Type 2 Diabetes Mellitus,Metabolic Syndrome,and Mixed Dyslipidemia: How Similar,How Different,and How to Treat?

Abstract

Individuals with mixed atherogenic dyslipidemia, type 2 diabetes mellitus (T2DM), and metabolic syndrome are at high risk of developing cardiovascular disease (CVD) and can often benefit greatly from preventive lifestyle and medical interventions. These conditions typically co-exist in an individual, and the lipid profiles associated with them have several features in common. The worldwide prevalence of T2DM, atherogenic dyslipidemia, and metabolic syndrome is increasing, particularly in southern Asia and the Middle East. Statins can lower low-density lipoprotein-cholesterol and reduce the risk of CVD in these high-risk individuals, but there is a residual risk of CVD associated with additional lipid abnormalities, such as high levels of triglycerides and low levels of high-density lipoprotein cholesterol. These abnormalities are commonly found in patients with T2DM and metabolic syndrome. Additional lipid-modifying therapies that target these abnormalities, such as fibrates and omega-3 polyunsaturated fatty acids, may be able to improve lipid profiles and further reduce the risk of CVD in these patients.

Introduction

Type 2 diabetes mellitus (T2DM) and dyslipidemia are important risk factors for the development of cardiovascular disease (CVD).^1,2 Patients with these conditions have the potential to benefit greatly from intensive primary and secondary CVD prevention strategies.^3,4 Patterns of dyslipidemia strongly associated with atherosclerosis, and an increased risk of CVD, are elevated apolipoprotein B, the presence of small, dense low-density lipoproteins (LDLs), elevated levels of triglycerides (TGs), and low levels of high-density lipoprotein-cholesterol (HDL-C).⁵ This combination is known as atherogenic dyslipidemia and is commonly observed in patients with T2DM.⁶ The clustering of T2DM and various components of atherogenic dyslipidemia, in combination with other risk factors for CVD, such as hypertension and obesity, has been referred to as metabolic syndrome.^7,8 As discussed below, several definitions of this condition have been proposed.

In line with the rising prevalence of obesity, T2DM and metabolic syndrome are becoming more prevalent worldwide. The rate of increase is particularly rapid in developing countries, and it is in these emerging economies that the greatest expansion in the number of patients with T2DM or metabolic syndrome is expected over the coming decades.^9,10 Areas with particularly high levels of obesity, diabetes, and metabolic syndrome include southern Asia and the Middle East.^9
–11

Definition of T2DM

T2DM is typically characterized by hyperglycemia resulting from a progressive defect in insulin production in the context of insulin resistance. Initially, insulin levels may be increased in absolute terms but low in relation to blood glucose levels; however, absolute insulin deficiency develops as pancreatic insulin production deteriorates.¹² T2DM can be diagnosed on the basis of a glycated hemoglobin A_1c (HbA_1c) concentration ≥6.5%, fasting plasma glucose (FPG) levels ≥126 mg/dL (7.0 mmol/L), or 2-hr plasma glucose levels ≥200 mg/dL (11.1 mmol/L) in an oral glucose tolerance test (OGTT).^13,14 An HbA_1c value of 6.5% by the Diabetes Control and Complications Trial measure is equivalent to 48 mmol/mol using International Federation of Clinical Chemistry units.¹⁵ Thresholds have also been defined for prediabetic conditions, where glucose levels are higher than normal but lower than the threshold for T2DM.¹⁶ These are impaired fasting glucose (IFG), defined by fasting plasma glucose levels of 100–125 mg/dL (5.6–6.9 mmol/L), and impaired glucose tolerance (IGT), defined by OGTT values of 140–199 mg/dL (7.8–11.0 mmol/L).¹³ Individuals with IFG or IGT are at high risk of T2DM, with around 5%–10% developing the condition annually, and they also have an increased risk of developing CVD.¹⁶

When originally defined by Reaven,¹⁷ metabolic syndrome was defined as a cluster of CVD risk factors caused by underlying insulin resistance. This original definition required complex laboratory measurements, whereas more recent definitions, intended for use by clinicians, are based on measurements that are easy to obtain, such as the International Diabetes Federation (IDF) criteria.⁷ However, the usefulness of diagnosing metabolic syndrome in a clinical setting has been questioned.^18,19 First, although metabolic syndrome is a good predictor for the future development of CVD and T2DM, it has been argued that it is no better for this purpose than the sum of its individual components or other risk prediction tools.¹⁹ Unlike the Framingham score,²⁰ metabolic syndrome is not an absolute risk indicator because it does not include a number of the factors required to determine absolute risk, for example, age, gender, and cigarette smoking status.^8,21 Furthermore, the pharmacological treatments appropriate for patients with metabolic syndrome do not differ from those for the individual components.¹⁹ One further limitation of the definition is that it applies a binary definition to a variable combination of factors that each have a continuous association with CVD risk.⁷

The existence of metabolic syndrome as a distinct entity has also been questioned; this is mainly because, although it is strongly associated with obesity, a specific underlying mechanism has not been identified.^18,19 Although it was originally thought to stem from insulin resistance,¹⁷ one-half to two-thirds of patients with metabolic syndrome might not be insulin resistant according to standard definitions, and the relationship between insulin resistance and other CVD risk factors is unclear.¹⁹

Definition of Metabolic Syndrome

Several expert groups have published criteria for the diagnosis of metabolic syndrome. These include the World Health Organization (WHO), the European Group for the Study of Insulin Resistance (EGIR), the IDF and the National Cholesterol Education Program Adult Treatment Panel III (NCEP ATP III). These definitions all contain four central components: Abnormal glucose metabolism, dyslipidemia, hypertension, and obesity.⁸ However, there are important differences between the definitions. For example, central obesity is obligatory for the IDF definition, but not the EGIR, WHO, and NCEP ATP III definitions.^7,8 Furthermore, waist circumference (WC) is used to define central obesity in the EGIR, IDF, and NCEP ATP III definitions, whereas waist-to-hip ratio is used for the WHO definition. The WC thresholds used to define central obesity also vary among definitions.²¹

The existence of different definitions has caused confusion, particularly for clinicians attempting to diagnose metabolic syndrome.^7,8 The IDF and the American Heart Association/National Heart, Lung, and Blood Institute (AHA/NHLBI) are therefore working toward a consensus definition that does not make obesity a mandatory requirement, provided at least three other risk factors are present.²¹ In addition, the IDF/AHA/NHLBI guidelines have incorporated ethnic-specific measurements for defining obesity by WC.²¹

Definitions of Atherogenic Dyslipidemia

Dyslipidemia is a characteristic pattern of abnormalities in serum lipids that is commonly observed in patients with T2DM or metabolic syndrome. Primary dyslipidemias can occur independently of metabolic syndrome or T2DM as a result of single or multiple gene mutations causing abnormal levels of one or more serum lipids. Familial hypercholesterolemia affects around 1 in 500 people (with higher frequencies in relatively isolated or founder populations, such as Ashkenazi Jews, Afrikaners, and South African Indians)²² and is associated with over 1200 polymorphisms in the genes encoding the LDL receptor, apolipoprotein B, or proprotein convertase subtilisin/kexin 9 (PCSK9), leading to elevated LDL-cholesterol (LDL-C).²³ Untreated, familial hypercholesterolemia is associated with early-onset CVD; LDL-C levels correlate directly with CVD across many populations.²⁴ Familial combined hyperlipidemia is characterized by overproduction of apolipoprotein B-containing lipoproteins and TGs, resulting in early-onset CVD.²⁵ The genetic defects underlying this disorder (prevalence 0.5%–0.25%) are not completely understood; at least 35 genes have been implicated.²⁶ Other causes of dyslipidemia in the absence of T2DM and metabolic syndrome include excessive alcohol consumption,^27,28 cholestatic liver diseases,²⁹ renal disease,^30
–32 hypothyroidism,³³ and some medications (e.g., thiazide diuretics, beta blockers, atypical antipsychotics, and HIV protease inhibitors).^34
–36

In patients with atherogenic dyslipidemia, the characteristic pattern of serum lipid abnormalities includes low levels of HDL-C, elevated levels of TGs, and the presence of small, dense LDL.³⁷ High levels of LDL–apolipoprotein B are sometimes included in the definition, because this provides a more accurate measurement of the number of LDL particles than LDL concentration alone because there is one apolipoprotein B molecule per LDL particle.³⁸ Elevated TGs and low HDL-C are also included in the definition of metabolic syndrome (Table 1).

Table 1.

Components of Metabolic Syndrome and Atherogenic Dyslipidemia

Component	Metabolic syndrome (IDF definition) ^a	Atherogenic dyslipidemia
T2DM diagnosis	Yes	No
Impaired fasting glucose	Yes	No
Large waist circumference	Yes	No
High LDL-C	No	No
High TGs	Yes	Yes
Low HDL-C	Yes	Yes
High Apo B	No	Yes
Small, dense LDL	No	Yes
Elevated arterial blood pressure^b	Yes	No

Yes=included in definition; No=not included in definition.

At least three of these factors should be present for a diagnosis of metabolic syndrome. The IDF definition includes fasting plasma glucose (FPG) ≥100 mg/dL (5.6 mmol/L) or previously diagnosed T2DM. If FPG >100 mg/dL (5.6 mmol/L), an oral glucose tolerance test is strongly recommended but is not necessary to define presence of the syndrome.

≥130/85 mmHg.^7,21

IDF, International Diabetes Federation; T2DM, type 2 diabetes mellitus; LDL-C, low-density lipoprotein-cholesterol; TGs, triglycerides; HDL-C, high-density lipoprotein-cholesterol; Apo, apolipoprotein.

The lipid abnormalities characterizing atherogenic dyslipidemia promote atherosclerosis and increase the risk of CVD.³⁸ HDL-C has a role in reverse cholesterol transport, removing excess cholesterol from the peripheral tissues, including the arterial walls, to the liver for metabolism and excretion in the bile salts.^38,39 There is a strong, independent correlation between reduced HDL-C and increased CVD risk, and it has been suggested that low levels of HDL-C may promote atherosclerosis through reduced reverse cholesterol transport as well as a range of other effects, such as reduced anti-inflammatory, antioxidant, and antiapoptotic effects.^40,41 Several studies have shown that elevated TGs are associated with an increased risk of CVD, but there is some controversy as to whether they are an independent risk factor,⁴² and mixed evidence as to whether treating high TG levels reduces cardiovascular outcomes.⁴³ The principal significance of an elevated TG level may be as a biomarker for increased levels and atherogenic properties of other lipoproteins.⁴⁴ These include several TG-rich lipoproteins, such as very low-density lipoproteins (VLDLs), which can be loaded with cholesterol and taken up by macrophages in the arterial wall.⁴⁵ Small, dense LDLs are independently associated with increased CVD risk.⁴⁶ The mechanism of their atherogenic potential is unclear, although their small size may allow easier access to the subintimal space, greater susceptibility to chemical modification, and enhanced uptake by, and activation of, macrophages in the arterial wall.³⁸

Coexistence of Diabetes Mellitus, Metabolic Syndrome, and Atherogenic Dyslipidemia: Implications for Management

Epidemiology

Diabetes mellitus

Diabetes (including type 1 and type 2) is a major cause of morbidity and mortality worldwide. The IDF estimated that 336 million people worldwide had diabetes in 2011, and this is predicted to increase to 552 million by 2030.⁴⁷ Diabetes was responsible for 4.6 million deaths in 2011, and this is expected to rise further in the future.^47,48 The risk of developing CVD increases significantly in patients with diabetes,^49
–51 and approximately half of all deaths related to diabetes are caused by CVD.⁴⁷ Up to 86% of patients with T2DM have metabolic syndrome, and a significant proportion have atherogenic dyslipidemia, which may further increase the risk of CVD in these already high-risk patients (Table 2).^52
–54

Table 2.

Coexistence of T2DM, Metabolic Syndrome, and Atherogenic Dyslipidemia

	Patients with concomitant condition (%)
Condition	T2DM	Metabolic syndrome	Atherogenic dyslipidemia ^a
T2DM	100%	86%³⁵	35–56%³⁷
Metabolic syndrome	34%³⁵	100%	100%^b
Atherogenic dyslipidemia^a	21% [patients with HDL-C <38 mg/dL (1 mmol/L) during statin therapy]²⁵	NA	100%

Low HDL-C, elevated TGs.

All definitions of metabolic syndrome include low HDL-C and elevated TGs.

T2DM, type 2 diabetes mellitus; HDL-C, high-density lipoprotein-cholesterol; NA, not applicable.

Although typically associated with the sedentary lifestyle and carbohydrate-rich diet common in developed countries, T2DM is rapidly becoming more common in the developing world.⁹ Approximately 80% of the global population with diabetes now live in low- or middle-income countries,⁴⁷ and the rise in T2DM prevalence is expected to be greater in these countries compared with high-income countries.^9,48 Areas with a particularly high prevalence of T2DM include India, China, and some countries in the Middle East, such as Saudi Arabia and the United Arab Emirates.⁹ Some ethnic minority populations in developed countries also have a high prevalence of T2DM, such as the Inuit and urbanized Hispanic populations in North America and South Asians in the United Kingdom.^9,47,48,55 A combination of environmental and genetic factors is responsible for the increase of T2DM in the developing world.⁹

Metabolic syndrome

Reports of the prevalence of metabolic syndrome should be compared with caution owing to the use of different definitions. However, it is estimated that 20%–25% of the global population have metabolic syndrome.⁵⁶ Individuals with metabolic syndrome are twice as likely to develop CVD within 5–10 years and have a five-fold increased risk of developing T2DM compared with those without the syndrome.²¹ Around 34% of patients with metabolic syndrome have T2DM (Table 2). The prevalence of metabolic syndrome is increasing in the developing world, with a particularly high burden in southern Asia.^10,57,58 In India, the prevalence ranges from 20% to 50%,¹⁰ with urban populations typically having a much higher prevalence than rural populations.⁵⁹

Lifestyle changes related to economic improvement are partly responsible for the rise in the prevalence of metabolic syndrome in the developing world. These include increasing urbanization, a shift toward diets rich in saturated and trans fats, refined carbohydrates and cholesterol, and a more sedentary lifestyle.^10,11,57 Ethnic and genetic factors are also important. Compared with white individuals, South Asians have more body fat relative to body mass index (BMI), and most notably, increased truncal subcutaneous and intra-abdominal fat.^10,11 As a result, diabetes and dyslipidemia can occur at a lower BMI in this population. Genetic polymorphisms present in South Asians have also been linked to obesity, diabetes, dyslipidemia, and metabolic syndrome.¹⁰ For example, the Xba1, Ins/Del, and EroR1 polymorphisms, which are more common in South Asians than white subjects, are associated with a higher BMI and high levels of total serum cholesterol and TG.⁶⁰ It has also been hypothesized that certain ethnic groups, such as South Asians, possess a so-called ‘thrifty genotype’ that is linked to more effective storage of food energy. This genotype is thought to have been selected during evolution because it improved survival during famine in certain preindustrial populations, but it predisposes to obesity when food is abundant.⁶¹ This idea is controversial and specific causal genes have not been identified.^61,62

Atherogenic dyslipidemia

Most definitions of atherogenic dyslipidemia include elevated TGs, low HDL-C, and the presence of small, dense LDLs.^5,38 The thresholds for defining what constitutes abnormal levels of these lipids vary between studies, and the definition of clinically relevant thresholds can be complicated by variations between ethnic groups.¹⁰

Indeed, the prevalence of atherogenic dyslipidemia varies between populations. In an analysis from the Framingham Heart Study, approximately 10% of the general population (119 of 1308 individuals) had elevated TGs (defined as ≥90th percentile for age and sex) and low HDL-C levels (defined as <25th percentile for age and sex).⁶³ A study in Germany found that despite statin therapy, 47% of patients had TGs above guideline target levels (1.7 mmol/L), 23% had HDL-C levels below target (1.0 and 1.2 mmol/L for men and women, respectively), and 15% had elevated TG and low HDL-C levels.⁶⁴

The incidence of atherogenic dyslipidemia increases dramatically in patients with T2DM.^54,65,66 The lipid profile is typically characterized by hypertriglyceridemia and low HDL-C, with this pattern becoming progressively more apparent in T2DM patients and those with IFG, compared with those with normal fasting glucose.⁶⁷ Over one-half of men and over two-thirds of women have low levels of HDL-C and over one-half have elevated TGs.⁶⁵ Additionally, changes related to insulin resistance lead to an increased presence of small, dense LDL particles, which are considered highly atherogenic.⁶⁸ The combination of T2DM and atherogenic dyslipidemia appears to increase the risk of CVD to three to four times that of a nondiabetic patient with dyslipidemia.^66,68 Despite these observations, several well-conducted studies showed no overall cardiovascular benefit from drugs that lowered TG or increased HDL-C levels.⁴³

The lipid abnormalities of atherogenic dyslipidemia are not consistently associated with an increased risk of CVD in all racial groups.¹⁰ For example, low HDL-C was not a significant risk factor for CVD in one Japanese population,⁶⁹ despite it being strongly linked to CVD in other populations.^40,41

The prevalence of atherogenic dyslipidemia ranges from 10% to 73% in South Asian populations, with higher levels in urban populations; recently, increases have been reported in those of low socioeconomic status.^11,70 South Asians have higher average levels of TG and lower levels of HDL-C compared with white populations.^11,70 Asian Indians have a higher prevalence of small, dense LDL (∼50%) compared with whites (∼30%) and blacks (∼20%).⁷¹ Polymorphisms present in the South Indian population may be associated with lipid abnormalities. These include variants of the genes coding for apolipoproteins B and E, which are associated with the transport and metabolism of lipids and myostatin, which regulates muscle mass and has been associated with the development of excess adiposity.^60,72
–74 A gender-specific role for a tumor necrosis factor-α-A gene variant associated with truncal fat in Asian women has been reported recently.⁷⁵ The independent significance of hypertriglyceridemia in these populations remains unclear, and cardiovascular outcomes studies of reduction of TGs in South Asian patients are lacking.

Implications for prognosis and management

Individuals with metabolic syndrome, atherogenic dyslipidemia, or T2DM have an increased risk of developing CVD and can therefore benefit from therapeutic intervention. Lifestyle interventions are important, and advice on exercise and diet should be a part of all treatment plans.⁴ In addition, pharmacological lipid management has been shown to improve CVD outcomes and mortality in both those with or at risk of CVD.

Statins

Statins reduce plasma LDL-C levels by inhibiting the cholesterol synthesizing enzyme 3-hydroxy-3-methylglutaryl coenzyme A.⁷⁶ Statins also have moderate effects on TG and HDL-C levels.^52,77 The mechanism by which statins affect TG levels is unclear, although there is evidence that they reduce hepatic secretion of VLDL TGs into the plasma.⁷⁶ Statins are thought to raise HDL levels by reducing the rate of cholesteryl ester transfer protein (CETP)-mediated flow of cholesterol from HDL, although the effects on HDL may vary between individual statins.⁷⁸

An updated meta-analysis by the Cholesterol Treatment Trialists' (CTT) collaboration included five trials of more versus less statin-intensive regimens (39,612 patients) and 21 trials of a statin versus control (129,526 patients). Across all 26 trials, all-cause mortality was reduced by 10% per 1.0 mmol/L LDL-C reduction (P<0.0001). This improvement mainly reflected the 20% reduction in deaths caused by coronary heart disease (P<0.0001) and the 11% reduction in deaths due to other cardiac causes (P=0.002). Because there was no evidence of a threshold within the cholesterol range studied, the authors proposed that a reduction of LDL-C by 2–3 mmol/L would reduce the risk of major cardiovascular events by 40–50% (Table 3).²⁴

Table 3.

Effect of Statins and Fibrates on Lipid Levels and/or Cardiovascular Event Rates in Clinical Trials

Study	Treatment comparison (dose/day)	No. of patients, duration	Diabetes, n (%) metabolic syndrome, n (%) atherogenic dyslipidemia, n (%)	End points	Outcomes
WOSCOPS⁹²	Pravastatin 40 mg versus placebo	6595, mean 4.9 years	76 (1) NR NR	Primary: nonfatal MI or death from CHD	RRR in primary end point: 31% (95% CI 17%–43%; P<0.001)
AFCAPS/TexCAPS⁸³	Lovastatin 20–40 mg versus placebo	6605, mean 5.2 years	155 (2) NR NR	Primary: fatal or nonfatal MI, unstable angina or sudden cardiac death	RRR in primary end point: 37% (RR 0.63; 95% CI 0.50–0.79; P<0.001)
ASCOT-LLA⁹¹	Atorvastatin 10 mg versus placebo	10,305, median 3.3 years	2532 (25) NR NR	Primary: nonfatal MI or death from CHD	RRR in primary end point: 36% (HR 0.64; 95% CI 0.50–0.83; P=0.0005)
CTT meta-analysis of 26 studies^100,a	Atorvastatin 10–80 mg, fluvastatin 40–80 mg, lovastatin 2.5–80 mg, simvastatin 20–80 mg, pravastatin 10–40 mg, rosuvastatin 10–20 mg versus placebo or no treatment	169,138, median 4.9 years	32,210 (19) NR NR	Principal: all-cause mortality, CHD mortality and non-CHD mortality	10% reduction in all-cause mortality (rate ratio 0.90; 95% CI 0.87–0.93; P<0.0001); 20% reduction in CHD mortality (0.80; 95% CI 0.74–0.87; P<0.0001) per mmol/L reduction in LDL-C
Meta-analysis of 12 studies⁸¹	Atorvastatin 10 mg, fluvastatin 40 mg b.i.d,, lovastatin 20 mg, simvastatin 20–40 mg, pravastatin 40 mg, gemfibrozil 600 mg b.i.d. versus placebo or no treatment	80,862, 3.2–6.1 years	16,279 (20) NR NR	Primary outcome: coronary events (CHD death, nonfatal MI, myocardial revascularization procedure)	Primary prevention Diabetic patients: RRR 21% (95% CI 11%–30%; P<0.0001) Nondiabetic patients: RRR 23% (12–33%; P=0.0003) Secondary prevention Diabetic patients: RRR 21% (95% CI 10%–31%; P=0.0005) Nondiabetic patients: RRR 23% (95% CI 19%–26%; P≤0.00001)
PREVEND substudy⁸⁵	Pravastatin 40 mg versus placebo	864, mean 3.8 years	69 (8) 283 (33) NR	Primary end point: major adverse cardiac events (total mortality and cardiovascular morbidity) at 4 years	In patients with metabolic syndrome the primary end point occurred in 12.2% of the control group versus 6.1% of the pravastatin group Pravastatin significantly reduced the HR for major adverse cardiac events (HR 0.39; 95% CI 0.17–0.89; P=0.025)
TNT subanalysis⁸²	Atorvastatin 10 or 80 mg	5584, mean 4.9 years	1231 (22) 5584 (100) NR	Primary end point: major cardiovascular event (CHD death, nonfatal MI, resuscitated cardiac arrest, or fatal or nonfatal stroke)	Primary end point in 13% of atorvastatin 10 mg patients versus 9.5% receiving 80 mg RRR 29% in favor of 80 mg (HR 0.71; 95% CI 0.61–0.84; P<0.0001)
4S post hoc analysis⁷⁹	Simvastatin 20–40 mg versus placebo	1003, median 5.4 years	65 (6) NR 458 (46)	End point: major coronary events	Greatest RRR versus placebo 52% in patients with lipid triad (RR 0.48; 95% CI 0.33–0.69) Significantly greater (P=0.03) than in patients with elevated LDL-C alone (RR 0.86; 95% CI 0.59–1.26)
FIELD⁸⁷	Fenofibrate 200 mg versus placebo	9795, median 5 years	9795 (100) NR 3710 (38)	Primary end point: CHD events (CHD death, nonfatal MI) Secondary: total cardiovascular events (CVD death, MI, stoke, revascularization)	Primary end point: RRR 11% (HR 0.89; 95% CI 0.75–1.05; P=0.16) Secondary: RRR 11% (HR 0.89; 95% CI 0.80–0.99; P=0.035)
ACCORD⁸⁶	Simvastatin 20–40 mg+placebo versus simvastatin 20–40 mg+fenofibrate 160 mg	5518, mean 4.7 years	5518 (100) NR NR	Primary end point: CHD death, nonfatal MI, nonfatal stroke	Primary end point: RRR with fenofibrate 8% (HR 0.92; 95% CI 0.79–1.08; P=0.32) In patients with high TGs and low HDL-C, primary outcome rate 12.4% with fenofibrate, 17.3% with placebo (P=0.057)
BIP⁸⁰	Bezafibrate (400 mg) versus placebo	3090, mean 6.3 years	309 (10) NR NR	Primary end point: fatal or nonfatal MI or sudden death	Primary end point: RRR 7.3% (P=0.24)
HHS^84,89	Gemfibrozil (1200 mg) versus placebo	4081, mean 5 years	135 (3) NR NR	Primary end point: CHD events	RRR 34%
LOCAT¹¹¹	Gemfibrozil (1200 mg) versus placebo	395, mean 2.7 years	0 NR NR	Primary end point: change in per-patient means of average diameters of native coronary segment	Primary end point: –0.04±0.11 mm in the placebo group and −0.01±0.10 mm in the gemfibrozil group (P=0.009)
VA-HIT⁹⁰	Gemfibrozil (1200 mg) versus placebo	2531, mean 5.1 years	NR NR NR	Primary end point: nonfatal MI and CHD death	Primary end point: RRR 22% (P=0.006)
Meta-analysis of six studies⁸⁸	Simvastatin 20–40 mg+placebo versus simvastatin 20–40 mg+fenofibrate 160 mg Bezafibrate versus placebo Fenofibrate 200 mg versus placebo Gemfibrozil versus placebo	25,410, 2.7–6.3 years	NR NR 5068 (20)	Primary end point: cardiovascular events (nonfatal MI, nonfatal stroke) or coronary events (nonfatal MI, nonfatal stroke, sudden death)	Primary end point: High TG and low HDL-C RRR 29% (RR 0.71; 95% CI 0.62–0.82; P<0.001) High TGs RRR 25% (RR 0.75; 95% CI 0.65–0.86; P<0.001) Low HDL-C RRR 16% (RR 0.84; 95% CI 0.77–0.91; P<0.001) Neither high TGs nor low HDL-C (RR 0.96; 95% CI 0.85–1.09; P=0.53)

Dose ranges summarized for each statin in the CTT meta-analysis.

4S, Scandinavian Simvastatin Survival Study; ACCORD, Action to Control Cardiovascular Risk in Diabetes; AFCAPS/TexCAPS, Air Force/Texas Coronary Atherosclerosis Prevention Study; ASCOT-LLA, Lipid-Lowering Arm of the Anglo-Scandinavian Cardiac Outcomes Study Trial; b.i.d., twice daily; BIP, Bezafibrate Infarction Prevention; CHD, coronary heart disease; CI, confidence interval; CTT, Cholesterol Treatment Trialists; FIELD, Fenofibrate Intervention and Event Lowering in Diabetes; HDL-C, high-density lipoprotein-cholesterol; HR, hazard ratio; HHS, Helsinki Heart Study; LDL-C, low-density lipoprotein-cholesterol; LOCAT, Lopid Coronary Angiography Trial; MI, myocardial infarction; NR, not reported/recorded; NS, not significant; PREVEND, Prevention of Renal and Vascular End-stage Disease; RR, relative risk; RRR, relative risk reduction; TGs, triglycerides; TNT, Treating to New Targets; VA-HIT, Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial; WOSCOPS, West of Scotland Coronary Prevention Study.

Statins are clearly effective at preventing morbidity and mortality from CVD in general populations and in many subgroups, including patients with T2DM, metabolic syndrome, or atherogenic dyslipidemia, and can slow the development of atherosclerosis (P<0.001 for statins versus placebo) (Table 3).^83,91,92

Although reduction of LDL-C with a statin is of proven benefit in diabetic patients,⁹³ patterns of atherogenic dyslipidemia persist in 35%–56% of them despite such treatment.⁵⁴ A meta-analysis of 20 trials indicated that the benefits of statins in patients with T2DM might be limited by residual low HDL-C.⁹⁴ Persistence of elevated TGs may also play a part.⁹⁵ Results from two recent trials in patients with prior stroke or transient ischemic attack support these suggestions,⁹⁶ but further evidence is required and the treatment of high TG levels to reduce cardiovascular risk is controversial.

A meta-analysis of diabetic versus nondiabetic individuals found that statins or gemfibrozil were equally efficacious in both populations—in primary prevention the relative risk reduction versus placebo for major coronary events was 21% in patients with diabetes versus 23% in nondiabetic patients (Table 3).⁸¹

In a post hoc analysis of the Scandinavian Simvastatin Survival Study (4S), the relative risk reduction in coronary events compared with placebo was greatest in patients with the lowest HDL-C (<1.00 mmol/L) and the highest TG (>1.8 mmol/L) levels, showing a significantly greater (P=0.03) treatment effect than in patients with elevated LDL-C alone (Table 3).⁷⁹ A substudy of the Prevention of REnal and Vascular ENdstage Disease (PREVEND) Intervention Trial found that pravastatin lowered the risk of CVD in patients with metabolic syndrome by approximately two-fold (P=0.025),⁸⁵ and a post hoc analysis of the Treating to New Targets (TNT) study found that atorvastatin (80 mg) reduced CVD events in patients with metabolic syndrome compared with atorvastatin (10 mg) (P<0.0001) (Table 3).⁸²

It has been suggested that East Asians (e.g., Chinese, Japanese, or Korean populations) may have greater responses to low doses of statins than Caucasians due to genetic differences in statin metabolism.⁹⁷ In the MEGA trial (Management of Elevated Cholesterol in the Primary Prevention Group of Adult Japanese) in Japan, pravastatin 10–20 mg/day significantly reduced cardiovascular events compared with the control group (P=0.01), suggesting that Japanese populations obtain substantial benefit from a relatively low statin dose.⁹⁸ The EVIREST study (Efficacy of Vasopressin Antagonism in Heart Failure Outcome Study with Tolvaptan) reported similar improvements in lipid profile between South Asian (Indian, Pakistani, Sri Lankan, or Bangladeshi), black (Afro-Caribbean or African origin), and Caucasian patients treated with 10 mg atorvastatin daily, but whether this translates to comparable improvements in CVD risk between these populations is unknown.⁹⁹

Statins are generally well tolerated, and the CTT meta-analysis found no increased risk for any noncardiovascular cause of death, in particular, no increased risk of cancer.^100,101 However, accumulating data suggest a relationship between statin use and the incidence of T2DM.¹⁰² One meta-analysis of over 90,000 individuals found that statins were associated with a 9% increased risk of developing T2DM (odds ratio [OR] 1.09; 95% confidence interval [CI] 1.02–1.17), but the benefits of statin therapy clearly outweigh this risk in those with higher baseline risk of CVD.¹⁰³ Treatment of 255 (95% CI 150–852) patients with statins for 4 years resulted in one extra case of diabetes, whereas statin therapy was associated with a reduction in major coronary events of 5.4 events per 255 patients compared with control therapy, for a 1 mmol/L reduction in LDL-C concentration.^100,103 The authors reported no clear difference between statins in terms of diabetes risk.¹⁰³ A number of mechanisms have been proposed to explain how statins might cause diabetes,¹⁰⁴ including inhibition of glucose-induced calcium signaling and insulin secretion by beta-cells, reduction in the synthesis of coenzyme Q10, and inhibition of the synthesis of isopenoids.

On the basis of the evidence described above, statins are recommended in higher-risk patients with metabolic syndrome¹⁰⁵ and T2DM.¹⁰⁶ However, clinically significant CVD risk can persist despite effective lowering of LDL-C through statin therapy. Additional lipid abnormalities, such as high TG and low HDL-C levels, may be components of this residual risk.¹⁰⁷ As a result, there has been considerable interest in combining statin therapy with drugs that target one or more of these abnormalities, such as fibrates, niacin, CETP antagonists, and other emerging agents.^107,108

Fenofibrate

Fibric acid derivatives (fibrates) are selective agonists of the peroxisome proliferator receptor-α. They increase HDL-C and reduce TG levels.^108
–110 Two large clinical trials—Fenofibrate Intervention and Event Lowering in Diabetes (FIELD)⁸⁷ and Action to Control Cardiovascular Risk in Diabetes (ACCORD)⁸⁶—investigated the effects of fenofibrate on cardiovascular events in high-risk patients.

In the FIELD trial, 9795 patients with T2DM not receiving statin therapy at entry were randomized to fenofibrate or placebo; 38% of the population had dyslipidemia (defined by high TG and low HDL-C levels).⁸⁷ Fenofibrate was associated with a nonsignificant 11% relative risk reduction (P=0.16) in myocardial infarction (MI) or death due to coronary heart disease, and a significant 24% relative risk reduction in nonfatal MI (P= 0.010) (Table 3).⁸⁷

In the ACCORD study, 5518 patients with T2DM already receiving simvastatin were randomized to receive, in addition, either fenofibrate 160 mg or placebo.⁸⁶ In the overall study population, fenofibrate was not associated with a decreased risk of major cardiovascular events. In patients with high TG (≥3.2 mmol/L) and low HDL-C (≤0.88 mmol/L) levels, the risk of major cardiovascular events was 12.4% in the fenofibrate group versus 17.3% in the placebo group, but the difference did not reach statistical significance (Table 3). The combination of fenofibrate and simvastatin was well tolerated, with a low risk of myopathy.⁸⁶

Despite the somewhat disappointing results in these two trials, a large meta-analysis of the six main outcome trials demonstrated a substantial reduction in risk of cardiovascular events in subjects with high TG (>200 mg/dL or >2.26 mmol/L) and low HDL-C (<40 mg/dL or <1.0 mmol/L) levels. No benefit was seen in patients without these lipid abnormalities (Table 3).⁸⁸ This meta-analysis included FIELD, ACCORD, the Bezafibrate Infarction Prevention (BIP)⁸⁰ study, the Helsinki Heart Study (HHS),⁸⁹ the Lopid Coronary Angiography Trial (LOCAT),¹¹¹ and the Veterans Affairs High-Density Lipoprotein Cholesterol Intervention Trial (VA-HIT).⁹⁰ These results would suggest a potential role for fibrate treatment in patients with residual atherogenic dyslipidemia, particularly those with T2DM, even if they are already receiving a statin. Fibrates vary in their potency in increasing HDL-C and in other properties, such as effects on glucose metabolism,¹¹² but the implications of these differences are not known.

Fibrate monotherapy reduces cardiovascular events in patients with metabolic syndrome, particularly those with low HDL and/or high TGs at baseline.^113,114 This suggests that addition of a fibrate might be logical for patients with metabolic syndrome if the lipid response to a statin is inadequate,¹¹⁵ and some guidelines recommend this option in patients with atherogenic dyslipidemia who have metabolic syndrome and/or diabetes mellitus.⁴ The evidence that this strategy reduces cardiovascular events comes from subgroups and meta-analyses of controlled trials.

Although they are generally well tolerated, there have been concerns about the risk of muscle disorders in patients co-treated with statins and fibrates.¹¹⁶ Monotherapy with statins or fibrates is associated with a low risk of myopathy and rhabdomyolysis, but this risk increases dramatically when statins and fibrates are co-prescribed.¹¹⁶ Case reports have also described this complication in patients with metabolic syndrome.¹¹⁷ The incidence of rhabdomyolysis between 1999 and 2002 was 59.6 cases per million prescriptions for gemfibrozil versus 5.5 per million for fenofibrate.¹¹⁸ Almost all cases occurred when gemfibrozil was co-prescribed with a statin, usually cerivastatin, which has been withdrawn from the market and is no longer available for clinical use.¹¹⁸ As a result, the European Society of Cardiology/European Atherosclerosis Society (ESC/EAS) guidelines recommend that gemfibrozil and statins are not co-prescribed.⁴

Niacin

Nicotinic acid (niacin) is a member of the vitamin B complex, and is thought to exert its effects by blocking fatty acid flux from adipose tissue and inhibiting the release of VLDLs.¹¹⁹ This results in reduced levels of TG and increased levels of HDL-C.¹¹⁹

The effect of niacin on the progression of atherosclerosis has been investigated in a number of trials. In the NIA-Plaque trial, 71 patients already receiving statin therapy were treated with niacin 2 grams daily or placebo.¹²⁰ The primary end point was change in carotid artery wall area, measured by magnetic resonance imaging. Niacin reduced carotid artery wall area by 1.64 mm² (P=0.03) compared with placebo, suggesting a regression of atherosclerosis (Table 4).¹²⁰ In the Arterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 6–HDL and LDL Treatment Strategies in Atherosclerosis (ARBITER 6-HALTS) trial, 363 patients with atherosclerotic CVD or coronary heart disease, with high LDL-C and low HDL-C, were treated with either extended-release niacin 2 grams daily or the cholesterol absorption inhibitor ezetimibe 10 mg daily in addition to a statin.¹²¹ Niacin treatment significantly reduced carotid intima media thickness (CIMT) compared with baseline (P<0.001), whereas ezetimibe had no effect (Table 4).¹²¹

Table 4.

Effect of Niacin With or Without Other Lipid-Lowering Strategies on Lipid Levels and/or Cardiovascular Event Rates in Clinical Trials

Study	Treatment comparison (dose/day)	No. of patients, duration	Diabetes, n (%) metabolic syndrome, n (%) atherogenic dyslipidemia, n (%)	End points	Outcomes
NIA-plaque¹²⁰	Statin+placebo versus statin+niacin 2 grams	71, mean 1 year	43 (61) NR NR	Primary end point: change in carotid wall area at 12 months measured by MRI	Primary end point: niacin group had greater changes in carotid wall area versus placebo (adjusted difference: −1.64 mm² (95% CI −3.12 to −0.16; P=0.03)
ARBITER 6-HALTS¹²¹	Statin+ezetimibe 10 mg versus statin+niacin 2 grams	363, 7±3 months	145 (40) NR NR	Primary end point: change in CIMT	Primary end point: niacin produced significant reductions in mean (−0.0102±0.0026 mm; P< 0.001) and maximal CIMT (−0.0124±0.0036 mm; P=0.001); ezetimibe did not reduce CIMT. Difference between ezetimibe and niacin in mean changes was significant for both mean (P=0.016) and maximal CIMT (P=0.01)
Coronary Drug Project^122,127	Niacin 3 grams, clofibrate 1.8 grams, dextrothyroxine 6 mg, estrogen 2.5 or 5 mg versus placebo	8341, mean 6.2 years (initial study)	NR NR NR	End points included nonfatal MI, total mortality	At 5 years, nonfatal MI was 27% lower in niacin group versus placebo, but there was no difference in total mortality. At a 15-year follow-up total mortality was 11% lower with niacin versus placebo (P=0.0004)
HATS¹²⁴	Simvastatin+niacin 1–4 grams, antioxidants, simvastatin+niacin 1–4 grams+antioxidants versus placebo	160, mean 3 years	25 (16) NR NR	Primary end points: CHD death, MI, stroke, or revascularization; change in coronary artery stenosis	Frequency of clinical end point: 3% with simvastatin+niacin 14% with simvastatin+niacin+antioxidants 21% with antioxidants alone, 24% with placebo Average stenosis: regressed 0.4% with simvastatin+niacin alone (P< 0.001 versus placebo). Progressed 0.7% with simvastatin+niacin+antioxidants (P=0.004 versus placebo) Progressed 1.8% with antioxidants (P=0.16 versus placebo) Progressed 3.9% with placebo
FATS¹²⁵	Lovastatin 40 mg+colestipol 30 mg Niacin 4 g+colestipol 30 mg versus placebo (±colestipol)	146, mean 2.5 years	NR NR NR	End points: progression of atherosclerosis in coronary arteries; clinical event (MI, death, or revascularization)	Clinical end point occurred in: 2/48 patients in niacin–colestipol arm (P=0.01 versus placebo); 3/46 in lovastatin–colestipol arm (P=0.01) versus placebo; 10/52 in placebo arm Progression of lesions less frequent with niacin+colestipol or lovastatin+colestipol, regression more frequent with placebo
ADMIT¹²⁸	Niacin 3 g versus placebo	468, mean 1.1 years	125 (27) NR NR	End point: changes in blood lipid profile	Niacin↑HDL-C 29% and 29%;↓TGs 23% and 28% and↓LDL-C 8% and 9% in patients with and without diabetes, respectively (P< 0.001 versus placebo for all)
ADVENT¹²⁹	Niacin 1 g or 1.5 g versus placebo (47% receiving statins)	148, mean 0.31 year	148 (100) NR 148 (100)	Primary end point: change in lipid profile	↑HDL-C 19–24% in both niacin arms versus placebo (P< 0.05) ↓TGs 13–28% versus placebo in 1.5 grams niacin arm (P< 0.05)
Meta-analysis of 14 studies¹²⁶	Niacin 0.25–4 g±statin, ezetimibe, cholestyramine, colestipol, clofibrate or gemfibrozil versus non-niacin-based treatment	6616, 0.5–6.2 years	0–64% NR NR	End points: cardiovascular and coronary events, regression of coronary atherosclerosis	RRR in major coronary events 25% (95% CI 13–35), 27% RRR in cardiovascular events (95% CI 15–37) and 26% RRR stroke (95% CI 8–41) versus non-niacin treatment In niacin group, more patients had regression of atherosclerosis: relative increase 92% (95% CI 39–67); rate of patients with progression↓41% (95% CI 25%–53%)
AIM-HIGH¹²³	Niacin 1.5–2 g+simvastatin 20–80 mg+ezetimibe versus placebo simvastatin 20–80 mg+ezetimibe 10 mg	3414, mean 3 years	34% 81% NR	Primary end point: CHD death, nonfatal MI, ischemic stroke, hospitalization for acute coronary syndrome, revascularization	Primary end point: 16.4% niacin group versus 16.2% placebo group (HR 1.02; 95% CI 0.87–1.21; P=0.79)
HPS2-THRIVE¹³⁰	Niacin 2 g+laropiprant 40 mg+simvastatin 40 mg+ezetimibe versus placebo+simvastatin 40 mg+ezetimibe	25,673, median 3.9 years	32% NR NR	Primary end point: major coronary events (nonfatal MI or coronary death), fatal or nonfatal stroke, revascularization	Primary end point: RR 0.96 (95% CI 0.90–1.03; P=0.29)

ADMIT, Arterial Disease Multiple Intervention Trial; ADVENT, Assessment of Diabetes Control and Evaluation of the Efficacy of Niaspan Trial; AIM-HIGH, Atherothrombosis Intervention in Metabolic Syndrome With Low HDL/High Triglycerides: Impact on Global Health Outcomes; ARBITER-6 HALTS, ARterial Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 6–HDL and LDL Treatment Strategies; CHD, coronary heart disease; CI, confidence interval; CIMT, carotid intimal thickness; FATS, Familial Atherosclerosis Treatment Study; HATS, HDL-Atherosclerosis Treatment Study; HDL-C, high-density lipoprotein-cholesterol; HR, hazard ratio; HPS2-THRIVE, Treatment of HDL to Reduce the Incidence of Vascular Events; LDL-C, low-density lipoprotein-cholesterol; MI, myocardial infarction; MRI, magnetic resonance imaging; NR, not reported; RR, relative risk; RRR, relative risk reduction; TGs, triglycerides.

In the Coronary Drug Project, niacin 3 grams daily was associated with significantly reduced all-cause mortality of 11% versus placebo at the 15-year follow-up (P=0.0004) (Table 4).¹²⁷ Subsequently, several studies in various patient populations showed that niacin has favorable effects on lipid profile and might reduce cardiovascular events (Table 4).^{124,125,128,129} A meta-analysis of these studies found that niacin significantly reduced major coronary events by 25%, strokes by 26%, and cardiovascular events by 27%.¹²⁶

Niacin has been associated with side effects, including incident diabetes in a small proportion of patients¹³¹ and an increase in fasting glucose levels. In a secondary analysis of 946 hyperlipidemic patients randomized to simvastatin/ezetimibe (20/10 mg) or simvastatin/ezetimibe plus extended release niacin, 3.5% of patients in the niacin arm met the criteria for new-onset diabetes, compared with 2.6% of those not receiving niacin¹³² (P=0.06). Similarly, in a post hoc analysis of the Coronary Drug Project,¹³³ niacin versus placebo was associated with a higher incidence of new onset T2DM in patients with IFG (19.8% versus 15.2%; P=0.05). The Arterial Disease Multiple Intervention Trial reported average blood glucose increases of 8.7 mg/dL and 6.3 mg/dL (P<0.05 versus placebo) in diabetics and nondiabetics, respectively, who were treated with up to 3 grams of niacin.¹²⁸ Niacin-induced hyperglycemia may be mediated by a G-protein-coupled receptor GPR109A. Binding of niacin to this receptor strongly inhibits adipocyte TGs lipolysis and fatty acid release, and this may lead to increased fasting glucose.¹³²

Given these data, it has been necessary to determine whether niacin provides additional cardiovascular risk reduction in patients already receiving statin therapy. This was assessed in two trials: Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides: Impact on Global Health Outcomes (AIM-HIGH) and Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE). In AIM-HIGH, 3414 patients receiving simvastatin were treated with niacin or placebo. At 3 years, the rate of cardiovascular events was 16.4% in patients treated with niacin versus 16.2% in placebo, leading to study discontinuation due to lack of efficacy (Table 4).¹²³ In HPS2-THRIVE, niacin plus the antiflushing agent laropiprant or placebo was added to statin therapy in 25,673 patients at high risk of CVD. Niacin again failed to reduce cardiovascular events (Table 4), and it increased diabetes diagnoses as well as the numbers of serious adverse events associated with the gastrointestinal system, musculoskeletal system, skin, infection, and bleeding.¹³⁰ These recent results suggest that niacin has no additional benefits in patients already receiving statin therapy. In view of the lack of efficacy and the increased serious adverse events observed in HPS2-THRIVE, the European Medicines Agency (EMA) suspended authorization of all niacin/laropiprant products in the European Union in January of 2013.¹³⁴ An additional report from AIM-HIGH also described an excess of serious gastrointestinal events and infections/infestations¹³⁵ with niacin. Thus, treatment with niacin cannot be recommended for the prevention of CVD events.

Omega-3 polyunsaturated fatty acids

The potential benefits of omega-3 polyunsaturated fatty acids (PUFAs), such as eicosapentenoic acid (EPA) and docosahexenoic acid (DHA), were first suggested by epidemiological studies linking dietary fish intake to reduced rates of CVD.¹³⁶ This was supported by the Diet and Reinfarction Trial (DART), which randomized over 2000 men with previous MI to either increased intake of dietary fish, increased intake of cereal fiber, or reduced intake of fat.¹³⁷ The patients advised to increase their dietary fish intake had a 29% reduction in 2-year mortality compared with the other groups (P<0.05) (Table 5). However, it should be noted that this study excluded patients with diabetes.

Table 5.

Effect of Omega Fatty Acids, With or Without Other Lipid-Lowering Strategies, on Lipid Levels and/or Cardiovascular Event Rates in Clinical Trials

Study	Treatment comparison (dose/day)	No. of patients, duration	Diabetes, n (%), metabolic syndrome, n (%), atherogenic dyslipidemia, n (%)	End points	Outcomes
DART¹³⁷	Dietary advice: Reduce fat intake, increase ratio of polyunsaturated to saturated fat to 1.0, increase fish intake, increase fiber intake	2033, mean 2 years	Exclusion criterion NR NR	Primary end points: all-cause mortality, CHD events (nonfatal MI, CHD deaths)	Primary end point: all-cause mortality↓29% in patients given versus not given fish advice (RR 0.71; 95% CI 0.54–0.92; P<0.05)
ANCHOR¹⁴⁰	EPA ethyl ester (AMR101) 2 or 4 mg+statin versus placebo+statin	702, 12 weeks	514 (73) NR NR	Primary end point: median percentage change in TG levels from baseline versus placebo	Primary end point: AMR101 4 and 2 g/day↓TG levels 21.5% (P<0.0001) and 10.1% (P=0.0005), respectively
MARINE¹⁴¹	EPA ethyl ester (AMR101) 2 or 4 mg±statin versus placebo±statin	229, 12 weeks	63 (28) NR NR	Primary end point: median percentage change in TG levels from baseline versus placebo	Primary end point: AMR101 4 g/day↓placebo-corrected TG levels 33.1% (P<0.0001); 2 g/day 19.7% (P=0.0051)
JELIS¹³⁹	Statin+EPA ethyl ester 1.8 grams versus statin alone	18,645, mean 4.6 years	3040 (16) NR NR	Primary end point: major coronary event (sudden cardiac death, fatal and nonfatal MI, unstable angina pectoris, revascularization, CABG)	Primary end point: 19% risk↓in major coronary events with EPA versus statin alone (P=0.011)
GISSI-P¹³⁸	Omega-3 PUFA 1 gram, vitamin E 300 mg, or both versus control	11,324, mean 3.5 years	1683 (15) NR NR	Primary end point: death, non-fatal MI, stroke	Primary end point: RRR 10% with omega-3 PUFA (95% CI 1%–18%; P=0.048) versus control; RRR 14% (95% CI 1%–26%) with combined treatment versus control; no effect with vitamin E alone
RP group¹⁴⁴	Omega-3 PUFA 1 gram/day versus placebo (olive oil)	6244 6269, median 5 years	7494 (60) NR NR	Revised primary end point: time to death from CV causes or admission to hospital for CV causes	Revised primary end point: 733 patients (11.7%) in omega-3 PUFA group versus 745 (11.9%) for placebo (HR 0.97; 95% CI 0.88–1.08; P=0.58).
Alpha Omega Trial group¹⁴²	Margarine with EPA+DHA (target intake 400 mg); margarine with ALA (target intake 2 grams); margarine with EPA–DHA and ALA versus placebo	4837, mean 3.3 years	1014 (21) NR NR	Primary end point: fatal and nonfatal CV events	No↓in primary end point with EPA–DHA (HR 1.01; 95% CI 0.87–1.17; P=0.93) or ALA (HR 0.91; 95% CI 0.78–0.05; P=0.20)
OMEGA¹⁴⁶	Standard care+placebo Standard care+omega-3 PUFA 1 gram	3851, 1 year	1032 (27) NR NR	Primary end point: sudden cardiac death	Primary end point: 1.5% in both groups (P=0.84)
Meta-analysis: 48 RCTs, 41 cohort studies¹⁴⁵	Range of doses of omega-3 fats versus control	36,913, 0.5–6 years	NR NR NR	End point: total mortality, cardiovascular events	Omega-3 produced no additional effects on total mortality (RR 0.87; 95% CI 0.73–1.03) or combined CV (RR 0.95; 95% CI 0.82–1.12)
ORIGIN¹⁴³	Omega-3 PUFA 1 gram/day plus insulin glargine or standard care Placebo+insulin glargine or standard care (2×2 factorial design)	6281 6255, median 6.2 years	∼100^a NR NR	Primary end point: death from cardiovascular causes	Primary end point: 574 patients (9.1%) in PUFA group versus 581 patients (9.3%) in placebo group (HR 0.98; 95% CI 0.87–1.10; P=0.72)

Impaired fasting glucose, impaired glucose tolerance or diabetes.

ALA, alpha-linolenic acid; CABG, coronary artery bypass graft; CHD, coronary heart disease; CI, confidence interval; DART, Diet And Reinfarction Trial; DHA, docosahexenoic acid; EPA, eicosapentenoic acid; GISSI-P, Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico-Prevenzione; RP, Risk and Prevention Study Collaborative Group; HR, hazard ratio; JELIS, Japan EPA Lipid Intervention Study; NR, not reported; MARINE, Multi-center, plAcebo-controlled, Randomized, double-blINd; MI, myocardial infarction; ORIGIN, Outcome Reduction with an Initial Glargine Intervention; PUFA, polyunsaturated fatty acid ethyl ester; RCT, randomized controlled trial; RR, relative risk; RRR, relative risk reduction; TGs, triglycerides.

Highly purified omega-3 PUFA preparations have subsequently been developed, and a number of studies have shown that these compounds have a beneficial effect on lipid profile when used at higher doses.^140,141 Several studies and a case report have described the successful use of a statin in combination with omega-3 PUFAs in patients with mixed dyslipidemia, with a particular benefit observed for TG and VLDL levels.^147
–149

Use of highly purified omega-3 supplements appears to reduce the risk of cardiovascular events (Table 5).^{138,139,141,150} In the largest of these studies (Japan EPA Lipid Intervention Study [JELIS]), 1.8 grams/day of EPA led to a significant reduction in major cardiovascular events, primarily via a reduction in coronary instability, with benefits most notable in those with high TG and low HDL levels.^139,151 However, the ORIGIN Trial investigators reported that a lower dose of 1 gram/day did not reduce major clinical CVD events in 6281 patients with or at risk of T2DM compared with 6255 similar patients treated with olive oil placebo,¹⁴³ despite a 23.5±3.0 mg/dL reduction in serum TGs, compared with a 9.0±3.0 mg/dL reduction in the placebo group (P<0.001).¹⁴³ The lack of efficacy on outcomes may have been due to high use of cardioprotective treatments (including statins in >50% of patients), reducing the statistical power to detect any effect.¹⁴³ Similar conclusions were drawn by the Risk and Prevention Study Collaborative Group who examined the effects of 1 gram of n-3 fatty acids in patients with high cardiovascular risk.¹⁴⁴ Analyses according to the presence or absence of atherogenic dyslipidemia at baseline were not reported in either trial.

The Gruppo Italiano per lo Studio della Sopravvivenza nell'Infarto miocardico-Prevenzione (GISSI-P) study of patients with a recent MI was published in 1999. In this trial, in which 15% of patients had diabetes, 1 gram/day of highly purified omega-3 acid ethyl ester supplements was associated with a 20% reduction in all-cause mortality, which in this study was primarily related to a reduction in sudden cardiac death.¹³⁸ Even at study end, <40% of patients were receiving an angiotensin-converting enzyme (ACE) inhibitor or a beta-blocker and <50% were receiving cholesterol-lowering drugs. By contrast, some recent studies have shown no effect of omega-3 fatty acids on the risk of cardiovascular events in post-MI patients, although it should be noted that these studies were considerably underpowered to address the primary end point.^142,146 A meta-analysis of 41 studies found no effect of omega-3 fatty acids on total mortality or combined cardiovascular events, but the composition and doses of supplements varied between studies, and diverse populations were included, ranging from primary prevention and diabetes/prediabetes to recent or distant post-MI (Table 5).¹⁴⁵

A recent large retrospective “real world” outcome evaluation involving over 12,000 patients in the UK demonstrated 21% lower all-cause mortality in those patients treated with 1 gram/day of licensed highly purified n-3 acid ethyl esters within 90 days of an MI (P<0.0001). This mortality benefit was consistent with that observed in the GISSI-P study, but in the context of contemporary care featuring high use of evidence-based medications.¹⁵² A total of 1517 deaths were reported in the study cohort (12.5% of patients). Benefits were particularly notable in patients with T2DM, with crude reductions in all-cause death rates of approximately 13 deaths per 1000 patient-years in patients without diabetes and 28 per 1000 patient-years in those with T2DM (number needed to treat ∼76 and ∼35, respectively). These benefits remained consistent in patients on dual antiplatelet therapy and/or more potent statins and regardless of co-morbidity, use of beta-blockers/ACE inhibitors/antihypertensive drugs, or whether target LDL-C levels were achieved.

Overall, the data summarized above suggest that higher doses and prolonged durations may be necessary to reduce nonfatal MI/acute coronary syndrome (ACS) appreciably. This is emphasized by a prospective observational study among over 40,000 Japanese men and women. Individuals in the highest quintile of dietary n-3 PUFA (median 2.1 grams/day, calculated from dietary fish consumption) had a 67% lower incidence of nonfatal coronary events versus those in the lowest quintile (median 0.3 grams/day).¹⁵³ Further studies are necessary to determine the effects of higher doses and specific formulations of n-3 fatty acids, including differences between ethnic groups.

Cholesterylester transfer protein inhibitors

CETP promotes the transfer of cholesterol from HDL particles to LDL particles. CETP inhibitors prevent this process, leading to increased HDL-C and reduced LDL-C.¹⁰⁸ However, the first large-scale study of a CETP inhibitor in combination with statin treatment, the Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events (ILLUMINATE) trial, was terminated prematurely owing to increased mortality in the torcetrapib treatment arm: 12% of patients in this study had diabetes¹⁵⁴ (Table 6). The mechanism for this increased mortality is unknown. The dal-OUTCOMES trial of dalcetrapib, in which 24% of patients had diabetes, was terminated due to lack of efficacy.¹⁵⁵ A further study, the Randomized EValuation of the Effects of Anacetrapib Through Lipid-modification [REVEAL] (HPS3 TIMI 55) trial with anacetrapib, is in progress.

Table 6.

Effect of CETP Inhibitors and Cholesterol Absorption Inhibitors, With or Without Other Lipid-Lowering Strategies, on Lipid Levels and/or Cardiovascular Event Rates in Clinical Trials

Study	Treatment comparison (dose/day)	No. of patients, duration	Diabetes, n (%) metabolic syndrome, n (%) atherogenic dyslipidemia, n (%)	End points	Outcomes
ILLUMINATE¹⁵⁴	Atorvastatin+torcetrapib 60 mg versus atorvastatin+placebo	15,067, mean 1 year	6661 (44) NR NR	Primary outcome: CHD death, nonfatal MI, stroke hospitalization for UA	Primary end point: torcetrapib↑cardiovascular events (HR 1.25; 95% CI 1.09–1.44; P=0.001) and death from any cause (HR 1.58; 95% CI 1.14–2.19; P=0.006)
dal-Outcomes¹⁵⁵	Evidence-based care+dalcetrapib 600 mg or placebo	15,871, mean 2.6 years	3882 (24) NR NR	Primary outcome: CHD death, nonfatal MI, ischemic stroke, UA, cardiac arrest with resuscitation	Primary end point: dalcetrapib no effect versus placebo (HR 1.04; 95% CI 0.93–1.16; P=0.52)
ENHANCE¹⁵⁹	Simvastatin 80 mg+ezetimibe 10 mg versus simvastatin 80 mg+placebo	720, mean 2 years	13 (0.2) NR NR	Primary outcome: change in mean CIMT	Mean±SE change in CIMT 0.0058±0.0037 mm with simvastatin versus 0.0111±0.0038 mm with simvastatin+ezetimibe (P=0.29)
SHARP¹⁵⁷	Simvastatin 20 mg+ezetimibe 10 mg versus simvastatin 20 mg+placebo	9270, mean 4.9 years	2094 (23) NR NR	Primary end point: major atherosclerotic events (nonfatal MI, CHD death, nonhemorrhagic stroke or revascularization)	Primary end point: 17%↓major atherosclerotic events versus placebo (RR 0.83; 95% CI 0.74–0.94; P=0.0021)
IMPROVE-IT¹⁵⁸	Simvastatin 40 mg+ezetimibe 10 mg versus simvastatin 40 mg+placebo	18,144, target 2.5 years	4916 (27) NR NR	Primary end point: cardiovascular death, nonfatal MI hospitalization for UA, revascularization, stroke	Data awaited

CETP, cholesteryl ester transfer protein; CHD, coronary heart disease; CI, confidence interval; CIMT, carotid-artery intima media thickness; ENHANCE, Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression; ILLUMINATE, Investigation of Lipid Level Management to Understand its Impact in Atherosclerotic Events; IMPROVE-IT, IMProved Reduction of Outcomes: Vytorin Efficacy International Trial; HR, hazard ratio; MI, myocardial infarction; NR, not reported; RR, rate ratio; SE, standard error; SHARP, Study of Heart and Renal Protection; UA, unstable angina.

Greater CETP activity in South Asians than in whites may be a major determinant of their higher prevalence of atherogenic dyslipidemia.¹⁵⁶ South Asians might therefore derive increased benefit from CETP inhibitors, but there are no outcome data to confirm this suggestion.

Cholesterol absorption inhibitors

Cholesterol absorption inhibitors reduce levels of LDL-C by binding to the Niemann–Pick C1-like 1 protein, which contributes to the uptake of cholesterols in the intestine.¹⁶⁰ A combination of a low-dose statin with a cholesterol absorption inhibitor is a promising alternative to high-dose statin therapy.

Two studies have investigated the combination of a statin and cholesterol absorption inhibitor. The Ezetimibe and Simvastatin in Hypercholesterolemia Enhances Atherosclerosis Regression (ENHANCE) trial investigated the effects of simvastatin and ezetimibe on the progression of atherosclerosis in patients with hypercholesterolemia.¹⁵⁹ This combination did not significantly reduce intima media thickness compared with simvastatin alone, although LDL-C levels were decreased (Table 6).¹⁵⁹ Only 0.2% of patients in this study had diabetes.¹⁵⁹ The Study of Heart and Renal Protection (SHARP) investigated the simvastatin–ezetimibe combination in 9270 patients with chronic kidney disease, of whom 23% had diabetes.¹⁵⁷ The combination significantly reduced the risk of major atherosclerotic events in these patients (P=0.0021), but the trial was not powered to determine the effect of ezetimibe on individual components of the composite end point (Table 6). This question may be addressed by the IMProved Reduction of Outcomes: Vytorin Efficacy International Trial (IMPROVE-IT), which is comparing simvastatin monotherapy with simvastatin plus ezetimibe in patients with high-risk acute coronary syndromes.^158,161

Anti-PCSK-9 monoclonal antibody therapy

PCSK9, which plays a key role in cellular cholesterol homeostasis through promotion of cellular degradation of the LDL receptor, is a promising therapeutic target for hypercholesterolemia and coronary heart disease. Antibodies that target PCSK9 are currently in clinical development for the treatment of hypercholesterolemia, including REGN727^162,163 and AMG145.^164,165

Summary of Published Guidelines Relating to Dyslipidemia

Therapeutic lifestyle changes relating to obesity management and cardiovascular risk reduction underpin guidelines relating to dyslipidemia and other markers of cardiovascular risk (some of which refer to metabolic syndrome as a high-risk condition).^4,166,167 These include increasing physical activity, stopping smoking, and avoiding excessive alcohol intake. Diets rich in fruit and vegetables, complex carbohydrates, mono-unsaturated fats, and omega-3 PUFAs and low in refined carbohydrates are recommended, whereas trans fats should be avoided.¹⁶⁷ Recent data from the PREDIMED study (Effects of the Mediterranean diet on the primary prevention of cardiovascular diseases) demonstrate the potential effect of dietary interventions. For example, patients at high CVD risk who consumed more than three servings of nuts (rich in unsaturated fatty acids) had a significant 39% lower risk of all-cause mortality than those who consumed no nuts.¹⁶⁸

Statins are recognized in the guidelines of the American Diabetes Association (ADA), American College of Clinical Endocrinologists (AACE), and the EAS as the first-line lipid-modifying treatment for most high-risk populations, including patients with T2DM, established CVD, elevated TGs, or metabolic syndrome.^106,167 The latest guidelines from the American College of Cardiology/American Heart Association (ACC/AHA) recommend a statin (on a background of lifestyle changes) as the first choice lipid-modifying drug.¹⁶⁹ These guidelines recommend that all patients aged over 21 years with any form of CVD or LDL-C ≥190 mg/dL should be treated with a high-dose statin (atorvastatin 40–80 mg or rosuvastatin 20–40 mg).¹⁶⁹ Any patient aged 40–75 years with diabetes and LDL-C 70–189 mg/dL should be treated with a moderate-dose statin, and a high-intensity statin should be considered for those at higher risk. These guidelines have been criticized for being too narrow in their focus and for their lack of detailed guidance for managing patients who do not respond adequately to statins.^170,171

The ESC/EAS guidelines recommend that the combination of a statin and a fibrate (particularly fenofibrate) can be prescribed to improve lipid profiles in patients with atherogenic dyslipidemia, especially in patients with metabolic syndrome and/or diabetes mellitus.⁴ The ADA guidelines note that the combination of fenofibrate or niacin with a statin may improve the lipid profile in patients with elevated TG, low HDL-C, and high LDL levels, but caution that there is an increased risk of adverse reactions.¹⁰⁶ The AACE states that combinations of a statin with other lipid-modifying agents can be considered in selected patients. (These guidelines include niacin but were published before the most recent trials of this agent.) However, on the basis of data from the AIM-HIGH and HPS2-THRIVE trials, the EMA no longer recommends the use of niacin.¹³⁴ The ESC/EAS and ADA guidelines both note that fish oil may be of benefit in patients with elevated TGs.^4,106

Conclusions

Metabolic syndrome, T2DM, and atherogenic dyslipidemia have similar lipid profiles and often coexist, especially in certain ethnic groups. All three of these conditions are associated with a residual risk of CVD, despite high-dose statin therapy. As well as therapeutic lifestyle modifications, additional lipid-modifying therapy can be considered in these patients, on the basis of clinical trial data and individual patient characteristics. Data from a recent meta-analysis suggest that the addition of fenofibrate to a statin might further reduce CVD, specifically in patients with the combination of high TG (>200 mg/dL or >2.26 mmol/L) and low HDL-C (<40 mg/dL or <1.0 mmol/L) levels.⁸⁸ Omega-3 fatty acids could also be considered as an add-on to statin therapy for the treatment of hypertriglyceridemia or as secondary prevention after recent MI. Ongoing studies will demonstrate the impact of CETP and PCSK-9 inhibitors on clinical events and determine their clinical utility.

Footnotes

Acknowledgments

The authors acknowledge editorial support provided by Adelphi Communications Ltd., UK.

The development of this article was supported by an unrestricted educational grant from Abbott Products Operations AG, Allschwil, Switzerland. Abbott had no control over the content of this review and Professors Halcox and Misra received no payment for any part of their work on this article. J.H. and A.M. were involved in the article concept, development, and reference selection, and in the development of the outline and each draft of the manuscript. J.H. and A.M. both approved the final submission manuscript.

Author Disclosure Statement

No competing financial interests exist.

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