Online Submissions: http://www.wjgnet.

com/esps/ World J Diabetes 2014 April 15; 5(2): 165-175

bpgoffice@wjgnet.com ISSN 1948-9358 (online)
doi:10.4239/wjd.v5.i2.165 © 2014 Baishideng Publishing Group Co., Limited. All rights reserved.

REVIEW

Origin and therapy for hypertriglyceridaemia in type 2

diabetes

Jing Pang, Dick C Chan, Gerald F Watts

Jing Pang, Dick C Chan, Gerald F Watts, School of Medicine practical guidance on the management of HTG in type
and Pharmacology, University of Western Australia, Perth, WA 2 diabetes.
6847, Australia
Gerald F Watts, Lipid Disorders Clinic, Royal Perth Hospital, © 2014 Baishideng Publishing Group Co., Limited. All rights
Perth, WA 6847, Australia reserved.
Author contributions: All the authors contributed to this paper.
Correspondence to: Gerald F Watts, DSc, MD, PhD, FRACP,
FRCP, School of Medicine and Pharmacology, University of Key words: Diabetes; Triglyceride; Therapy
Western Australia, GPO Box X2213, Perth, WA 6847,
Australia. gerald.watts@uwa.edu.au Core tip: Diabetic dyslipidemia relates collectively to
Telephone: +6-8-92240245 Fax: +6-8-92240245 hyperglycaemia, insulin resistance, hyperinsulinaemia,
Received: November 5, 2013 Revised: March 8, 2014 abdominal visceral adipose disposition, increased liver
Accepted: March 17, 2014 fat content, and dysregulated fatty acid metabolism.
Published online: April 15, 2014 Insulin resistance in diabetes induces hypertriglyceri-
daemia by increasing the enterocytic production of
chylomicrons and an impaired clearance capacity is also
involved. Usual care for diabetic dyslipidemia is statin
Abstract treatment, but a significant proportion of patients have
Hypertriglyceridaemia (HTG) is a risk factor for car- residual dyslipidemia, related to hypertriglyceridaemia
diovascular disease (CVD) in type 2 diabetes and is and atherogenic dyslipidemia. Current evidence sup-
caused by the interaction of genes and non-genetic ports the use of fenofibrate in type 2 diabetics with
factors, specifically poor glycaemic control and obe- high triglyceride levels.
sity. In spite of statin treatment, residual risk of CVD
remains high in type 2 diabetes, and this may relate to
HTG and atherogenic dyslipidemia. Treatment of HTG Pang J, Chan DC, Watts GF. Origin and therapy for hypertriglycer-
emphasises correcting secondary factors and adverse idaemia in type 2 diabetes. World J Diabetes 2014; 5(2): 165-175
lifestyles, in particular, diet and exercise. Pharmaco- Available from: URL: http://www.wjgnet.com/1948-9358/full/v5/
therapy is also required in most type 2 diabetic pa- i2/165.htm DOI: http://dx.doi.org/10.4239/wjd.v5.i2.165
tients. Statins are the first-line therapy to achieve rec-
ommended therapeutic targets of plasma low-density
lipoprotein cholesterol and non-high-density lipoprotein
cholesterol. Fibrates, ezetimibe and n-3 fatty acids are INTRODUCTION
adjunctive treatment options for residual and persis-
tent HTG. Evidence for the use of niacin has been chal-
Hypertriglyceridaemia (HTG) is an important risk factor
lenged by non-significant CVD outcomes in two recent for cardiovascular disease (CVD)[1] and is defined as a
large clinical trials. Further investigation is required to fasting plasma triglyceride concentration > 95th percentile
clarify the use of incretin-based therapies for HTG in for age and sex in a population. HTG may be as preva-
type 2 diabetes. Extreme HTG, with risk of pancreati- lent as 50% in type 2 diabetes and is often unresponsive
tis, may require insulin infusion therapy or apheresis. to statin treatment[2,3]. We review recent evidence on the
New therapies targeting HTG in diabetes need to be role of HTG in atherosclerotic CVD and provide practi-
tested in clinical endpoint trials. The purpose of this cal guidance on the management of HTG in type 2 dia-
review is to examine the current evidence and provide betes.

WJD|www.wjgnet.com 165 April 15, 2014|Volume 5|Issue 2|

 Pang J et al . Origin and therapy for hypertriglyceridaemia in type 2 diabetes

PATHOPHYSIOLOGY OF and APOA5) and myocardial infarction[13]. This supports

that TRL causes CVD, and this probably applies to diabetes.
HYPERTRIGLYCERIDAEMIA IN TYPE 2 Hence, diabetic dyslipidemia relates collectively to
DIABETES hyperglycaemia, insulin resistance, hyperinsulinaemia,
abdominal visceral adipose disposition, increased liver fat
Triglycerides, which originate from the intestine post- content, and dysregulated fatty acid metabolism. Diabetic
prandially or endogenously from the liver, are packaged dyslipidemia may also be exacerbated by chronic kidney
into lipoprotein particles containing apolipoprotein disease and by co-prescribed medications, such as thia-
B-48 (apoB-48; chylomicrons) and apolipoprotein B-100 zide diuretics, non-selective beta-blockers and steroids.
(apoB-100; very-low density lipoprotein, VLDL), respec-
tively. Abnormalities in triglyceride-rich lipoprotein (TRL)
metabolism are cardinal features of type 2 diabetes. Met- MANAGEMENT OF
abolic dysregulation resulting in HTG include enhanced HYPERTRIGLYCERIDAEMIA IN TYPE 2
hepatic secretion of TRL due to insulin resistance and
delayed clearance of TRL involving lipoprotein lipase DIABETES
(LPL)-mediated lipolysis. Several genes causing loss of Measurement and assessment
function of LPL can result in severe HTG, such as LPL, Triglyceride concentration is commonly measured with
APOC2, APOA5, GPD1, CPIHBP1 and LMF1[4,5]. Very a fasting lipid profile. The fasting triglyceride level fa-
few patients will have a monogenic disorder. Individuals cilitates the calculation of the LDL cholesterol by the
with severe HTG are likely to be homozygous or com- Friedewald equation[14]. Non-fasting triglyceride concen-
pound heterozygous for mutations which impair the TRL trations are reflective of the postprandial state and can be
catabolic pathway. However, HTG in type 2 diabetes due useful as a simple and practical screening test for HTG. A
to several genes with mild effects that interact with non- second non-fasting measurement is recommended if the
genetic factors is probably more likely. These non-genetic initial triglyceride is > 2.0 mmol/L. Two or more mea-
factors include hyperglycaemia, alcohol abuse, concomi- surements of elevated triglyceride in both postabsorptive
tant medication, sedentary lifestyle, chronic kidney dis- and postprandial states are clinically indicative of HTG.
ease and insulin resistance[6]. Categories of HTG are differentially defined in interna-
Insulin resistance activates de novo lipogenesis, result- tional guidelines (Table 1).
ing in oversecretion of hepatic TRLs. This is also evident Non-HDL cholesterol is another appealing method
in the postprandial state, with enterocytic oversecretion of assessment as it does not attract additional costs. Non-
of TRLs in the form of chylomicrons. With both secre- HDL cholesterol (total cholesterol minus HDL-choles-
tion pathways on overdrive, competition between the terol) does not rely on a fasting triglyceride concentration
TRLs and their remnants for lipolytic and receptor-medi- and provides a simple amalgamated measure all the ath-
ated clearance further induces HTG. Insulin resistance is erogenic lipoproteins[15]. ApoB, on the other hand, does
also associated with increased rates of apolipoprotein C- not adequately reflect chylomicron remnants and involves
Ⅲ (apoC-Ⅲ) secretion, which further impairs receptor- additional laboratory expenses. Discordance between
mediated uptake of hepatic chylomicron remnants[7]. non-HDL cholesterol and apoB measures, particularly
Glucose has also found to activate apoC-Ⅲ transcription, in patients with type 2 diabetes and HTG, questions its
which may be the link between hyperglycaemia, HTG value in assessing risk and defining treatment targets[16].
and CVD in type 2 diabetics[8]. In the context of statin-treated patients, a meta-analysis
Both LPL and hepatic lipase (HL) control the clear- has shown that non-HDL cholesterol is superior in its as-
ance of triglycerides. HL plays a particularly important sociation with risk of future major cardiovascular events
role in the delipidation cascade from VLDL to LDL. Tri- compared with LDL cholesterol and apoB[17]. Other TRL
glyceride-rich VLDL derives small, dense LDL particles markers such as remnant-like particle cholesterol, apoC-
which are more susceptible to oxidation[9]. Additionally, Ⅲ and apoB-48 are expensive and are yet to be clinically
increased TRL in postprandial diabetic dyslipidemia leads established.
to the exchange of TRL-triglyceride for HDL-cholesteryl The hypertriglyceridaemic waist (HTWC) phenotype
ester and hence, triglyceride enrichment of HDL via has suggested to be useful in assessing glucometabolic
cholesteryl ester transfer protein (CETP). CETP progres- risk[18-21], in particular, among patients with a family his-
sively decreases postprandially and limits the efficient tory of diabetes[22]. The HTWC phenotype is defined by
removal of cholesterol[10]. Triglycerides in HDL are good a waist circumference of ≥ 90 cm in men and ≥ 85 cm in
substrates for hepatic lipase which leads to the produc- women and triglyceride concentration ≥ 2.0 mmol/L. Men
tion of small dense HDL particles and enhanced apoli- with the HTWC phenotype have been shown to have a
poprotein A-Ⅰ (apoA-Ⅰ) clearance[11]. four-fold risk of diabetes compared to those with waist
Given that HTG is related to a plethora of risk fac- circumference and triglyceride in the normal ranges[23].
tors, the lack of independent association between tri- There is also a two-fold risk for development of coro-
glyceride and CVD is expected[12], although two recent nary artery disease (CAD) in women[24] and an overall
Mendelian randomisation studies have shown a causal deterioration of cardiometabolic risk[25] in relation to pro-
association between variations in two related genes (LPL gression of type 2 diabetes[26].

WJD|www.wjgnet.com 166 April 15, 2014|Volume 5|Issue 2|

 Pang J et al . Origin and therapy for hypertriglyceridaemia in type 2 diabetes

Table 1 Clinical categorisation of hypertriglyceridaemia Table 2 Clinical guide for the assessment and treatment of
according to guidelines based on fasting triglyceride hypertriglyceridaemia in type 2 diabetes
concentrations
Steps
Ref. Year Triglyceride Triglyceride
published categories concentration (mmol/L) 1 Obtain fasting lipid profile
2 Classify LDL-cholesterol concentration (primary target of
National institutes 2001 Normal 1.7
therapy)
of Health[31] Borderline high 1.7-2.3
< 2.60 mmol/L – optimal
High 2.3-5.6
2.60-3.39 mmol/L – above optimal
Very high > 5.6
3.40-4.14 mmol/L – borderline high
Rydén et al[33] 2011 Desirable < 1.7
4.15-4.90 mmol/L – high
Elevated 1.7-5.5
> 4.90 mmol/L – very high
Very high 5.5-25.0
Establish therapy:
Extremely high > 25.0
LDL-cholesterol > 2.60 mmol/L – initiate dietary and lifestyle
Berglund et al[34] 2012 Normal < 1.7
modifications
Mild 1.7-2.3
LDL-cholesterol > 3.40 mmol/L – consider pharmacotherapy
Moderately high 2.3-11.2
simultaneously with dietary and lifestyle modifications
Severely high 11.2-22.4
3 Identify presence of atherosclerotic disease
Very severely high > 22.4
[37]
Clinical coronary heart disease
Hegele et al 2013 Normal < 2.0
Symptomatic carotid artery disease
Mild-to-moderate 2.0-10.0
Peripheral artery disease
Severe > 10.0
4 Assess:
Glycaemic control
Obesity
Guidelines and recommendations Dietary intake (e.g., Fructose, simple sugars, caloric intake)
Physical activity
Guidelines for managing HTG in diabetes have been Determine presence of other risk factors:
published, with lifestyle modifications being first-line Smoking
therapy followed by statins, fibrates, n-3 fatty acids Hypertension
and/or niacin[27-30]. The national cholesterol education Family history of premature coronary heart disease (i.e,. in first-
program (NCEP) adult treatment panel (ATP) Ⅲ guide- degree relative, male < 55 years, female < 65 years)
Low HDL-cholesterol, < 1.0 mmol/L
lines recommend LDL cholesterol as the primary treat- 5 Order of treatment considerations:
ment target and non-HDL cholesterol as a secondary Improve glycaemia (dietary and lifestyle modifications)
target, with the exception of a fasting triglyceride > 5.60 Treat secondary risk factors
mmol/L, only then, triglyceride becomes the primary Statins
target owing to the risk of pancreatitis[31]. A simplifica- Fibrates
n-3 fatty acids/niacin
tion of the NCEP ATP Ⅲ guideline is presented in 6 Treat elevated triglyceride if triglyceride concentrations are >
Table 2. Regardless of atherosclerotic disease and pres- 2.30 mmol/L after LDL-cholesterol concentration target of < 2.60
ence of other cardiovascular risk factors, type 2 diabetes mmol/L is reached
is considered a coronary heart disease risk equivalent by Target non-HDL cholesterol (< 3.40 mmol/L)
the NCEP ATP Ⅲ. Triglyceride > 2.30 mmol/L – intensify LDL-lowering therapy or
add fibrate
The American Diabetes Association (ADA)/Ameri-
Triglyceride > 5.60 mmol/L – very low-fat diet (< 15% of calories
can College of Cardiology Foundation consensus state- from fat), weight management, physical activity and add fibrate
ment recommends a non-HDL cholesterol target of 3.40
mmol/L in diabetic patients with no other cardiovascular Adapted from the NCEP ATP Ⅲ guidelines[31]. LDL: Low density lipopro-
risk factor and a target of 2.60 mmol/L if there is one tein; HDL: High density lipoprotein.
or more cardiovascular risk factor such as hypertension,
smoking, dyslipidemia and family history of CAD[32].
diabetes and CVD developed in collaboration with the
The LDL cholesterol target is 2.60 and 1.80 mmol/L,
respectively[32] or alternatively a 30%-40% reduction from European Association for the Study of Diabetes (EASD)
baseline levels[30]. The ADA position statement is the suggests targeting residual risk in patients with elevated
only guideline that provides desirable targets for triglycer- TG (> 2.2 mmol/L), with dietary and lifestyle advice and
ide levels for patients with type 2 diabetes: less than 1.70 improved glucose control[33], post first-line treatment. The
mmol/L[30]. Both the NCEP ATP and ADA guidelines Endocrine Society task force agrees with the NCEP ATP
place emphasis on weight loss and physical activity. A Ⅲ treatment goals and recommends fibrates as first-line
summary of recommended treatment targets is presented treatment for lowering triglycerides in patients at-risk for
in Table 3. pancreatitis[34].
The Scientific Statement from the American Heart The International Atherosclerosis Society position
Association (AHA) on triglycerides and CVD particularly paper recognises the atherogenicity of VLDL and triglyc-
emphasises the dietary and lifestyle modifications (weight erides and also favours non-HDL cholesterol as the main
loss, macronutrient distribution and aerobic exercise) for target for therapy, optimally at < 3.40 mmol/L[35]. The
the treatment of elevated triglycerides, presenting a prac- American College of Cardiology (ACC)/AHA published
tical algorithm for screening and management[28]. The a new clinical practice guideline for the treatment of el-
European Society of Cardiology (ESC) guidelines on evated blood cholesterol in people at high risk for CVD.

WJD|www.wjgnet.com 167 April 15, 2014|Volume 5|Issue 2|

 Pang J et al . Origin and therapy for hypertriglyceridaemia in type 2 diabetes

Table 3 Recommended treatment targets for diabetic dyslipidaemia

NCEP ATP Ⅲ
[31] [30] [128] [33]
ADA NVDPA European Guidelines

LDL-cholesterol (mmol/L) Very high risk < 1.8 < 1.8 < 2.0 < 1.8
High risk < 2.6 < 2.6 < 2.0 < 2.5
Triglycerides (mmol/L) < 1.7 < 2.0 < 1.7
HDL-cholesterol (mmol/L) Male > 1.0 ≥ 1.0 > 1.0
Female > 1.3 ≥ 1.0 > 1.2
Non-HDL cholesterol (mmol/L) Very high risk < 2.6 < 2.6 < 2.5 < 2.6
High risk < 3.4 < 3.4 < 2.5 < 3.3
ApoB (g/L) Very high risk < 0.8 < 0.8
High risk < 0.9 < 1.0

NCEP ATP Ⅲ: Third Report of the National Cholesterol Education Program (NCEP) expert panel on detection, evaluation and treatment of high blood cho-
lesterol in adults (Adult treatment panel Ⅲ); ADA: American diabetes association; NVDPA: National vascular disease prevention alliance of australia; LDL:
Low density lipoprotein; HDL: High density lipoprotein.

The guidelines do not provide recommendations for specific lowering TG in individuals with overt HTG[47]. Alcohol
LDL-cholesterol or non-HDL targets and instead defines abstinence in patients with excessive alcohol intake can
four major groups of primary and secondary prevention pa- markedly lower plasma triglyceride levels[48,49]. Smoking
tients for whom LDL lowering is proven to be most benefi- cessation is also imperative[50].
cial[36]. Future guidelines to cover the treatment of HTG are
proposed. A recent review by Hegele et al[37] recommended Pharmacotherapy
the simplification and redefinition of HTG: < 2.0 mmol/ Statin monotherapy: Statin therapy is the cornerstone
L as normal, 2.0-10.0 mmol/L as mild-to-moderate and of treatment of dyslipidemia in diabetes. Whilst reach-
> 10.0 mmol/L as severe; with desirable targets of < 1.7 ing the LDL cholesterol target in most patients, only
mmol/L for triglycerides, < 2.6 mmol/L for non-HDL modest effects are exerted on triglyceride and HDL cho-
cholesterol and < 0.8 g/L for apoB in high-risk patients lesterol. Hence, diabetics with HTG often have residual
Treatment of HTG depends on its severity, co-ex- CVD risk [51] in spite of an optimal LDL cholesterol
isting lipid abnormalities and overall cardiovascular risk. target. Statins may lower plasma triglyceride by increas-
Severe HTG serves as increased risk of pancreatitis and ing lipolysis and the clearance of TRLs, particularly with
warrants treatment to acutely reduce triglyceride levels. potent statins such as atorvastatin and rosuvastatin (up
Current therapeutic strategies include diet and lifestyle to 26% and 28% reduction in plasma triglyceride, respec-
modification, pharmacotherapy and in rare cases, con- tively)[52-54]. Large statin outcome trials have supported
tinuous insulin infusion and apheresis. its use in reducing coronary events and mortality[55-58].
All trials to-date have not specifically selected for HTG
Dietary and lifestyle modifications and in diabetics. However, sub-group analyses have been
Lifestyle interventions are central for controlling hyper- undertaken showing risk prevention with pravastatin[59],
glycaemia and HTG in patients with type 2 diabetic pa- simvastatin[60] and rosuvastatin[61] in a subset of patients with
tients and impaired fasting glucose. These interventions high plasma triglyceride, recently reviewed by Maki et al[62],
include weight reduction, altered dietary composition, ex- and supporting statins as first line of therapy. Whilst use
ercise and regulation of alcohol consumption. In type 2 of higher doses of statin has been linked to incidence of
diabetes, modest (5%-10%) weight loss can lower plasma diabetes[63-65], the benefits of statin therapy for reducing
triglyceride levels by up to 25%[38,39] and normalise post- CVD risk and events are outweighed for all diabetic pa-
prandial triglyceride concentration[40]. Physical activity can tients with high CVD risk[57,63]. Aminotransferase, creatine
aid the maintenance of weight loss achieved through ca- kinase, creatinine and glucose should be monitored prior
loric restrictions[41], although evidence for linking lifestyle to initiating statins and before initiating a second agent, if
modifications and sustained weight is limited[42]. required.
The recently published look AHEAD trial, an inten-
sive lifestyle intervention in type 2 diabetics, employing Fibrates and statin-fibrate combination: Fibrates
weight loss through caloric restriction and increased (gemfibrozil, fenofibrate) act on peroxisome proliferator-
physical activity did not reduce the rate of cardiovascular activated receptor alpha. Fibrates decreases hepatic
events[43]. Whether alterations in dietary composition, VLDL secretion and can confer an up to 30% reduc-
such as with the Mediterranean diet, improves clinical tion in plasma triglyceride, TRL remnants and apoB[66].
outcome in diabetes warrants additional investigation[44], Five fibrate trials have undertaken secondary analyses in
though the Mediterranean and low-carbohydrate diet can high triglyceride subgroups[67-79], two of these trials were
produce a greater reduction in triglyceride levels com- in type 2 diabetic patients[70-72] and one had a subset of
pared to the restricted-calorie diet in moderately obese diabetics[73,74]. Collectively, these trials advocate the use
individuals[45,46]. Plant sterols have been suggested for of fibrates in reducing CVD events among patients with

WJD|www.wjgnet.com 168 April 15, 2014|Volume 5|Issue 2|

 Pang J et al . Origin and therapy for hypertriglyceridaemia in type 2 diabetes

a high triglyceride and low HDL cholesterol levels[75-78]. ering with a statin plus ezetimibe may not consistently
Of note, the Fenofibrate Intervention and Event Lower- lower subclinical carotid atherosclerosis in type 2 diabe-
ing in Diabetes (FIELD) study showed that fenofibrate tes, although progression of carotid artery intima-media
decreased progression of diabetic retinopathy[79], though thickness was inhibited with the combination[100,101]. The
unrelated to dyslipidemia, and the Action to Control Car- Improved Reduction of Outcomes: Vytorin Efficacy In-
diovascular Risk in Diabetes (ACCORD) study also showed ternational Trial (IMPROVE-IT) study that is currently
a delay in the onset of eye complications[80]. Meta-analyses entering completion will endeavour to provide definitive
suggest that fibrates are useful for treatment of HTG[76] in evidence for the role of ezetimibe in high risk subjects
diabetic patients[71,81,82]. Every 0.10 mmol/L reduction in on optimal statin therapy[102,103].
triglyceride with fibrates confers a 5% reduction in CVD
event, although no benefits were found on cardiovascular n-3 fatty acid and statin-n-3 fatty acid combination:
mortality[77,78]. Supplemental n-3 polyunsaturated fatty acids (PUFAs),
mainly eicosapentaenoic acid (EPA) and docosahexae-
Niacin and statin-niacin combination: Niacin can de- noic acid (DHA), are well known to improve HTG[104].
crease plasma triglyceride by 30%[83] via the inhibition of However, recent clinical outcome trials with have failed
hepatic diacylglycerol acyltransferase-2 (DGAT-2), a rate- to show significant CVD benefits in high risk subjects
limiting enzyme of triglyceride synthesis. Despite the ear- including diabetics[105,106]. Both trials were undertaken
lier studies showing reduced mortality[84] and regression against a background of optimal therapy, including
of subclinical atherosclerosis[85-87], the current use of nia- statins. Also, patients were not selected for elevated plas-
cin has been challenged by two large recent clinical trials ma triglyceride levels. Pure EPA (1800 mg/d), added to
which have failed to show significant benefits on CVD statin therapy, showed promise in the Japan Eicosapen-
events[88,89] in spite of positive changes in lipid param-
taenoic acid Lipid Intervention Study (JELIS) with major
eters. Both trials have limitations. The Atherothrombosis
coronary events reduced by 19% (P = 0.011) in hyper-
Intervention in Metabolic Syndrome with Low HDL/
cholesterolaemic patients[107]. Two 12-wk EPA (AMR101)
High Triglycerides: Impact on Global Health (AIM-
intervention trials in patients with very high[108] and per-
HIGH) study was underpowered and confounded by the
sistent[109] baseline triglyceride observed significant reduc-
higher statin and/or ezetimibe doses to match LDL cho-
lesterol between groups[88]. The Heart Protection Study tions in triglyceride levels. The greatest decrease was seen
2-Treatment of HDL to Reduce the Incidence of Vascu- in the highest triglyceride tertile where there was a 31%
lar Events (HPS2-THRIVE) study is the largest extend- reduction compared to placebo on 4 g/d of AMR101.
release niacin trial to-date combined with laropiprant, a The Reduction of Cardiovascular Events with EPA-
prostaglandin D2 inhibitor[89]. Despite no significant ben- Intervention Trial (REDUCE-IT) is in progress and will
efit on primary CVD endpoints, a recent sub-analysis in endeavour obtain the CVD outcome data with AMR101
patients with both high triglyceride (> 2.24 mmol/L) and 4 g/d in high-risk patients with HTG and at-target LDL
low HDL cholesterol (< 0.85 mmol/L) showed a trend cholesterol on statin therapy[110]. There are also recent
towards benefit with niacin, although not reaching statis- data suggesting an increased risk of prostate cancer with
tical significance (HR = 0.74, P = 0.073)[90]. Of note, the high dietary intake of n-3 PUFAs[111]. Hence, caution is
lack of potential benefit or harm in the HPS2-THRIVE warranted when recommending long-term intake.
study may not necessarily be due to niacin, but potentially
to laropiprant. The safety of niacin use in type 2 diabetes Incretin-based therapy: Incretins, such as glucagon-
has previously been questioned owing to impairment in like peptide-1 (GLP-1), are insulinotropic, gut-derived
glycaemic control and insulin sensitivity[91-93]. However, hormones secreted in response to diet. GLP-1 receptor
two prospective trials have showed that the effect of nia- analogs such as liraglutide and exenatide, delay gastric
cin on glycaemic control is minimal in a majority of pa- emptying and this parallels the reduction in postprandial
tients with stable diabetes[94] and with no changes in low- triglyceride response[112]. This mechanism may ameliorate
dose (1 g/d) niacin[95]. impaired TRL metabolism in type 2 diabetes. By increasing
plasma concentrations of GLP-1, Dipeptidyl peptidase-4
Ezetimibe and statin-ezetimibe combination: Ezeti- (DPP-4) inhibitors, such as sitagliptin, saxagliptin and alo-
mibe inhibits intestinal cholesterol absorption and pri- gliptin, can improve insulin sensitivity, β-cell function[113]
marily lowers LDL cholesterol via the Niemann-Pick C1- and postprandial glycaemia[114] and lipaemia[115]. These
Like 1 protein. Ezetimibe has minimal effects in lowering agents could potentially prevent CVD events, indepen-
plasma fasting triglyceride (8%)[96]. A more prominent dent of changes in glucose and lipid metabolism. A recent
effect is observed in ameliorating postprandial lipaemia saxagliptin outcome trial failed to demonstrate significant
and lowering TRL remnants in spite of background changes in ischaemic events, though the rate of heart fail-
statin[97,98]. In a 6-wk trial of simvastatin-ezetimibe vs. ure increased significantly[116]. Similarly, a trial in type 2 dia-
simvastatin monotherapy, fasting and postprandial plasma betic patients post-acute coronary syndrome with aloglipi-
triglyceride and apoB-48 concentrations were lowered in tin did not improve cardiovascular event rates compared
type 2 diabetic patients[99]. However, intensive lipid low- with placebo[117]. Further investigation is required to clarify

WJD|www.wjgnet.com 169 April 15, 2014|Volume 5|Issue 2|

 Pang J et al . Origin and therapy for hypertriglyceridaemia in type 2 diabetes

their mechanism and use in type 2 diabetes. high triglyceride and low HDL, but also to prevent and
treat diabetic retinopathy. More evidence is required from
CVD outcome trials for the other add-on options, some
MANAGEMENT OF SEVERE of which are currently underway. Several new therapies
HYPERTRIGLYCERIDAEMIA IN TYPE 2 with potential applications for treating HTG are DGAT
inhibitors, microsomal triglyceride transfer protein inhibi-
DIABETES tors, and apoC-Ⅲ antisense oligonucleotides. These will
Insulin infusion, apheresis and gene replacement agents will require to be tested for efficacy, safety and
therapy cost-effectiveness in future clinical trials.
In severe cases of diabetic HTG and poorly controlled
diabetes, continuous intravenous insulin infusion appears
to be beneficial in restoring serum glucose and triglyc- REFERENCES
eride[118]. Most of these patients will have an underlying 1 Murad MH, Hazem A, Coto-Yglesias F, Dzyubak S, Gupta
genetic defect in TRL metabolism. A recent study in a S, Bancos I, Lane MA, Erwin PJ, Berglund L, Elraiyah T,
Montori VM. The association of hypertriglyceridemia with
group of 15 diabetics with a median triglyceride concen- cardiovascular events and pancreatitis: a systematic review
tration of 26.23 mmol/L at admission had their triglyc- and meta-analysis. BMC Endocr Disord 2012; 12: 2 [PMID:
eride levels corrected to a median of 5.75 mmol/L at 22463676 DOI: 10.1186/1472-6823-12-2]
discharge with an average of 48 h of continuous insulin 2 Leiter LA, Lundman P, da Silva PM, Drexel H, Jünger C,
Gitt AK. Persistent lipid abnormalities in statin-treated
infusion[119]. For prevention of recurrent severe HTG in
patients with diabetes mellitus in Europe and Canada:
susceptible patients, counselling on medication adherence results of the Dyslipidaemia International Study. Diabet
and long-term diet and lifestyle medications should be Med 2011; 28: 1343-1351 [PMID: 21679231 DOI: 10.1111/
considered[120]. j.1464-5491.2011.03360.x]
In extremely severe HTG and drug refractory HTG, 3 Feher M, Greener M, Munro N. Persistent hypertriglyceride-
mia in statin-treated patients with type 2 diabetes mellitus.
plasma apheresis may be required[121,122], particularly with Diabetes Metab Syndr Obes 2013; 6: 11-15 [PMID: 23341741
severe chylomicronaemia complicated by acute pancreati- DOI: 10.2147/DMSO.S35053]
tis. A single session of apheresis can dramatically lower 4 Johansen CT, Kathiresan S, Hegele RA. Genetic determi-
excessive triglyceride levels, 65.8% reduction in 2 h[123,124]. nants of plasma triglycerides. J Lipid Res 2011; 52: 189-206
[PMID: 21041806 DOI: 10.1194/jlr.R009720]
This method of triglyceride lowering is only indicated
5 Surendran RP, Visser ME, Heemelaar S, Wang J, Peter
in medical emergencies owing to high costs and limited J, Defesche JC, Kuivenhoven JA, Hosseini M, Péterfy M,
availability[125]. Further study is required to clarify the role Kastelein JJ, Johansen CT, Hegele RA, Stroes ES, Dallinga-
of plasma exchange in the treatment of hyperlipidaemic Thie GM. Mutations in LPL, APOC2, APOA5, GPIHBP1
pancreatitis. and LMF1 in patients with severe hypertriglyceridaemia. J
Intern Med 2012; 272: 185-196 [PMID: 22239554 DOI: 10.1111/
In patients genetically diagnosed with familial LPL j.1365-2796.2012.02516.x]
deficiency, Glybera® (alipogene tiparvovec; Amsterdam 6 Simental-Mendía LE, Rodríguez-Morán M, Simental-Sauce-
Molecular Therapeutics, Amsterdam, the Netherlands) do L, Guerrero-Romero F. Insulin secretion is increased in
is the first approved gene-replacement therapy [126,127]. non-diabetic subjects with fasting hypertriglyceridaemia.
Diabetes Metab Res Rev 2013; 29: 214-219 [PMID: 23225554
Glybera® has only been studied in 27 patients, in whom
DOI: 10.1002/dmrr.2379]
the agent was well tolerated and with plasma triglyceride 7 Ooi EM, Barrett PH, Chan DC, Watts GF. Apolipoprotein
concentration significantly lowered with reduced rates of C-III: understanding an emerging cardiovascular risk fac-
acute pancreatitis[126]. Long-term follow-up data and cost- tor. Clin Sci (Lond) 2008; 114: 611-624 [PMID: 18399797 DOI:
effectiveness studies is warranted[126,127]. 10.1042/CS20070308]
8 Caron S, Verrijken A, Mertens I, Samanez CH, Mautino G,
Haas JT, Duran-Sandoval D, Prawitt J, Francque S, Vallez
E, Muhr-Tailleux A, Berard I, Kuipers F, Kuivenhoven JA,
CONCLUSION Biddinger SB, Taskinen MR, Van Gaal L, Staels B. Transcrip-
HTG is common in type 2 diabetes. HTG associates with tional activation of apolipoprotein CIII expression by glucose
a spectrum of cardiometabolic risk factors and increases may contribute to diabetic dyslipidemia. Arterioscler Thromb
Vasc Biol 2011; 31: 513-519 [PMID: 21183731 DOI: 10.1161/
CVD risk in type 2 diabetes. Dietary and lifestyle modi- ATVBAHA.110.220723]
fication involving weight loss and exercise is fundamen- 9 Chait A, Brazg RL, Tribble DL, Krauss RM. Susceptibility of
tal to the management of HTG. Improved glycaemic small, dense, low-density lipoproteins to oxidative modifica-
control with use of metformin, DPP-4 inhibitors and tion in subjects with the atherogenic lipoprotein phenotype,
pattern B. Am J Med 1993; 94: 350-356 [PMID: 8475928 DOI:
insulin can also improve HTG. The expression of HTG
10.1016/0002-9343(93)90144-E]
in context of diabetes may depend on co-existing mono- 10 Durlach V, Attia N, Zahouani A, Leutenegger M, Girard-
genic and/or multigenic disorders of lipid metabolism, Globa A. Postprandial cholesteryl ester transfer and high
such as familial combined hyperlipidaemia, familial hy- density lipoprotein composition in normotriglyceridemic
pertriglyceridaemia and type Ⅱ hyperlipoproteinaemia. non-insulin-dependent diabetic patients. Atherosclerosis 1996;
120: 155-165 [PMID: 8645357 DOI: 10.1016/0021-9150(95)056
Statins are the first-line of lipid-lowering therapy to tar- 97-1]
get LDL cholesterol and triglycerides. Current evidence 11 Lamarche B, Rashid S, Lewis GF. HDL metabolism in
supports the use of fenofibrate in type 2 diabetics, with hypertriglyceridemic states: an overview. Clin Chim

WJD|www.wjgnet.com 170 April 15, 2014|Volume 5|Issue 2|

 Pang J et al . Origin and therapy for hypertriglyceridaemia in type 2 diabetes

Acta 1999; 286: 145-161 [PMID: 10511289 DOI: 10.1016/ artery disease in women. Metabolism 2012; 61: 56-64 [PMID:
S0009-8981(99)00098-4] 21733531 DOI: 10.1016/j.metabol.2011.05.017]
12 Durrington PN. Triglycerides are more important in athero- 25 Arsenault BJ, Lemieux I, Després JP, Wareham NJ, Kastelein
sclerosis than epidemiology has suggested. Atherosclerosis JJ, Khaw KT, Boekholdt SM. The hypertriglyceridemic-
1998; 141 Suppl 1: S57-S62 [PMID: 9888644 DOI: 10.1016/ waist phenotype and the risk of coronary artery disease:
S0021-9150(98)00219-6] results from the EPIC-Norfolk prospective population study.
13 Johansen CT, Hegele RA. Using Mendelian randomization CMAJ 2010; 182: 1427-1432 [PMID: 20643837 DOI: 10.1503/
to determine causative factors in cardiovascular disease. J cmaj.091276]
Intern Med 2013; 273: 44-47 [PMID: 22928522 DOI: 10.1111/ 26 St-Pierre J, Lemieux I, Perron P, Brisson D, Santuré M, Vohl
j.1365-2796.2012.02586.x] MC, Després JP, Gaudet D. Relation of the "hypertriglyceri-
14 Friedewald WT, Levy RI, Fredrickson DS. Estimation of demic waist" phenotype to earlier manifestations of coronary
the concentration of low-density lipoprotein cholesterol in artery disease in patients with glucose intolerance and type
plasma, without use of the preparative ultracentrifuge. Clin 2 diabetes mellitus. Am J Cardiol 2007; 99: 369-373 [PMID:
Chem 1972; 18: 499-502 [PMID: 4337382] 17261400 DOI: 10.1016/j.amjcard.2006.08.041]
15 Chan DC, Pang J, Romic G, Watts GF. Postprandial hypertri- 27 Chapman MJ, Ginsberg HN, Amarenco P, Andreotti F,
glyceridemia and cardiovascular disease: current and future Borén J, Catapano AL, Descamps OS, Fisher E, Kovanen PT,
therapies. Curr Atheroscler Rep 2013; 15: 309 [PMID: 23345190 Kuivenhoven JA, Lesnik P, Masana L, Nordestgaard BG, Ray
DOI: 10.1007/s11883-013-0309-9] KK, Reiner Z, Taskinen MR, Tokgözoglu L, Tybjærg-Hansen
16 Ganda OP, Jumes CG, Abrahamson MJ, Molla M. Quan- A, Watts GF. Triglyceride-rich lipoproteins and high-density
tification of concordance and discordance between apoli- lipoprotein cholesterol in patients at high risk of cardiovas-
poprotein-B and the currently recommended non-HDL- cular disease: evidence and guidance for management. Eur
cholesterol goals for cardiovascular risk assessment in Heart J 2011; 32: 1345-1361 [PMID: 21531743 DOI: 10.1093/
patients with diabetes and hypertriglyceridemia. Diabetes eurheartj/ehr112]
Res Clin Pract 2012; 97: 51-56 [PMID: 22459987 DOI: 10.1016/ 28 Miller M, Stone NJ, Ballantyne C, Bittner V, Criqui MH,
j.diabres.2012.02.013] Ginsberg HN, Goldberg AC, Howard WJ, Jacobson MS, Kris-
17 Boekholdt SM, Arsenault BJ, Mora S, Pedersen TR, LaRosa Etherton PM, Lennie TA, Levi M, Mazzone T, Pennathur
JC, Nestel PJ, Simes RJ, Durrington P, Hitman GA, Welch S. Triglycerides and cardiovascular disease: a scientific
KM, DeMicco DA, Zwinderman AH, Clearfield MB, statement from the American Heart Association. Circula-
Downs JR, Tonkin AM, Colhoun HM, Gotto AM, Ridker tion 2011; 123: 2292-2333 [PMID: 21502576 DOI: 10.1161/
PM, Kastelein JJ. Association of LDL cholesterol, non-HDL CIR.0b013e3182160726]
cholesterol, and apolipoprotein B levels with risk of cardio- 29 Reiner Z, Catapano AL, De Backer G, Graham I, Taskinen
vascular events among patients treated with statins: a meta- MR, Wiklund O, Agewall S, Alegria E, Chapman MJ, Dur-
analysis. JAMA 2012; 307: 1302-1309 [PMID: 22453571 DOI: rington P, Erdine S, Halcox J, Hobbs R, Kjekshus J, Filardi
10.1001/jama.2012.366] PP, Riccardi G, Storey RF, Wood D. ESC/EAS Guidelines for
18 Lemieux I, Poirier P, Bergeron J, Alméras N, Lamarche B, the management of dyslipidaemias: the Task Force for the
Cantin B, Dagenais GR, Després JP. Hypertriglyceridemic management of dyslipidaemias of the European Society of
waist: a useful screening phenotype in preventive cardiolo- Cardiology (ESC) and the European Atherosclerosis Society
gy? Can J Cardiol 2007; 23 Suppl B: 23B-31B [PMID: 17932584 (EAS). Eur Heart J 2011; 32: 1769-1818 [PMID: 21712404 DOI:
DOI: 10.1016/S0828-282X(07)71007-3] 10.1093/eurheartj/ehr158]
19 He S, Zheng Y, Shu Y, He J, Wang Y, Chen X. Hypertri- 30 American Diabetes Association. Standards of medical care
glyceridemic waist might be an alternative to metabolic in diabetes--2012. Diabetes Care 2012; 35 Suppl 1: S11-S63
syndrome for predicting future diabetes mellitus. PLoS [PMID: 22187469 DOI: 10.2337/dc12-s011]
One 2013; 8: e73292 [PMID: 24039903 DOI: 10.1371/journal. 31 National Institutes of Health. Third Report of the National
pone.0073292] Cholesterol Education Program Expert Panel on detection,
20 Sam S, Haffner S, Davidson MH, D'Agostino RB, Feinstein evaluation, and treatment of high blood cholesterol in adults.
S, Kondos G, Perez A, Mazzone T. Hypertriglyceridemic Available from: URL: http://www.nhlbi.nih.gov/guide-
waist phenotype predicts increased visceral fat in subjects lines/cholesterol/atp3full.pdf
with type 2 diabetes. Diabetes Care 2009; 32: 1916-1920 [PMID: 32 Brunzell JD, Davidson M, Furberg CD, Goldberg RB, How-
19592623 DOI: 10.2337/dc09-0412] ard BV, Stein JH, Witztum JL. Lipoprotein management in
21 de Graaf FR, Schuijf JD, Scholte AJ, Djaberi R, van Velzen patients with cardiometabolic risk: consensus statement
JE, Roos CJ, Kroft LJ, de Roos A, van der Wall EE, Wouter from the American Diabetes Association and the American
Jukema J, Després JP, Bax JJ. Usefulness of hypertriglyc- College of Cardiology Foundation. Diabetes Care 2008; 31:
eridemic waist phenotype in type 2 diabetes mellitus to 811-822 [PMID: 18375431 DOI: 10.2337/dc08-9018]
predict the presence of coronary artery disease as assessed 33 Rydén L, Grant PJ, Anker SD, Berne C, Cosentino F, Danchin
by computed tomographic coronary angiography. Am J N, Deaton C, Escaned J, Hammes HP, Huikuri H, Marre
Cardiol 2010; 106: 1747-1753 [PMID: 21126619 DOI: 10.1016/ M, Marx N, Mellbin L, Ostergren J, Patrono C, Seferovic P,
j.amjcard.2010.08.015] Uva MS, Taskinen MR, Tendera M, Tuomilehto J, Valensi P,
22 Amini M, Esmaillzadeh A, Sadeghi M, Mehvarifar N, Amini Zamorano JL, Zamorano JL, Achenbach S, Baumgartner H,
M, Zare M. The association of hypertriglyceridemic waist Bax JJ, Bueno H, Dean V, Deaton C, Erol C, Fagard R, Fer-
phenotype with type 2 diabetes mellitus among individuals rari R, Hasdai D, Hoes AW, Kirchhof P, Knuuti J, Kolh P,
with first relative history of diabetes. J Res Med Sci 2011; 16: Lancellotti P, Linhart A, Nihoyannopoulos P, Piepoli MF,
156-164 [PMID: 22091225] Ponikowski P, Sirnes PA, Tamargo JL, Tendera M, Torbicki
23 Carlsson AC, Risérus U, Arnlöv J. Hypertriglyceridemic A, Wijns W, Windecker S, De Backer G, Sirnes PA, Ezquerra
waist phenotype is associated with decreased insulin sensi- EA, Avogaro A, Badimon L, Baranova E, Baumgartner H,
tivity and incident diabetes in elderly men. Obesity (Silver Betteridge J, Ceriello A, Fagard R, Funck-Brentano C, Gulba
Spring) 2014; 22: 526-529 [PMID: 23512911 DOI: 10.1002/ DC, Hasdai D, Hoes AW, Kjekshus JK, Knuuti J, Kolh P,
oby.20434] Lev E, Mueller C, Neyses L, Nilsson PM, Perk J, Ponikowski
24 Blackburn P, Lemieux I, Lamarche B, Bergeron J, Perron P, P, Reiner Z, Sattar N, Schächinger V, Scheen A, Schirmer
Tremblay G, Gaudet D, Després JP. Hypertriglyceridemic H, Strömberg A, Sudzhaeva S, Tamargo JL, Viigimaa M,
waist: a simple clinical phenotype associated with coronary Vlachopoulos C, Xuereb RG. ESC Guidelines on diabetes,

WJD|www.wjgnet.com 171 April 15, 2014|Volume 5|Issue 2|

 Pang J et al . Origin and therapy for hypertriglyceridaemia in type 2 diabetes

pre-diabetes, and cardiovascular diseases developed in Arós F, Gómez-Gracia E, Ruiz-Gutiérrez V, Fiol M, Lapetra
collaboration with the EASD: the Task Force on diabetes, J, Lamuela-Raventos RM, Serra-Majem L, Pintó X, Basora J,
pre-diabetes, and cardiovascular diseases of the European Muñoz MA, Sorlí JV, Martínez JA, Martínez-González MA.
Society of Cardiology (ESC) and developed in collaboration Primary prevention of cardiovascular disease with a Medi-
with the European Association for the Study of Diabetes terranean diet. N Engl J Med 2013; 368: 1279-1290 [PMID:
(EASD). Eur Heart J 2013; 34: 3035-3087 [PMID: 23996285 23432189 DOI: 10.1056/NEJMoa1200303]
DOI: 10.1093/eurheartj/eht108] 45 Schwarzfuchs D, Golan R, Shai I. Four-year follow-up af-
34 Berglund L, Brunzell JD, Goldberg AC, Goldberg IJ, Sacks ter two-year dietary interventions. N Engl J Med 2012; 367:
F, Murad MH, Stalenhoef AF. Evaluation and treatment of 1373-1374 [PMID: 23034044 DOI: 10.1056/NEJMc1204792]
hypertriglyceridemia: an Endocrine Society clinical practice 46 Nordmann AJ, Suter-Zimmermann K, Bucher HC, Shai I,
guideline. J Clin Endocrinol Metab 2012; 97: 2969-2989 [PMID: Tuttle KR, Estruch R, Briel M. Meta-analysis comparing
22962670 DOI: 10.1210/jc.2011-3213] Mediterranean to low-fat diets for modification of cardio-
35 Grundy SM. An International Atherosclerosis Society Posi- vascular risk factors. Am J Med 2011; 124: 841-851.e2 [PMID:
tion Paper: global recommendations for the management of 21854893 DOI: 10.1016/j.amjmed.2011.04.024]
dyslipidemia. J Clin Lipidol 2013; 7: 561-565 [PMID: 24314355 47 Theuwissen E, Plat J, van der Kallen CJ, van Greevenbroek
DOI: 10.1016/j.jacl.2013.10.001] MM, Mensink RP. Plant stanol supplementation decreases
36 Stone NJ, Robinson J, Lichtenstein AH, Merz CN, Blum CB, serum triacylglycerols in subjects with overt hypertriglyc-
Eckel RH, Goldberg AC, Gordon D, Levy D, Lloyd-Jones eridemia. Lipids 2009; 44: 1131-1140 [PMID: 19904567 DOI:
DM, McBride P, Schwartz JS, Shero ST, Smith SC Jr, Watson 10.1007/s11745-009-3367-6]
K, Wilson PW. 2013 ACC/AHA Guideline on the Treatment 48 Brinton EA. Effects of ethanol intake on lipoproteins. Curr
of Blood Cholesterol to Reduce Atherosclerotic Cardiovascu- Atheroscler Rep 2012; 14: 108-114 [PMID: 22350634 DOI:
lar Risk in Adults: A Report of the American College of Car- 10.1007/s11883-012-0230-7]
diology/American Heart Association Task Force on Practice 49 Bessembinders K, Wielders J, van de Wiel A. Severe hy-
Guidelines. Circulation 2013 Nov 12; Epub ahead of print pertriglyceridemia influenced by alcohol (SHIBA). Alcohol
[PMID: 24222016 DOI: 10.1161/01.cir.0000437738.63853.7a] Alcohol 2011; 46: 113-116 [PMID: 21245063 DOI: 10.1093/al-
37 Hegele RA, Ginsberg HN, Chapman MJ, Nordestgaard BG, calc/agq088]
Kuivenhoven JA, Averna M, Borén J, Bruckert E, Catapano 50 Kabagambe EK, Ordovas JM, Tsai MY, Borecki IB, Hopkins
AL, Descamps OS, Hovingh GK, Humphries SE, Kovanen PN, Glasser SP, Arnett DK. Smoking, inflammatory patterns
PT, Masana L, Pajukanta P, Parhofer KG, Raal FJ, Ray and postprandial hypertriglyceridemia. Atherosclerosis 2009;
KK, Santos RD, Stalenhoef AFH, Stroes E, Taskinen M-R, 203: 633-639 [PMID: 18804210 DOI: 10.1016/j.atherosclerosis.
Tybjærg-Hansen A, Watts GF, Wiklund O. The polygenic 2008.08.005]
nature of hypertriglyceridaemia: implications for definition, 51 Hamilton SJ, Watts GF. Atherogenic dyslipidemia and
diagnosis, and management. Lancet Diabetes Endocrinol 2013; combination pharmacotherapy in diabetes: recent clinical tri-
Epub ahead of print [DOI: 10.1016/S2213-8587(13)70191-8] als. Rev Diabet Stud 2013; 10: 191-203 [PMID: 24380092 DOI:
38 Wing RR, Lang W, Wadden TA, Safford M, Knowler WC, 10.1002/pdi.1610]
Bertoni AG, Hill JO, Brancati FL, Peters A, Wagenknecht L. 52 Ginsberg HN. REVIEW: Efficacy and mechanisms of action
Benefits of modest weight loss in improving cardiovascular of statins in the treatment of diabetic dyslipidemia. J Clin
risk factors in overweight and obese individuals with type 2 Endocrinol Metab 2006; 91: 383-392 [PMID: 16291700 DOI:
diabetes. Diabetes Care 2011; 34: 1481-1486 [PMID: 21593294 10.1210/jc.2005-2084]
DOI: 10.2337/dc10-2415] 53 Deedwania PC, Hunninghake DB, Bays HE, Jones PH, Cain
39 Dattilo AM, Kris-Etherton PM. Effects of weight reduction VA, Blasetto JW. Effects of rosuvastatin, atorvastatin, sim-
on blood lipids and lipoproteins: a meta-analysis. Am J Clin vastatin, and pravastatin on atherogenic dyslipidemia in
Nutr 1992; 56: 320-328 [PMID: 1386186] patients with characteristics of the metabolic syndrome. Am
40 Maraki MI, Aggelopoulou N, Christodoulou N, Anastasiou J Cardiol 2005; 95: 360-366 [PMID: 15670545 DOI: 10.1016/
CA, Toutouza M, Panagiotakos DB, Kavouras SA, Magkos j.amjcard.2004.09.034]
F, Sidossis LS. Lifestyle intervention leading to moderate 54 Jones PH, Davidson MH, Stein EA, Bays HE, McKenney
weight loss normalizes postprandial triacylglycerolemia JM, Miller E, Cain VA, Blasetto JW. Comparison of the ef-
despite persisting obesity. Obesity (Silver Spring) 2011; 19: ficacy and safety of rosuvastatin versus atorvastatin, simv-
968-976 [PMID: 20885389 DOI: 10.1038/oby.2010.218] astatin, and pravastatin across doses (STELLAR* Trial). Am
41 Mooradian AD. Obesity: a rational target for manag- J Cardiol 2003; 92: 152-160 [PMID: 12860216 DOI: 10.1016/
ing diabetes mellitus. Growth Horm IGF Res 2001; 11 S0002-9149(03)00530-7]
Suppl A: S79-S83 [PMID: 11527093 DOI: 10.1016/ 55 Pedersen TR, Kjekshus J, Berg K, Haghfelt T, Faergeman
S1096-6374(01)80013-7] O, Faergeman G, Pyörälä K, Miettinen T, Wilhelmsen L,
42 Aucott L, Gray D, Rothnie H, Thapa M, Waweru C. Effects Olsson AG, Wedel H. Randomised trial of cholesterol
of lifestyle interventions and long-term weight loss on lipid lowering in 4444 patients with coronary heart disease: the
outcomes - a systematic review. Obes Rev 2011; 12: e412-e425 Scandinavian Simvastatin Survival Study (4S). 1994. Ath-
[PMID: 21371252 DOI: 10.1111/j.1467-789X.2010.00819.x] eroscler Suppl 2004; 5: 81-87 [PMID: 15531279 DOI: 10.1016/
43 Wing RR, Bolin P, Brancati FL, Bray GA, Clark JM, Coday S0140-6736(94)90566-5]
M, Crow RS, Curtis JM, Egan CM, Espeland MA, Evans M, 56 Ridker PM, Pradhan A, MacFadyen JG, Libby P, Glynn RJ.
Foreyt JP, Ghazarian S, Gregg EW, Harrison B, Hazuda HP, Cardiovascular benefits and diabetes risks of statin therapy
Hill JO, Horton ES, Hubbard VS, Jakicic JM, Jeffery RW, in primary prevention: an analysis from the JUPITER trial.
Johnson KC, Kahn SE, Kitabchi AE, Knowler WC, Lewis Lancet 2012; 380: 565-571 [PMID: 22883507 DOI: 10.1016/
CE, Maschak-Carey BJ, Montez MG, Murillo A, Nathan S0140-6736(12)61190-8]
DM, Patricio J, Peters A, Pi-Sunyer X, Pownall H, Rebous- 57 Kearney PM, Blackwell L, Collins R, Keech A, Simes J, Peto R,
sin D, Regensteiner JG, Rickman AD, Ryan DH, Safford M, Armitage J, Baigent C. Efficacy of cholesterol-lowering ther-
Wadden TA, Wagenknecht LE, West DS, Williamson DF, apy in 18,686 people with diabetes in 14 randomised trials
Yanovski SZ. Cardiovascular effects of intensive lifestyle in- of statins: a meta-analysis. Lancet 2008; 371: 117-125 [PMID:
tervention in type 2 diabetes. N Engl J Med 2013; 369: 145-154 18191683 DOI: 10.1016/S0140-6736(08)60104-X]
[PMID: 23796131 DOI: 10.1056/NEJMoa1212914] 58 Shepherd J, Kastelein JJ, Bittner V, Deedwania P, Breazna A,
44 Estruch R, Ros E, Salas-Salvadó J, Covas MI, Corella D, Dobson S, Wilson DJ, Zuckerman A, Wenger NK. Effect of

WJD|www.wjgnet.com 172 April 15, 2014|Volume 5|Issue 2|

 Pang J et al . Origin and therapy for hypertriglyceridaemia in type 2 diabetes

intensive lipid lowering with atorvastatin on renal function triglycerides in patients with coronary artery disease. Cir-
in patients with coronary heart disease: the Treating to New culation 2000; 102: 21-27 [PMID: 10880410 DOI: 10.1161/01.
Targets (TNT) study. Clin J Am Soc Nephrol 2007; 2: 1131-1139 CIR.102.1.21]
[PMID: 17942759 DOI: 10.2215/CJN.04371206] 70 Keech A, Simes RJ, Barter P, Best J, Scott R, Taskinen MR,
59 Shepherd J, Cobbe SM, Ford I, Isles CG, Lorimer AR, Mac- Forder P, Pillai A, Davis T, Glasziou P, Drury P, Kesäniemi
Farlane PW, McKillop JH, Packard CJ. Prevention of coro- YA, Sullivan D, Hunt D, Colman P, d'Emden M, Whiting
nary heart disease with pravastatin in men with hypercho- M, Ehnholm C, Laakso M. Effects of long-term fenofibrate
lesterolemia. West of Scotland Coronary Prevention Study therapy on cardiovascular events in 9795 people with type 2
Group. N Engl J Med 1995; 333: 1301-1307 [PMID: 7566020 diabetes mellitus (the FIELD study): randomised controlled
DOI: 10.1056/NEJM199511163332001] trial. Lancet 2005; 366: 1849-1861 [PMID: 16310551 DOI:
60 Ballantyne CM, Olsson AG, Cook TJ, Mercuri MF, Pedersen 10.1016/S0140-6736(05)67667-2]
TR, Kjekshus J. Influence of low high-density lipoprotein 71 Scott R, O'Brien R, Fulcher G, Pardy C, D'Emden M, Tse D,
cholesterol and elevated triglyceride on coronary heart dis- Taskinen MR, Ehnholm C, Keech A. Effects of fenofibrate
ease events and response to simvastatin therapy in 4S. Cir- treatment on cardiovascular disease risk in 9,795 individu-
culation 2001; 104: 3046-3051 [PMID: 11748098 DOI: 10.1161/ als with type 2 diabetes and various components of the
hc5001.100624] metabolic syndrome: the Fenofibrate Intervention and Event
61 Glynn RJ, Koenig W, Nordestgaard BG, Shepherd J, Ridker Lowering in Diabetes (FIELD) study. Diabetes Care 2009; 32:
PM. Rosuvastatin for primary prevention in older persons 493-498 [PMID: 18984774 DOI: 10.2337/dc08-1543]
with elevated C-reactive protein and low to average low- 72 Ginsberg HN, Elam MB, Lovato LC, Crouse JR, Leiter LA,
density lipoprotein cholesterol levels: exploratory analysis of Linz P, Friedewald WT, Buse JB, Gerstein HC, Probstfield
a randomized trial. Ann Intern Med 2010; 152: 488-496, W174 J, Grimm RH, Ismail-Beigi F, Bigger JT, Goff DC, Cushman
[PMID: 20404379 DOI: 10.7326/0003-4819-152-8-201004200-0 WC, Simons-Morton DG, Byington RP. Effects of combina-
0005] tion lipid therapy in type 2 diabetes mellitus. N Engl J Med
62 Maki KC, Bays HE, Dicklin MR. Treatment options for the 2010; 362: 1563-1574 [PMID: 20228404 DOI: 10.1056/NEJ-
management of hypertriglyceridemia: strategies based on Moa1001282]
the best-available evidence. J Clin Lipidol 2012; 6: 413-426 73 Bloomfield Rubins H, Davenport J, Babikian V, Brass LM,
[PMID: 23009777 DOI: 10.1016/j.jacl.2012.04.003] Collins D, Wexler L, Wagner S, Papademetriou V, Rutan
63 Sattar N, Preiss D, Murray HM, Welsh P, Buckley BM, de G, Robins SJ. Reduction in stroke with gemfibrozil in men
Craen AJ, Seshasai SR, McMurray JJ, Freeman DJ, Jukema with coronary heart disease and low HDL cholesterol: The
JW, Macfarlane PW, Packard CJ, Stott DJ, Westendorp RG, Veterans Affairs HDL Intervention Trial (VA-HIT). Circula-
Shepherd J, Davis BR, Pressel SL, Marchioli R, Marfisi RM, tion 2001; 103: 2828-2833 [PMID: 11401940 DOI: 10.1161/01.
Maggioni AP, Tavazzi L, Tognoni G, Kjekshus J, Pedersen CIR.103.23.2828]
TR, Cook TJ, Gotto AM, Clearfield MB, Downs JR, Naka- 74 Rubins HB, Robins SJ, Collins D, Nelson DB, Elam MB,
mura H, Ohashi Y, Mizuno K, Ray KK, Ford I. Statins and Schaefer EJ, Faas FH, Anderson JW. Diabetes, plasma insulin,
risk of incident diabetes: a collaborative meta-analysis of and cardiovascular disease: subgroup analysis from the De-
randomised statin trials. Lancet 2010; 375: 735-742 [PMID: partment of Veterans Affairs high-density lipoprotein inter-
20167359 DOI: 10.1016/S0140-6736(09)61965-6] vention trial (VA-HIT). Arch Intern Med 2002; 162: 2597-2604
64 Culver AL, Ockene IS, Balasubramanian R, Olendzki BC, [PMID: 12456232 DOI: 10.1001/archinte.162.22.2597]
Sepavich DM, Wactawski-Wende J, Manson JE, Qiao Y, Liu S, 75 Rizos E, Mikhailidis DP. Are high-density lipoprotein and
Merriam PA, Rahilly-Tierny C, Thomas F, Berger JS, Ockene triglyceride levels important in secondary prevention:
JK, Curb JD, Ma Y. Statin use and risk of diabetes mellitus in impressions from the BIP and VA-HIT trials. Int J Cardiol
postmenopausal women in the Women's Health Initiative. 2002; 82: 199-207; discussion 207-208 [PMID: 11911905 DOI:
Arch Intern Med 2012; 172: 144-152 [PMID: 22231607 DOI: 10.1016/S0167-5273(01)00625-8]
10.1001/archinternmed.2011.625] 76 Lee M, Saver JL, Towfighi A, Chow J, Ovbiagele B. Efficacy
65 Preiss D, Seshasai SR, Welsh P, Murphy SA, Ho JE, Waters of fibrates for cardiovascular risk reduction in persons with
DD, DeMicco DA, Barter P, Cannon CP, Sabatine MS, Braun- atherogenic dyslipidemia: a meta-analysis. Atherosclerosis
wald E, Kastelein JJ, de Lemos JA, Blazing MA, Pedersen 2011; 217: 492-498 [PMID: 21592479 DOI: 10.1016/j.atheroscl
TR, Tikkanen MJ, Sattar N, Ray KK. Risk of incident diabetes erosis.2011.04.020]
with intensive-dose compared with moderate-dose statin 77 Jun M, Foote C, Lv J, Neal B, Patel A, Nicholls SJ, Grobbee
therapy: a meta-analysis. JAMA 2011; 305: 2556-2564 [PMID: DE, Cass A, Chalmers J, Perkovic V. Effects of fibrates on
21693744 DOI: 10.1001/jama.2011.860] cardiovascular outcomes: a systematic review and meta-
66 Staels B. Fibrates in CVD: a step towards personalised analysis. Lancet 2010; 375: 1875-1884 [PMID: 20462635 DOI:
medicine. Lancet 2010; 375: 1847-1848 [PMID: 20510999 DOI: 10.1016/S0140-6736(10)60656-3]
10.1016/S0140-6736(10)60758-1] 78 Bruckert E, Labreuche J, Deplanque D, Touboul PJ, Ama-
67 Frick MH, Elo O, Haapa K, Heinonen OP, Heinsalmi P, Helo renco P. Fibrates effect on cardiovascular risk is greater in
P, Huttunen JK, Kaitaniemi P, Koskinen P, Manninen V. Hel- patients with high triglyceride levels or atherogenic dys-
sinki Heart Study: primary-prevention trial with gemfibrozil lipidemia profile: a systematic review and meta-analysis. J
in middle-aged men with dyslipidemia. Safety of treatment, Cardiovasc Pharmacol 2011; 57: 267-272 [PMID: 21052016 DOI:
changes in risk factors, and incidence of coronary heart dis- 10.1097/FJC.0b013e318202709f]
ease. N Engl J Med 1987; 317: 1237-1245 [PMID: 3313041 DOI: 79 Keech AC, Mitchell P, Summanen PA, O'Day J, Davis TM,
10.1056/NEJM198711123172001] Moffitt MS, Taskinen MR, Simes RJ, Tse D, Williamson E,
68 Manninen V, Tenkanen L, Koskinen P, Huttunen JK, Mänt- Merrifield A, Laatikainen LT, d'Emden MC, Crimet DC,
täri M, Heinonen OP, Frick MH. Joint effects of serum tri- O'Connell RL, Colman PG. Effect of fenofibrate on the need
glyceride and LDL cholesterol and HDL cholesterol concen- for laser treatment for diabetic retinopathy (FIELD study):
trations on coronary heart disease risk in the Helsinki Heart a randomised controlled trial. Lancet 2007; 370: 1687-1697
Study. Implications for treatment. Circulation 1992; 85: 37-45 [PMID: 17988728 DOI: 10.1016/S0140-6736(07)61607-9]
[PMID: 1728471 DOI: 10.1161/01.CIR.85.1.37] 80 Ismail-Beigi F, Craven T, Banerji MA, Basile J, Calles J,
69 Schlesinger Z, Vered Z, Friedenson A, Reisin L, Jafari J, Cohen RM, Cuddihy R, Cushman WC, Genuth S, Grimm
Flieb T, Sclarovsky S, Friedman Y, Ostfeld B, Solodky A. Sec- RH, Hamilton BP, Hoogwerf B, Karl D, Katz L, Krikorian A,
ondary prevention by raising HDL cholesterol and reducing O'Connor P, Pop-Busui R, Schubart U, Simmons D, Taylor

WJD|www.wjgnet.com 173 April 15, 2014|Volume 5|Issue 2|

 Pang J et al . Origin and therapy for hypertriglyceridaemia in type 2 diabetes

H, Thomas A, Weiss D, Hramiak I. Effect of intensive treat- on insulin secretion and insulin sensitivity in low and high
ment of hyperglycaemia on microvascular outcomes in type insulin responders. Scand J Clin Lab Invest 1996; 56: 563-570
2 diabetes: an analysis of the ACCORD randomised trial. [PMID: 8903118 DOI: 10.3109/00365519609088812]
Lancet 2010; 376: 419-430 [PMID: 20594588 DOI: 10.1016/ 94 Elam MB, Hunninghake DB, Davis KB, Garg R, Johnson C,
S0140-6736(10)60576-4] Egan D, Kostis JB, Sheps DS, Brinton EA. Effect of niacin on
81 Tonkin AM, Chen L. Effects of combination lipid therapy in lipid and lipoprotein levels and glycemic control in patients
the management of patients with type 2 diabetes mellitus in with diabetes and peripheral arterial disease: the ADMIT
the Action to Control Cardiovascular Risk in Diabetes (AC- study: A randomized trial. Arterial Disease Multiple Inter-
CORD) trial. Circulation 2010; 122: 850-852 [PMID: 20733114 vention Trial. JAMA 2000; 284: 1263-1270 [PMID: 10979113
DOI: 10.1161/CIRCULATIONAHA.110.960112] DOI: 10.1001/jama.284.10.1263]
82 Elam M, Lovato L, Ginsberg H: The ACCORD-Lipid study: 95 Grundy SM, Vega GL, McGovern ME, Tulloch BR, Kendall
implications for treatment of dyslipidemia in type 2 diabetes DM, Fitz-Patrick D, Ganda OP, Rosenson RS, Buse JB, Rob-
mellitus. Clin Lipidol 2011; 6: 9-20 [DOI: 10.2217/clp.10.84] ertson DD, Sheehan JP. Efficacy, safety, and tolerability of
83 Chapman MJ, Redfern JS, McGovern ME, Giral P. Niacin once-daily niacin for the treatment of dyslipidemia associ-
and fibrates in atherogenic dyslipidemia: pharmacotherapy ated with type 2 diabetes: results of the assessment of dia-
to reduce cardiovascular risk. Pharmacol Ther 2010; 126: betes control and evaluation of the efficacy of niaspan trial.
314-345 [PMID: 20153365 DOI: 10.1016/j.pharmthera.2010.01 Arch Intern Med 2002; 162: 1568-1576 [PMID: 12123399 DOI:
.008] 10.1001/archinte.162.14.1568]
84 Canner PL, Berge KG, Wenger NK, Stamler J, Friedman L, 96 Pandor A, Ara RM, Tumur I, Wilkinson AJ, Paisley S, Due-
Prineas RJ, Friedewald W. Fifteen year mortality in Coronary nas A, Durrington PN, Chilcott J. Ezetimibe monotherapy
Drug Project patients: long-term benefit with niacin. J Am for cholesterol lowering in 2,722 people: systematic review
Coll Cardiol 1986; 8: 1245-1255 [PMID: 3782631 DOI: 10.1016/ and meta-analysis of randomized controlled trials. J Intern
S0735-1097(86)80293-5] Med 2009; 265: 568-580 [PMID: 19141093 DOI: 10.1111/
85 Brown BG, Zhao XQ, Chait A, Fisher LD, Cheung MC, j.1365-2796.2008.02062.x]
Morse JS, Dowdy AA, Marino EK, Bolson EL, Alaupovic 97 Kikuchi K, Nezu U, Inazumi K, Miyazaki T, Ono K, Orime K,
P, Frohlich J, Albers JJ. Simvastatin and niacin, antioxidant Shirakawa J, Sato K, Koike H, Wakasugi T, Sato M, Kawaka-
vitamins, or the combination for the prevention of coronary mi C, Watanabe S, Yamakawa T, Terauchi Y. Double-blind
disease. N Engl J Med 2001; 345: 1583-1592 [PMID: 11757504 randomized clinical trial of the effects of ezetimibe on post-
DOI: 10.1056/NEJMoa011090] prandial hyperlipidaemia and hyperglycaemia. J Atheroscler
86 Taylor AJ, Sullenberger LE, Lee HJ, Lee JK, Grace KA. Arte- Thromb 2012; 19: 1093-1101 [PMID: 22878697 DOI: 10.5551/
rial Biology for the Investigation of the Treatment Effects of jat.12427]
Reducing Cholesterol (ARBITER) 2: a double-blind, placebo- 98 Nakamura T, Hirano M, Kitta Y, Fujioka D, Saito Y, Kawa-
controlled study of extended-release niacin on atherosclero- bata K, Obata JE, Watanabe Y, Watanabe K, Kugiyama K.
sis progression in secondary prevention patients treated with A comparison of the efficacy of combined ezetimibe and
statins. Circulation 2004; 110: 3512-3517 [PMID: 15537681 statin therapy with doubling of statin dose in patients
DOI: 10.1161/01.CIR.0000148955.19792.8D] with remnant lipoproteinemia on previous statin therapy.
87 Taylor AJ, Lee HJ, Sullenberger LE. The effect of 24 months J Cardiol 2012; 60: 12-17 [PMID: 22445441 DOI: 10.1016/
of combination statin and extended-release niacin on carotid j.jjcc.2012.02.005]
intima-media thickness: ARBITER 3. Curr Med Res Opin 2006; 99 Bozzetto L, Annuzzi G, Corte GD, Patti L, Cipriano P, Man-
22: 2243-2250 [PMID: 17076985 DOI: 10.1185/030079906X148 gione A, Riccardi G, Rivellese AA. Ezetimibe beneficially
508] influences fasting and postprandial triglyceride-rich lipo-
88 Boden WE, Probstfield JL, Anderson T, Chaitman BR, Des- proteins in type 2 diabetes. Atherosclerosis 2011; 217: 142-148
vignes-Nickens P, Koprowicz K, McBride R, Teo K, Wein- [PMID: 21481394 DOI: 10.1016/j.atherosclerosis.2011.03.012]
traub W. Niacin in patients with low HDL cholesterol levels 100 Fleg JL, Mete M, Howard BV, Umans JG, Roman MJ, Ratner
receiving intensive statin therapy. N Engl J Med 2011; 365: RE, Silverman A, Galloway JM, Henderson JA, Weir MR,
2255-2267 [PMID: 22085343 DOI: 10.1056/NEJMoa1107579] Wilson C, Stylianou M, Howard WJ. Effect of statins alone
89 HPS2-THRIVE Collaborative Group. HPS2-THRIVE ran- versus statins plus ezetimibe on carotid atherosclerosis in
domized placebo-controlled trial in 25 673 high-risk patients type 2 diabetes: the SANDS (Stop Atherosclerosis in Native
of ER niacin/laropiprant: trial design, pre-specified muscle Diabetics Study) trial. J Am Coll Cardiol 2008; 52: 2198-2205
and liver outcomes, and reasons for stopping study treat- [PMID: 19095139 DOI: 10.1016/j.jacc.2008.10.031]
ment. Eur Heart J 2013; 34: 1279-1291 [PMID: 23444397 DOI: 101 Taylor AJ, Villines TC, Stanek EJ, Devine PJ, Griffen L,
10.1093/eurheartj/eht055] Miller M, Weissman NJ, Turco M. Extended-release niacin or
90 Guyton JR, Slee AE, Anderson T, Fleg JL, Goldberg RB, ezetimibe and carotid intima-media thickness. N Engl J Med
Kashyap ML, Marcovina SM, Nash SD, O'Brien KD, Wein- 2009; 361: 2113-2122 [PMID: 19915217 DOI: 10.1056/NEJ-
traub WS, Xu P, Zhao XQ, Boden WE. Relationship of lipo- Moa0907569]
proteins to cardiovascular events: the AIM-HIGH Trial (Ath- 102 Cannon CP, Giugliano RP, Blazing MA, Harrington RA,
erothrombosis Intervention in Metabolic Syndrome With Peterson JL, Sisk CM, Strony J, Musliner TA, McCabe CH,
Low HDL/High Triglycerides and Impact on Global Health Veltri E, Braunwald E, Califf RM. Rationale and design of
Outcomes). J Am Coll Cardiol 2013; 62: 1580-1584 [PMID: IMPROVE-IT (IMProved Reduction of Outcomes: Vytorin
23916935 DOI: 10.1016/j.jacc.2013.07.023] Efficacy International Trial): comparison of ezetimbe/simv-
91 Garg A. Lipid-lowering therapy and macrovascular disease astatin versus simvastatin monotherapy on cardiovascular
in diabetes mellitus. Diabetes 1992; 41 Suppl 2: 111-115 [PMID: outcomes in patients with acute coronary syndromes. Am
1526329 DOI: 10.2337/diab.41.2.S111] Heart J 2008; 156: 826-832 [PMID: 19061694 DOI: 10.1016/
92 Poynten AM, Gan SK, Kriketos AD, O'Sullivan A, Kelly j.ahj.2008.07.023]
JJ, Ellis BA, Chisholm DJ, Campbell LV. Nicotinic acid- 103 Califf RM, Lokhnygina Y, Cannon CP, Stepanavage ME,
induced insulin resistance is related to increased circulating McCabe CH, Musliner TA, Pasternak RC, Blazing MA, Gi-
fatty acids and fat oxidation but not muscle lipid content. ugliano RP, Harrington RA, Braunwald E. An update on the
Metabolism 2003; 52: 699-704 [PMID: 12800094 DOI: 10.1016/ IMProved reduction of outcomes: Vytorin Efficacy Inter-
S0026-0495(03)00030-1] national Trial (IMPROVE-IT) design. Am Heart J 2010; 159:
93 Alvarsson M, Grill V. Impact of nicotinic acid treatment 705-709 [PMID: 20435175 DOI: 10.1016/j.ahj.2010.03.004]

WJD|www.wjgnet.com 174 April 15, 2014|Volume 5|Issue 2|

 Pang J et al . Origin and therapy for hypertriglyceridaemia in type 2 diabetes

104 Saravanan P, Davidson NC, Schmidt EB, Calder PC. Car- based therapies and cardiovascular disease: looking beyond
diovascular effects of marine omega-3 fatty acids. Lancet glycaemic control. Diabetes Obes Metab 2011; 13: 302-312
2010; 376: 540-550 [PMID: 20638121 DOI: 10.1016/S0140- [PMID: 21205117 DOI: 10.1111/j.1463-1326.2010.01345.x]
6736(10)60445-X] 116 Scirica BM, Bhatt DL, Braunwald E, Steg PG, Davidson J,
105 Bosch J, Gerstein HC, Dagenais GR, Díaz R, Dyal L, Jung H, Hirshberg B, Ohman P, Frederich R, Wiviott SD, Hoffman
Maggiono AP, Probstfield J, Ramachandran A, Riddle MC, EB, Cavender MA, Udell JA, Desai NR, Mosenzon O, Mc-
Rydén LE, Yusuf S. n-3 fatty acids and cardiovascular out- Guire DK, Ray KK, Leiter LA, Raz I. Saxagliptin and cardio-
comes in patients with dysglycemia. N Engl J Med 2012; 367: vascular outcomes in patients with type 2 diabetes mellitus.
309-318 [PMID: 22686415 DOI: 10.1056/NEJMoa1203859] N Engl J Med 2013; 369: 1317-1326 [PMID: 23992601 DOI:
106 Roncaglioni MC, Tombesi M, Avanzini F, Barlera S, Caimi 10.1056/NEJMoa1307684]
V, Longoni P, Marzona I, Milani V, Silletta MG, Tognoni G, 117 White WB, Cannon CP, Heller SR, Nissen SE, Bergenstal
Marchioli R. n-3 fatty acids in patients with multiple car- RM, Bakris GL, Perez AT, Fleck PR, Mehta CR, Kupfer S,
diovascular risk factors. N Engl J Med 2013; 368: 1800-1808 Wilson C, Cushman WC, Zannad F. Alogliptin after acute
[PMID: 23656645 DOI: 10.1056/NEJMoa1205409] coronary syndrome in patients with type 2 diabetes. N Engl
107 Yokoyama M, Origasa H, Matsuzaki M, Matsuzawa Y, Saito J Med 2013; 369: 1327-1335 [PMID: 23992602 DOI: 10.1056/
Y, Ishikawa Y, Oikawa S, Sasaki J, Hishida H, Itakura H, Kita NEJMoa1305889]
T, Kitabatake A, Nakaya N, Sakata T, Shimada K, Shirato K. 118 Denecker N, Decochez K. Poorly controlled type 2 diabetes
Effects of eicosapentaenoic acid on major coronary events in complicated by an episode of severe hypertriglyceridaemia-
hypercholesterolaemic patients (JELIS): a randomised open- induced pancreatitis. BMJ Case Rep 2013; 2013: [PMID:
label, blinded endpoint analysis. Lancet 2007; 369: 1090-1098 23632173 DOI: 10.1136/bcr-2012-008455]
[PMID: 17398308 DOI: 10.1016/S0140-6736(07)60527-3] 119 Henderson SR, Maitland R, Mustafa OG, Miell J, Crook
108 Bays HE, Ballantyne CM, Kastelein JJ, Isaacsohn JL, MA, Kottegoda SR. Severe hypertriglyceridaemia in Type 2
Braeckman RA, Soni PN. Eicosapentaenoic acid ethyl ester diabetes mellitus: beneficial effect of continuous insulin infu-
(AMR101) therapy in patients with very high triglyceride sion. QJM 2013; 106: 355-359 [PMID: 23417910 DOI: 10.1093/
levels (from the Multi-center, plAcebo-controlled, Random- qjmed/hcs238]
ized, double-blINd, 12-week study with an open-label Exten- 120 Schaefer EW, Leung A, Kravarusic J, Stone NJ. Management
sion [MARINE] trial). Am J Cardiol 2011; 108: 682-690 [PMID: of severe hypertriglyceridemia in the hospital: a review. J
21683321 DOI: 10.1016/j.amjcard.2011.04.015] Hosp Med 2012; 7: 431-438 [PMID: 22128096 DOI: 10.1002/
109 Ballantyne CM, Bays HE, Kastelein JJ, Stein E, Isaacsohn JL, jhm.995]
Braeckman RA, Soni PN. Efficacy and safety of eicosapentae- 121 Seda G, Meyer JM, Amundson DE, Daheshia M. Plasma-
noic acid ethyl ester (AMR101) therapy in statin-treated pa- pheresis in the management of severe hypertriglyceridemia.
tients with persistent high triglycerides (from the ANCHOR Crit Care Nurse 2013; 33: 18-23; quiz 24 [PMID: 23908166 DOI:
study). Am J Cardiol 2012; 110: 984-992 [PMID: 22819432 DOI: 10.4037/ccn2013346]
10.1016/j.amjcard.2012.05.031] 122 Hovland A, Hardersen R, Mollnes TE, Lappegård KT. Selec-
110 Lairon D, Defoort C. Effects of nutrients on postprandial li- tive whole blood lipoprotein apheresis to prevent pancre-
pemia. Curr Vasc Pharmacol 2011; 9: 309-312 [PMID: 21314626 atitis in drug refractory hypertriglyceridemia. JOP 2010; 11:
DOI: 10.2174/157016111795495576] 467-469 [PMID: 20818118]
111 Brasky TM, Darke AK, Song X, Tangen CM, Goodman PJ, 123 Bayraktaroglu T, Ozkaya M, Kutluturk F, Azezli AD, Orhan
Thompson IM, Meyskens FL, Goodman GE, Minasian LM, Y. Severe hypertriglyceridemia and triglyceride apheresis.
Parnes HL, Klein EA, Kristal AR. Plasma phospholipid fatty Endocrine 2009; 20: Abstr437
acids and prostate cancer risk in the SELECT trial. J Natl Can- 124 Chen JH, Yeh JH, Lai HW, Liao CS. Therapeutic plasma ex-
cer Inst 2013; 105: 1132-1141 [PMID: 23843441 DOI: 10.1093/ change in patients with hyperlipidemic pancreatitis. World J
jnci/djt174] Gastroenterol 2004; 10: 2272-2274 [PMID: 15259080]
112 Meier JJ, Gethmann A, Götze O, Gallwitz B, Holst JJ, 125 Ewald N, Kloer HU. Treatment options for severe hypertri-
Schmidt WE, Nauck MA. Glucagon-like peptide 1 abolishes glyceridemia (SHTG): the role of apheresis. Clin Res Cardiol
the postprandial rise in triglyceride concentrations and low- Suppl 2012; 7: 31-35 [PMID: 22528130 DOI: 10.1007/s11789-
ers levels of non-esterified fatty acids in humans. Diabetologia 012-0042-x]
2006; 49: 452-458 [PMID: 16447057 DOI: 10.1007/s00125-005- 126 Gaudet D, Méthot J, Déry S, Brisson D, Essiembre C, Trem-
0126-y] blay G, Tremblay K, de Wal J, Twisk J, van den Bulk N, Sier-
113 Tremblay AJ, Lamarche B, Deacon CF, Weisnagel SJ, Ferreira V, van Deventer S. Efficacy and long-term safety of
Couture P. Effect of sitagliptin therapy on postprandial alipogene tiparvovec (AAV1-LPLS447X) gene therapy for
lipoprotein levels in patients with type 2 diabetes. Diabetes lipoprotein lipase deficiency: an open-label trial. Gene Ther
Obes Metab 2011; 13: 366-373 [PMID: 21226820 DOI: 10.1111/ 2013; 20: 361-369 [PMID: 22717743 DOI: 10.1038/gt.2012.43]
j.1463-1326.2011.01362.x] 127 Wierzbicki AS, Viljoen A. Alipogene tiparvovec: gene ther-
114 Barnett AH, Charbonnel B, Donovan M, Fleming D, Chen R. apy for lipoprotein lipase deficiency. Expert Opin Biol Ther
Effect of saxagliptin as add-on therapy in patients with poor- 2013; 13: 7-10 [PMID: 23126631 DOI: 10.1517/14712598.2013.
ly controlled type 2 diabetes on insulin alone or insulin com- 738663]
bined with metformin. Curr Med Res Opin 2012; 28: 513-523 128 Guidelines for the management of absolute cardiovas-
[PMID: 22313154 DOI: 10.1185/03007995.2012.665046] cular disease risk [article online], 2012. Available from:
115 Anagnostis P, Athyros VG, Adamidou F, Panagiotou A, Kita URL: http://strokefoundation.com.au/site/media/
M, Karagiannis A, Mikhailidis DP. Glucagon-like peptide-1- AbsoluteCVD_GL_webready.pdf

P- Reviewers: Cheung BMY, Ramana KV S- Editor: Zhai HH

L- Editor: A E- Editor: Wu HL

WJD|www.wjgnet.com 175 April 15, 2014|Volume 5|Issue 2|

Published by Baishideng Publishing Group Co., Limited
Flat C, 23/F., Lucky Plaza,
315-321 Lockhart Road, Wan Chai, Hong Kong, China
Fax: +852-65557188
Telephone: +852-31779906
E-mail: bpgoffice@wjgnet.com
http://www.wjgnet.com

© 2014 Baishideng Publishing Group Co., Limited. All rights reserved.