatically. Given the increased cardiovascular risk associated with these conditions, this European Consensus Panel views aggressive reduction of CHD risk as a priority in clinical management.

Current treatment guidelines20-22,78 recognise the increased risk of cardiovascular morbidity and mortality associated with diabetes and metabolic syndrome, and highlight the statins, in addition to dietary and lifestyle intervention, as the foundation of lipid- modifying in these patients. However, while there is no doubt that statins are effective in patients with diabetes (although there is less evidence in patients with metabolic syndrome), there remains a high level of residual vascular risk.

Clearly, there is a need to target other lipids, particularly the low HDL-C, elevated triglycerides and increase in small, dense LDL characteristic of the atherogenic dyslipidaemia associated with both diabetes and metabolic syndrome. The combination of a statin (which targets LDL-C) with another treatment specifically targeting HDL-C and triglycerides would be a logical strategy to optimise cardiovascular risk reduction.

The current evidence base supports that the use of combination therapy with a statin and nicotinic acid or a fibrate, in addition to diet and lifestyle intervention, may further reduce cardiovascular risk. Nicotinic acid is the more potent agent for increasing HDL-C; it also substantially lowers triglycrides and LDL- C, as well as promoting a shift in LDL composition from small, dense particles, characteristic of the dyslipidaemia associated with type 2 diabetes and metabolic syndrome, to larger more buoyant (and potentially less atherogenic) LDL particles. Thus, the available evidence indicates that prolonged-release nicotinic acid in combination with a statin would be a useful treatment strategy.

Clinical trial data support the potential of this combination in patients with diabetes and (to a lesser extent) metabolic syndrome. Data have shown that this combination reduced the frequency of major coronary events and was useful in slowing of progression of atherosclerosis, as demonstrated by reduced CIMT progression rates.

Recent studies have clarified that nicotinic acid may be used safely in diabetic patients without any clinically relevant deterioration in glycaemic control. In fact, treatment recommendations produced by the ADA in 200478 state that nicotinic acid (≤ 2 g/day) is a suitable treatment for use in combination with a statin, with any deterioration in glycaemic control easily remediable by adjustment of hypoglycaemic medications.

The overall consensus of this Panel is that nicotinic acid combined with a statin is an acceptable treatment option in patients with type 2 diabetes and metabolic syndrome considered at high CHD risk. The availability of a prolonged-release formulation of nicotinic acid with improved tolerability compared with previous formulations is an obvious advantage for clinicians and patients.

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