Review article 27

Dyslipidemia in diabetes mellitus and cardiovascular disease

Haider J. Warraicha and Jamal S. Ranab,c

Patients with diabetes have a high residual risk for benefit when given in addition to statins. PCSK9 inhibitors
cardiovascular disease (CVD) and adverse outcomes are a promising category, although clinical outcome data in
despite statin therapy and lifestyle modifications. Particular individuals with diabetes are pending. Cardiovasc
to individuals with diabetes is the pattern of elevated Endocrinol 6:2732 Copyright 2017 Wolters Kluwer
triglycerides, small dense low density lipoprotein Health, Inc. All rights reserved.
cholesterol, and reduced levels of high density lipoprotein Cardiovascular Endocrinology 2017, 6:2732
cholesterol, described as dyslipidemia of diabetes. The role
of combination therapy with an additional agent such as Keywords: dyslipidemia, ezetimibe, fibrates, fish oil, PCSK9 inhibitors,
statins, type 2 diabetes mellitus
niacin, ezetimibe, fenofibrate, and n-3 fatty acids has been
a
studied; however, at the same time, these agents have Department of Medicine, Division of Cardiology, Duke University Medical Center,
Durham, North Carolina, bThe Division of Cardiology, Kaiser Permanente, Oakland
come under criticism for their limitations. We performed a and cDepartment of Medicine, University of California San Francisco, San
review of key trials assessing the benefit of combination Francisco, California, USA

therapy to reduce CVD risk from dyslipidemia. Of the Correspondence to Jamal S. Rana MD, PhD, FACC, Division of Cardiology, 3600
currently available agents that can be used in combination Broadway Kaiser Permanente Medical Center, Oakland, CA 94611, USA
Tel: + 1 510 752 1276; fax: + 510 752 7456; e-mail: jamal.s.rana@kp.org
with statins, ezetimibe has the most favorable risk profile,
with a recent trial demonstrating modest incremental Received 15 September 2016 Accepted 24 January 2017

Introduction independently of the serum LDL level [14]. The pattern

The burden of cardiovascular disease (CVD), the major of dyslipidemia usually presents with elevated triglycer-
cause of morbidity and mortality around the world [1], is ides and small dense LDL and reduced levels of high
particularly high among patients with type 2 diabetes density lipoprotein cholesterol (HDL-C) [15]. Increased
mellitus (T2DM) [2,3], with the proportion of CVD LDL particle numbers from either elevated ApoB or
attributable to diabetes increasing in the general popu- LDL-P are a prominent feature of dyslipidemia in dia-
lation [4]. With the prevalence of diabetes itself rising, betes. Small dense LDL particles are more atherogenic
particularly among ethnic minorities, CVD risk reduction and are associated with a higher rate of nephropathy [16].
in this population is of great public health importance [5]. Individuals with diabetes have also been noted to have
Although lifestyle modifications and statins are the first- lower HDL levels [17].
line interventions for CVD risk reduction in individuals
with diabetes [6], they remain at considerable risk for Insulin resistance is the primary mechanism leading to
adverse cardiovascular events [7,8]. lipid derangements in individuals with diabetes [18].
Peripheral resistance to insulin increases the release of
In this narrative review, we review the pathophysiology
free fatty acids from adipose tissue, which are taken up
of dyslipidemia in individuals with diabetes and sum-
by the liver; increased hepatic uptake of free fatty acids
marize the key trials that report on cardiovascular risk
reduction in these patients. We conclude by summarizing leads to more synthesis of triglycerides. Triglyceride
the positions of major professional bodies on the man- synthesis subsequently stimulates hepatic production of
agement of dyslipidemia in individuals with diabetes and triglyceride-rich very low density lipoprotein cholesterol
conclude by presenting recommendations for future (VLDL) and increased secretion of ApoB [19].
research in this area. Triglyceride-laden VLDL enrich LDL and HDL
through the action of the cholesterol ester transfer pro-
tein, making them more cholesterol rich [20]. These
Mechanisms of dyslipidemia in individuals with diabetes triglyceride-rich LDL molecules are then hydrolyzed by
Patients with diabetes are at an elevated risk for adverse hepatic or lipoprotein lipase leading to the production of
cardiovascular outcomes compared with controls [9,10]. small dense LDL.
Although in nondiabetic individuals LDL is predictive of
cardiovascular outcomes [11], the prevalence of LDL is Therefore, the lipid derangements associated with dia-
similar between individuals with diabetes and non- betes are widespread, beyond just LDL elevation,
diabetic individuals [12,13], and data suggest that the making it challenging to rely on conventional means for
elevated risk for CVD in individuals with diabetes occurs cardiovascular risk reduction.
2162-688X Copyright 2017 Wolters Kluwer Health, Inc. All rights reserved. DOI: 10.1097/XCE.0000000000000120

Copyright r 2017 Wolters Kluwer Health, Inc. All rights reserved.

28 Cardiovascular Endocrinology 2017, Vol 6 No 1

Lifestyle modifications: diet and exercise therapy still leave patients with T2DM with a substantial
Lifestyle modification in individuals with diabetes per- risk for future CVD [39]. One of seven individuals with
tains to dietary restriction and physical exercise. Dietary diabetes on statins experience major adverse cardiovascular
restrictions benefit is realized through weight loss. In events within 5 years [31]. In one trial, despite a multi-
this regard, caloric restriction is essential and any degree dimensional approach, 50% of patients went on to have
of weight loss is beneficial. In a randomized study, caloric microvascular complications from dyslipidemia [40].
restriction led to improvements in all markers, including Although agents including ezetimibe, fibrates, niacin, and
glycemic control, HbA1c, and lipid profile, in obese and n-3 fatty acids have been used, they have no established
overweight individuals with diabetes [21]. It remains role as monotherapy in statin-tolerant patients [41].
unclear, however, as to what type of dietary modification
is best for individuals with diabetes. Although both the Combination therapy: a review of key clinical trials
American Diabetic Association [22] and the Adult The role of monotherapy with a nonstatin agent is only
Treatment Panel III guidelines [23] recommend a diet indicated in patients who are statin-intolerant. The role,
low in monosaturated fats, recent data support a low- if any, of adding a medication to supplement statin risk
carbohydrate diet. A trial in Spain randomizing patients reduction has been extensively studied and here we
to a fat-rich Mediterranean diet showed a significant summarize key clinical trials by pharmacologic category.
reduction in cardiovascular events [24] and a lower inci-
dence of diabetes compared with patients advised a low- Ezetimibe
fat diet [25]. However, despite dietary modification Ezetimibe is a cholesterol absorption inhibitor that
improving some measures, no mortality benefit has yet reduces uptake from the intestine while also increasing
been demonstrated in diabetic patients. One multicenter the breakdown of LDL. Ezetimibe has been extensively
randomized controlled trial (Look Action for Health in tested in combination with statins (Table 1).
Diabetes), which randomized overweight and obese
Many trials show improved lipid profile with the addition
individuals with diabetes to either caloric restriction and
of ezetimibe to statins. In EASE, patients with at-goal
physical exercise or usual care, resulted in improvement
LDL levels were randomized 2 : 1 to receive ezetimibe or
in obesity, but was unable to show improvement in lipid
placebo in combination with a statin and were found to
profiles, cardiovascular events, or mortality [26]. Similar
have better LDL control after 6 weeks of treatment [42].
to diet, exercise has been shown to result in better gly-
In VYTAL, 1229 individuals with diabetes were rando-
cemic control [27] and lipid profiles [2830]; no reduction
mized for 6 months to receive ezetimibe and simvastatin
in cardiovascular events or mortality has ever
or atorvastatin alone, with the ezetimibe/simvastatin
been shown.
combination demonstrating better lipid profiles [43]. In
ENHANCE, 720 patients with familial hypercholester-
Statin therapy olemia receiving simvastatin were randomized to receive
Statins are the first-line treatment for hyperlipidemia in ezetimibe or placebo and found that, although LDL was
all patients, including those with diabetes, and have the lower, there was no difference in CIMT in the combi-
strongest evidence base of any intervention in patients nation group [44]. A substudy of SANDS, which rando-
with or without diabetes [31]. The benefits of statins mized 499 diabetic patients with intensive lipid and
increase with dose intensity [32] and are independent of blood pressure control or conventional control for 3 years,
the patients initial lipid profile, as demonstrated in the showed no additional benefit when ezetimibe was added
CARDS trial [33,34]. The cardiovascular risk reduction to statin therapy with regard to CIMT regression or
that individuals with diabetes accrue is independent of LDL. [45]. ARBITER 6-HALTS analyzed the addition
their individualized risk for future events [35]. of niacin or ezetimibe to ongoing statin therapy and
One concern about statin use has been the increased showed greater CIMT regression and lower cardiovas-
incidence of T2DM in patients taking statins [36]. In one cular events (1 vs. 5%, P = 0.04) with niacin compared
trial, 270 patients on rosuvastatin developed diabetes with ezetimibe [46].
versus 216 on placebo [37]. The small increase in inci- IMPROVE-IT was a double-blind trial enrolling 18 144
dence is offset by the benefits of statin therapy. One high-risk patients within 10 days of an acute coronary
meta-analysis showed that one of 255 patients would syndrome, which randomized patients to receive sim-
develop diabetes after being treated with statins for vastatin and ezetimibe or simvastatin and placebo with an
4 years, most of whom were prediabetic; however, in this LDL less than 125 mg/dl. The trial demonstrated a 6.4%
same cohort, 5.4 vascular events were prevented [38]. relative risk reduction in the primary endpoint, which
was a composite of cardiovascular death, myocardial
Residual risk in individuals with diabetes infarction (MI), hospital admission for unstable angina,
There remains residual risk for CVD with all mono- coronary revascularization more than a month after ran-
therapies, despite intensification of statins. Implementation domization, and stroke [47]. Results in the prespecific
of lifestyle modifications and the institution of statin diabetic subpopulation were presented at the European

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 Diabetic dyslipidemia in CVD Warraich and Rana 29

Table 1 Key clinical trials analyzing combination of ezetimibe and statins

Ezetimibe

Trials Designs Results Additional findings

EASE, 2005, statin and ezetimibe vs. 3030 patients with LDL exceeding ATP III LDL control better with Ezetimibe found to be beneficial to
statin and placebo [42] goal, randomized 2 : 1 to ezetimibe or combination (71 vs. 21%, reach lower LDL level when added
placebo for 6 weeks P < 0.05); improvement in CRP to statin therapy
also noted
VYTAL, 2006, ezetimibe and simvastatin 1229 adults with type 2 diabetes randomized LDL better controlled with Simvastatin and ezetimibe
vs. atorvastatin [43] for 6 months combination compared with combination had better lipid profile
atorvastatin alone with similar risk compared with atorvastatin alone
profile
ENHANCE, 2008, simvastatin 80 mg 720 patients with familial No difference in CIMT; LDL lower No difference in adverse effects
with ezetimibe vs. simvastatin 80 mg hypercholesterolemia randomized in a 16% in the combination group between the two groups
alone [44] double-blind study over 24 months
SANDS, 2008, simvastatin and 499 individuals with diabetes > 40 years of No difference in LDL lowering and CIMT and left ventricular mass
ezetimibe vs. simvastatin alone (LDL age without CVD randomized to aggressive CIMT regression in the statin regressed greater in aggressive arm
goal < 70 mg/dl, SBP < 115 mmHg) LDL, SBP arm, and conventional arm (LDL alone vs. the combination group but no difference in clinical events
vs. statin alone (conventional arm) [45] goal < 100 mg/dl, SBP < 130) over 3 years in aggressive arm between conventional and
aggressive arms
ARBITER 6-HALTS, 2009, extended 208 patients with CVD with LDL < 100 mg/dl Greater CIMT regression and lower Greater LDL reductions with ezetimibe
release niacin and statin vs. ezetimibe and HDL < 5055 mg/dl; terminated early cardiovascular events (1 vs. 5%, were paradoxically associated with
and statin [46] after 14 months on the basis of efficacy P = 0.04) with niacin compared an increase in CIMT
with ezetimibe
IMPROVE-IT, 2014, ezetimibe and 18 144 moderate-high risk patients post Absolute risk reduction of 2.0% in Greater LDL reductions were
simvastatin 40 mg vs. simvastatin acute coronary syndrome with LDL primary endpoint with the associated with improved
40 mg alone [47] < 125 mg/dl (statin naive) or and > 79 mg/ addition of ezetimibe. Greater outcomes. 10% reduction in
dl over 5.7 years LDL reductions also noted in the cardiovascular death, nonfatal MI or
ezetimibe arm nonfatal stroke but not all-cause
mortality

CIMT, carotid intimamedia thickness; CRP, C-reactive protein; CVD, cardiovascular disease; HDL, high-density lipoprotein cholesterol; LDL, low-density lipoprotein
cholesterol; MI, myocardial infarction; SBP, systolic blood pressure.

Society of Cardiology conference, which showed a 14% more than 6.5 mmol/l to eicosapentoic acid versus pla-
relative risk reduction over placebo in the ezetimibe arm cebo. These patients were followed up for a mean of
compared with 2% for nondiabetic individuals for major 4.6 years. This trial demonstrated fewer adverse cardio-
adverse cardiovascular outcomes [48]. Although the vascular events in patients with known coronary artery
manuscript has not yet been published, these results disease (8.7 vs. 10.7%, P = 0.01) but not in those without
suggest that ezetimibe may have a future possible role as [53]. Another RCT randomized 188 patients without
an agent for treating diabetic dyslipidemia in combina- prior CAD on simvastatin, with triglycerides between 200
tion with statins. and 500 mg/dl and tight LDL control, to omega-3-acid
ethyl esters versus placebo. Although a reduction in
Fibrates HDL was noted, no improvement was noted in clinical
Fibrates enhance ApoA1 synthesis, resulting in increased events [54].
levels of HDL and also reduce hepatic triglyceride pro-
duction [49]. In a placebo-controlled trial, fenofibrate Niacin
resulted in a significant reduction in nonfatal MIs and Niacin, a nicotinic acid derivative, slows the hepatic
revascularization in individuals with diabetes [50]. This uptake of HDL by downregulating hepatic HDL-ApoA1
benefit was not realized when fibrates were administered receptors and increases HDL production. Clinical studies
in combination with statins. In the ACCORD trial, which have demonstrated that niacin produces a very robust
randomized 5518 patients on statin therapy to addition of increase in serum HDL [55] more so than even statins in
fenofibrate or placebo, there was no reduction in cardio- one study [56]. However, success in improving clinical
vascular events [51]. However, in the prespecified group outcomes in combination with statins has not been
with high triglycerides and low HDL, there was a demonstrated (Table 2). The combination of niacin with
reduction in clinical events that approached significance a statin was compared with statin in placebo in
(12.4 vs. 17.3%, P = 0.057); a subsequent meta-analysis ARBITER 2 showing an improvement in HDL but none
showed a reduction in cardiovascular events in this high in CIMT regression [57]. ARBITER 3, however, did
triglycerides and low HDL-C diabetic population [52]. show a difference in CIMT regression between the
niacin-statin group and the statin-placebo group [58].
N-3 fatty acid ethyl esters Similarly, patients treated with niacin-statin in the
The addition of n-3 fatty acids has been analyzed in two OXFORD-NIASPAN study showed a greater reduction
randomized clinical trials. The JELIS trial randomized in carotid wall area on magnetic resonance imaging
18 645 Japanese patients on statins with total cholesterol compared with the statin-placebo group [62].

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30 Cardiovascular Endocrinology 2017, Vol 6 No 1

Table 2 Key clinical trials analyzing combination of statins and niacin

Niacin

Trials Designs Results Additional findings

ARBITER 2, 2004, extended release 167 patients with CAD, HDL < 45 mg/ HDL increased 21% in the niacin group; no CIMT progression slower on niacin in
niacin and statin vs. statin and dl randomly assigned in a double- change in CIMT progression after 1 year patients with insulin resistance
placebo [57] blind study (P = 0.026)
ARBITER 3, 2006, extended release 130 patients with CAD, HDL < 45 mg/ 9 mg/dl increase in HDL; net regression Changes in HDL associated with CIMT
niacin and statin vs. statin and dl randomly assigned in a double- noted in CIMT regression ( 0.041 mm, regression after multivariate analysis
placebo [58] blind study who completed P < 0.05)
ARBITER 2
OXFORD NIASPAN, 2009, high- 71 patients with HDL < 40 mg/dl Carotid wall area on MRI was significantly The niacin group also had higher HDL
dose niacin and statin vs. statin randomly assigned in a double-blind reduced in the niacin group ( 1.1 vs. compared with placebo
and placebo study followed up for 12 months + 1.2 mm, P < 0.05)
AIM HIGH, 2011, extended release 3414 patients with CVD; trial stopped No difference in clinical endpoints with niacin Niacin also noted to increase the rate
niacin vs. placebo in patients on after a mean of 3 years for lack of despite improved lipid profile; post-hoc of serious infections and
simvastatin with ezetimibe for LDL clinical efficacy; 34% individuals with trend toward benefit in lowest HDL, highest gastrointestinal disorders in
< 70 mg/dl [59] diabetes TG group (P = 0.07) [60] subsequent analysis
HPS2 Thrive, 2014, extended 25 673 patients with vascular disease; No clinical benefit with niacin; significant Merck withdrew tredaptive from
release niacin-laropiprant followed up for a median of increase in diabetes, diabetic disturbances market; future role of niacin in the
(tredaptive) vs. placebo in patients 3.9 years; 32% individuals with and other adverse events treatment of hyperlipidemia
on statins [61] diabetes questionable

CAD, coronary artery disease; CIMT, carotid intima media thickness; CVD, cardiovascular disease; HDL, high-density lipoprotein cholesterol; LDL, low-density lipoprotein
cholesterol; TG, triglyceride.

AIM-HIGH randomized 3414 patients with known CVD of a statin, or who are completely statin intolerant may
to extended release niacin or placebo [59]. This trial was consider the addition of a nonstatin cholesterol-lowering
stopped after 3 years due to lack of clinical efficacy and therapy [64]. They denoted that individuals with dia-
an increase in serious infections and gastrointestinal dis- betes between 40 and 75 years of age were in the high-
orders. Results from HPS-2 Thrive, in which 25 673 risk group and pointed to ezetimibe as a potential option
patients were randomized to extended release niacin- in this situation (IMPROVE-IT had not been published
laropiprant versus placebo in patients on statins and tight at the time the guidelines were published) [64].
LDL control, were similarly disappointing [61]. Not only Additional guidelines have also been published by other
was there an absence of any clinical benefit with niacin established organizations such as the American Diabetes
after 3.9 years of median follow-up but also a wide array Association, the European Society of Cardiology, the
of serious adverse effects including new onset diabetes National Lipid Association, and the National Clinical
and worsening of pre-existing diabetes was noted. The Guideline Center in the UK [65]. Subtle differences in
manufacturer removed this compound from the market the guidelines pertain to risk stratification of patients and
after these results were released. Results from either trial use of lipid targets for tailored and targeted therapy.
did not show any difference based on the presence of Although most organizations do not make a specific
diabetes. Although a post-hoc analysis of AIM-HIGH recommendation for combination therapy, the European
suggested that patients with high triglycerides and low Society of Cardiology guidelines did indicate that ezeti-
HDL demonstrated a trend toward possible benefit [60], mibe may be added to statins after intensification of
given a negative result and a wide array of serious adverse statin therapy in individuals with diabetes (level of evi-
events, there appears to be no role at present for niacin in dence IIa) [66]. However, the Food and Drug
statin-tolerant patients. Administration refused to approve ezetimibe as combi-
nation therapy citing modest benefit, missing data in the
Guideline positions ezetimibe arm, and questioning the relevance of the
The recent American Heart Association/American reduction in nonfatal strokes and MIs that drove the risk
College of Cardiology guidelines for cholesterol man- reduction seen in the intervention arm.
agement have rightly made statins the cornerstone for
dyslipidemia management [63]. They recommend that Promising agents: ezetimibe and PCSK9 inhibitors
diabetes be treated with statins if patients are between 40 Despite the plethora of research in this area, the role of
and 75 years of age. If the diabetic patients 10-year combination therapy in diabetic dyslipidemia remains
atherosclerotic CVD risk is at least 7.5% based on the controversial. However, the favorable results of the
pooled cohort risk calculator, a high-intensity statin such IMPROVE-IT trial may point to a role of ezetimibe as an
as atorvastatin 80 mg or rosuvastatin 40 mg is recom- adjunct to statin therapy, particularly if results are similarly
mended. However, the guidelines authors have clarified positive in the diabetic subpopulation. PCSK-9 inhibitors,
subsequently that clinicians treating high-risk patients of whom Alirocumab (Regeneron Pharmaceuticals Inc.,
who have a less-than-anticipated response to statins, who Eastview, New York, USA) and Evolocumab (Amgen Inc.,
are unable to tolerate a less-than-recommended intensity Thousand Oaks, California, USA) have been approved,

Copyright r 2017 Wolters Kluwer Health, Inc. All rights reserved.

 Diabetic dyslipidemia in CVD Warraich and Rana 31

have emerged as a category that has shown significant 11 Stamler J, Wentworth D, Neaton JD. Is relationship between serum
reductions in LDL [67]. A recent meta-analysis of three cholesterol and risk of premature death from coronary heart disease
continuous and graded? Findings in 356,222 primary screenees of the
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ongoing and additional information is still required about differential diet composition in a weight loss program in type 2 diabetes: a
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Acknowledgements 24 Estruch R, Ros E, Salas-Salvado J, Covas MI, Corella D, Aros F, et al. Primary
Conflicts of interest prevention of cardiovascular disease with a Mediterranean diet. N Engl J
Med 2013; 368:12791290.
Jamal S. Rana received Institutional research grant from 25 Salas-Salvado J, Bullo M, Estruch R, Ros E, Covas MI, Ibarrola-Jurado N,
Regeneron and Sanofi. For the remaining author there et al. Prevention of diabetes with Mediterranean diets: a subgroup analysis of
are no conflicts of interest. a randomized trial. Ann Intern Med 2014; 160:110.
26 Look ARG, Wing RR, Bolin P, Brancati FL, Bray GA, Clark JM, et al.
Cardiovascular effects of intensive lifestyle intervention in type 2 diabetes.
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