Diabetes and Vascular Disease Research

http://dvr.sagepub.com/

Statins and beyond: Concurrent strategies for prevention of cardiovascular disease in patients with
type 2 diabetes
Eberhard Standl
Diabetes and Vascular Disease Research 2013 10: 99 originally published online 20 June 2012
DOI: 10.1177/1479164112448876

The online version of this article can be found at:

http://dvr.sagepub.com/content/10/2/99

Published by:

http://www.sagepublications.com

Additional services and information for Diabetes and Vascular Disease Research can be found at:

Email Alerts: http://dvr.sagepub.com/cgi/alerts

Subscriptions: http://dvr.sagepub.com/subscriptions

Reprints: http://www.sagepub.com/journalsReprints.nav

Permissions: http://www.sagepub.com/journalsPermissions.nav

>> Version of Record - Feb 14, 2013

OnlineFirst Version of Record - Jun 20, 2012

What is This?

Downloaded from dvr.sagepub.com by guest on February 27, 2013

10210.1177/1479164112448876StandlDiabetes and Vascular Disease Research
2012

Review Article
Diabetes & Vascular Disease Research

Statins and beyond: Concurrent 10(2) 99­–114

© The Author(s) 2012
Reprints and permissions:
strategies for prevention of cardiovascular sagepub.co.uk/journalsPermissions.nav
DOI: 10.1177/1479164112448876

disease in patients with type 2 diabetes dvr.sagepub.com

Eberhard Standl

Abstract
Diabetes is a significant risk factor for the development of cardiovascular disease (CVD), particularly in the presence of
high blood pressure, poor glycaemic control and high total cholesterol. While efforts to control blood pressure or blood
glucose beyond levels considered ‘normal’ in patients with diabetes have not produced the expected reduction in CVD,
treatment with statins to reduce levels of low-density lipoprotein cholesterol (LDL-C) has been much more successful.
However, many patients with diabetes who receive statins (even at high doses) remain at significant residual risk of CVD
due to the presence of atherogenic dyslipidaemia. Markers of persisting risk include low levels of high-density lipoprotein
cholesterol (HDL-C), high levels of triglycerides (TG) and LDL-C levels above target despite high-dose statin therapy.
Combining statins with drugs that target HDL-C and TG, such as fibrates, niacin and omega-3 polyunsaturated fatty acid
(PUFA) ethyl esters, may offer further protection from CVD in patients with diabetes.

Keywords
Type 2 diabetes, cardiovascular disease, statins, fibrates, ezetimibe, nicotinic acid

Abbreviations and acronyms

ACS: acute coronary syndrome PUFAs: polyunsaturated fatty acids
ADA: American Diabetes Association RRR: relative risk reduction
AHA: American Heart Association SCORE: Systematic COronary Risk Evaluation (European
AP: angina pectoris Society of Cardiology)
ARR: absolute risk reduction TG: triglycerides
CAD: coronary artery disease TNT: Treating to New Targets
CABG: coronary artery bypass graft UKPDS: United Kingdom Prospective Diabetes Study
CAWA: carotid artery wall area
CHD: coronary heart disease
CIMT: carotid intima media thickness
Key messages
CKD: chronic kidney disease
CTT: Cholesterol Treatment Trialists Diabetes is a significant risk factor for the development of
CV: cardiovascular cardiovascular disease (CVD).
CVD: cardiovascular disease Treatment of patients with diabetes with statins to reduce
DHA: docosahexaenoic acid low-density lipoprotein cholesterol (LDL-C) has been suc-
EAS: European Atherosclerosis Society cessful in the reduction of CVD but many such patients
EPA: eicosapentaenoic acid
ESC: European Society of Cardiology Munich Diabetes Research Group at the Munich Helmholtz Centre,
HDL-C: high-density lipoprotein cholesterol Germany
HPS: Heart Protection Study
HR: hazard ratio LDL-C: low-density lipoprotein cholesterol Corresponding author:
Eberhard Standl, Munich Diabetes Research Group at the Munich
MI: myocardial infarction Helmholtz Centre, Ingolstaedter Landstrasse 1, DE-85764 Munich-
PCI: percutaneous coronary intervention Neuherberg, Germany.
PTCA: percutaneous transluminal coronary angioplasty Email: Eberhard.Standl@lrz.uni-muenchen.de

Downloaded from dvr.sagepub.com by guest on February 27, 2013

100 Diabetes & Vascular Disease Research 10(2)
remain at significant residual risk of CVD despite statin
therapy (even at high doses).
Markers of persisting risk include low levels of high-
density lipoprotein cholesterol (HDL-C), high levels of tri-
glycerides (TG) and LDL-C levels above target.
Combining statins with drugs that target HDL-C and
TG, such as fibrates, niacin and omega-3 polyunsaturated
fatty acid (PUFA) ethyl esters, may offer further protection
from CVD in patients with diabetes.
Introduction
Diabetes mellitus is found in almost every human popula-
tion in the world, with type 2 diabetes accounting for >85%
of cases.1 In 2009, it was estimated that 285 million people
aged 20–79 years had diabetes (6.6% of the global popula-
tion).1 This figure is expected to rise to 438 million (7.8%)
by 2030.1 Excess mortality due to diabetes in adults was
estimated to be nearly 4 million deaths per year in 2010,
and approximately 50–70% of these deaths are thought to
be due to cardiovascular disease (CVD).1–3 Of the interven-
tions to reduce CVD in people with diabetes, statins have
been highly successful.2
The value of statins in the reduction of mortality and
morbidity in patients with diabetes has been demonstrated
by subgroup analyses of trials in broad patient populations
and by trials specifically in diabetic populations.
Primary prevention studies
The Collaborative AtoRvastatin Diabetes Study (CARDS)
trial compared atorvastatin 10 mg/day with placebo in
patients with type 2 diabetes with no previous CVD and
low low-density lipoprotein cholesterol (LDL-C) (< 4.14
mmol/L) but with one or more risk factors, such as micro-
albuminuria or retinopathy. After a median 3.9 years of
follow-up there were 127 CVD events in the placebo group
compared with 83 in the treatment group, equivalent to a
relative risk reduction (RRR) of 37% (p =  0.001). At this
point the study reached prespecified efficacy criteria and
was terminated early as permitted by the protocol. These
results indicated that a statin significantly reduces CV
events in patients with diabetes after a relatively short dura-
tion of treatment even in the absence of an LDL-cholesterol
level considered ‘high’ when the study was designed.4
However, the Atorvastatin Study for the Prevention of cor-
onary heart disease Endpoints in Non-insulin dependent
diabetes mellitus (ASPEN) trial found contrary results in
patients with type 2 diabetes. The primary composite end-
point was combined cardiovascular death, non-fatal myo-
cardial infarction (MI), non-fatal stroke, revascularisation,
coronary artery bypass graft (CABG) or unstable angina.
Compared with placebo, atorvastatin 10 mg/day had no
Downloaded from dvr.sagepub.com by guest on February 27, 2013
significant effect on the rate of the primary endpoint in the
overall population (13.7% vs 15.0%, respectively) or in the
primary prevention subgroup (10.4% vs 10.8%, respec-
tively).5 A Cochrane review of 14 randomised primary pre-
vention trials, however, including several in patients with
diabetes, concluded that statins reduce overall mortality
and combined fatal and non-fatal CVD endpoints.6
Secondary prevention studies
A subanalysis of the Treating to New Targets (TNT) study
investigated the effect of atorvastatin in patients with dia-
betes and previous coronary heart disease (CHD) whose
LDL-C reached < 3.4 mmol/L after the run-in period of the
study when all participants received low-dose atorvastatin.
Atorvastatin 80 mg/day significantly reduced the relative
risk of a secondary cardiovascular event compared with
atorvastatin 10 mg/day (absolute risk reduction (ARR)
4.1%; RRR 25%; p =  0.026 for RRR).7
The largest subanalysis of statins in patients with diabe-
tes was conducted by the Heart Protection Study (HPS),
which investigated the effect of simvastatin in nearly 6000
patients (10% with type 1 diabetes and 90% with type 2
diabetes). Approximately half the population also had a his-
tory of vascular disease. The study found that the combined
risk of a major vascular event (major coronary event, stroke
or revascularisation) was significantly reduced compared
with placebo (ARR 4.8%; RRR 22%; p < 0.0001). The risks
of individual events were reduced by a similar degree.
Results in diabetic patients were not significantly different
from those in non-diabetic patients with occlusive arterial
disease (p =  0.60).8
Subgroup analyses of the 4S trial, the Lescol Intervention
Prevention Study (LIPS) and the GREek Atorvastatin and
CHD Evaluation (GREACE) study found that statins sig-
nificantly reduce the risk of major vascular events in
patients with diabetes and previous CHD.9–11 However, in
the ASPEN study, atorvastatin 10 mg/day had no signifi-
cant effect on the primary endpoint in patients with prior
MI or coronary intervention (26.2% on atorvastatin vs.
30.8% on placebo).5
Intensive therapy
Intensive therapy in type 2 diabetes patients using high
doses of statins to achieve very low LDL-C levels may fur-
ther reduce CVD risk when compared with standard doses.
The main TNT study,12 the Pravastatin or Atorvastatin
Evaluation and Infection Therapy-Thrombolysis in
Myocardial Infarction 22 (PROVE IT-TIMI 22) secondary
prevention study13 and a meta-analysis of trials comparing
moderate with intense statin therapy14 support this
hypothesis.
Standl 101
Although some studies did not show a benefit of statins
in patients with diabetes, this can sometimes be explained
by the trial design or execution. For example, the
Antihypertensive and Lipid-Lowering Treatment to Prevent
Heart Attack (ALLHAT-LLT) study of pravastatin versus
usual care in patients with hypertension did not meet its
primary endpoint of all-cause mortality overall or in
patients with diabetes.15 This may have been due to the
modest differences in total cholesterol and LDL-C between
the pravastatin and control arms (9.6% and 16.7%, respec-
tively for the overall population), together with an increas-
ing proportion of patients in the ‘usual care’ control arm
receiving statins. Similarly, the Study of the Effectiveness
of Additional Reductions in Cholesterol and Homocysteine
(SEARCH) trial reported a non-significant 6% RRR in
major CV events overall in survivors of MI treated with
simvastatin 80 mg/day compared with 20 mg/day.16 In this
trial, as a result of increasing use of non-study intensive
statin regimens in patients randomised to the 20 mg/day
dose, the difference in LDL-C between treatment arms was
only 0.35 mmol/L.
The Anglo-Scandinavian Cardiac Outcomes Trial-
Lipid-Lowering Arm (ASCOT-LLA) study of atorvastatin
10 mg/day versus placebo was stopped early because of the
significant reduction in its primary endpoint (non-fatal MI
or fatal CHD) in the overall population, but the early trial
closure reduced the numbers of events recorded; the benefit
of pravastatin, therefore, was not statistically significant in
patients with diabetes.17
In view of these considerations, these studies do not
refute the principle that the main lipid target for patients
with diabetes should be LDL-C and statins are the best-
proven agents for reduction of this parameter. (In some
populations, including patients with diabetes receiving hae-
modialysis18–20 and patients with diabetes and chronic heart
failure or reduced left ventricular ejection fractions,21,22 the
benefits of statins on CV events are less clear.)
Table 1 summarises the findings of the principal statin
studies that specifically described results for patients with
diabetes. Overall, these trials included nearly 15,000
patients with diabetes.
A meta-analysis by the Cholesterol Treatment Trialists
(CTT) investigated the effects of statins in 26 trials, includ-
ing ALLHAT-LLT and ASCOT-LLA, with more than
170,000 participants including more than 32,000 patients
with diabetes.23 It confirmed that patients with diabetes tak-
ing a statin experienced a significant reduction in major CV
events compared with controls (RRR approximately 18%).
The RRR was approximately 20% per 1 mmol/L reduction
in LDL-C. The RRR was similar in individuals with or
without diabetes (although absolute rates of CV events
were higher in the presence of diabetes) and was demon-
strated even in a subgroup with a baseline LDL-C < 2.0
mmol/L. Overall, results from individual trials and the CTT
meta-analysis show that statins reduce CVD risk in patients
Downloaded from dvr.sagepub.com by guest on February 27, 2013
with or without type 2 diabetes or prior CVD and over a
wide range of baseline cholesterol levels.
As a result of these trials of statins in patients with dia-
betes, guidelines for the prevention of CVD from the
European Society of Cardiology (ESC), American Heart
Association (AHA) and American Diabetes Association
(ADA) strongly recommend statin therapy for patients with
diabetes and overt CVD irrespective of LDL-C levels.2,24–26
The guidelines published recently by the ESC and European
Atherosclerosis Society (EAS) also recommend statin ther-
apy in these patients.27 For patients with diabetes, guide-
lines recommend lifestyle intervention with the addition of
pharmacological treatment if necessary, with the intention
of reducing LDL-C levels to < 2.5 mmol/L (< 100 mg/dL)
or, in patients at the highest risk, to < 1.7–2.0 mmol/L
(< 70–80 mg/dL).2,24–27 If these targets are not met, the first
‘add-on’ step according to the CTT should be to intensify
statin therapy to the highest tolerated (or highest licensed)
dose and to consider replacing a ‘weak’ statin with a more
potent one.23 The definitions of highest risk vary between
guidelines but generally include established CVD or the
presence of additional risk factors such as smoking. In
practice, these guidelines imply that statins are the drugs of
choice and should be prescribed to the majority of patients
with diabetes, either because they have markers of increased
risk such as microalbuminuria or because lifestyle interven-
tion alone does not achieve the desired LDL-C level.2,24–27
However, Table 2 shows that the attained mean LDL-C
levels of patients receiving statin therapy alone in ran-
domised trials still ranged from 1.99 to 3.17 mmol/L.
Therefore, if statin therapy, after appropriate adjustment of
the dose or drug,23 does not achieve the desired lipid goals,
the ESC/EAS guidelines recommend addition of a choles-
terol absorption inhibitor, a bile acid sequestrant or niacin,
while other guidelines suggest the addition of these com-
pounds or a fibrate.2,24–28
Data from recent longitudinal studies (e.g. European
Prospective Investigation into Cancer and Nutrition
(EPIC)-Netherlands, EPIC-Potsdam, Hoorn and Action in
Diabetes and Vascular Disease: Preterax and Diamicron-MR
Controlled Evaluation Study (ADVANCE)) seem to indi-
cate that the risks of middle-aged cohorts with diabetes
developing CHD and CVD have dropped to around 3–5%
and 6–8% respectively over follow-up of four to 10
years.29–31 The reasons for these long-term trends may be
manifold and most likely include the much wider use of
statins (50–80% of patients) in these cohorts. However,
despite treatment with statins, patients with diabetes remain
at a twofold increased risk of CVD compared with the gen-
eral population.32 In addition, the CTT meta-analysis found
that even following statin therapy, 4.6% of participants
with diabetes died of CHD compared with 3.1% of those
without diabetes.33 Moreover the RRR achieved with
statins is about 20–40%, leaving 60–80% of CVD events
not prevented: the remaining CVD events have been
 Table 1.  Trials of statins to reduce risk of cardiovascular disease that reported results for patients with diabetes.
Study Treatments Total number of Primary or Primary Primary endpoint
  patients (Number secondary CVD endpoint
102
with diabetes) prevention Patients with diabetes Patients without diabetes Whole cohort

Rate (%) ARR (%) RRR (%) Rate (%) ARR (%) RRR (%) Rate (%) ARR (%) RRR (%)
4S10,36 Simvastatin 2221 Secondary Total mortality 14.3 10.4 43 7.9 3.0 29 8 4 30
20 mg/day (105) (previous MI or (p =  0.087) (p =  0.001) (p =  0.0003)
AP)
  Placebo 2223 24.7 10.9 12  
(96)
CARDS4 Atorvastatin 1410 Primary CVD event 5.8 3.2 37 NR NR NR NR NR NR
10 mg/day (1410) (but with additional (p =  0.001)
CVD risk factor)
  Placebo 1428 9 NR NR  
(1428)
ASPEN5 Atorvastatin 1211* Mixed CV death, 13.7 1.3 10 NA NA NA NA NA NA
10 mg/day (1211) (1°/2°) MI, stroke, (1°/2°) (1°/2°) (p =  0.34)
coronary (10.4/26.2) (0.4/4.6) (1°/2°)
intervention (3/18)
procedure or (NS/NS)
angina
  Placebo 1199** 15.0 NA NA  
(1199) (1°/2°)
(10.8/30.2)
TNT7,12 Atorvastatin 4995 Secondary CVD event 13.8 4.1 25 NR NR NR 8.7 2.2 22
80 mg/day (753) (CHD) (p =  0.026) (p < 0.001)
  Atorvastatin 5006 17.9 NR 10.9  
10 mg/day (748)
HPS8,37 Simvastatin 10,269 Mixed Major vascular 20.2 4.9 22 19.6 5.6 25 19.8 5.4 24
40 mg/day (2980) (51% with diabetes event (p < 0.0001) (p < 0.0001) (p < 0.0001)
and 98% without
diabetes had
previous vascular
disease)

Downloaded from dvr.sagepub.com by guest on February 27, 2013

  Placebo 10,267 25.1 25.2 25.2  
(2969)
LIPS11 Fluvastatin 80 844 Secondary Major adverse 22 16 51 21 4 18 NR NR NR
mg/day (120) (previous PCI) cardiac event (p =  0.0088) (p =  0.074)
  Placebo 833 38 25 NR  
(82)
GREACE9,38 Atorvastatin 800 Secondary Major vascular 12.5 17.8 58 NR NR NR 12 12.5 51
mean 23.7 (161) (CHD) event or death (p < 0.0001) (p < 0.0001)
mg/day
  Physician’s 800 30.3 NR 24.5  
standard of (152)
care

Note: In total these trials included nearly 15,000 such patients.

4S: Scandinavian Simvastatin Survival Study; CARDS: Collaborative AtoRvastatin Diabetes Study; ASPEN: Atorvastatin Study for the Prevention of coronary heart disease Endpoints in
Non-insulin dependent diabetes mellitus trial; TNT: Treating to New Targets; HPS: Heart Protection Study; LIPS: Lescol Intervention Prevention Study; GREek Atorvastatin and Coronary
Heart Disease Evaluation; *Primary prevention on atorvastatin = 959 patients; secondary prevention on atorvastatin = 252 patients. **Primary prevention on placebo = 946 patients; secondary
prevention on placebo = 253 patients. ACS: acute coronary syndrome; AP: angina pectoris; ARR: absolute risk reduction; CHD: coronary heart disease; CVD: cardiovascular disease; LDL-C:
Diabetes & Vascular Disease Research 10(2)

low-density lipoprotein cholesterol; MI: myocardial infarction; NA: not applicable; NR: not reported; RRR: relative risk reduction; PCI: percutaneous coronary intervention.
Standl 103

Table 2.  Concentration of plasma lipids in trials of statins.

Study Lipid data collected at: Intervention Concentration of plasma lipids at specified time point (mmol/L)

  LDL HDL TG
4S36 Study close (mean follow- Placebo 4.92 1.20 1.62
  up =  5.4 years) Simvastatin 3.17§ 1.27§ 1.34§
CARDS4 Four years Placebo 3.12 1.23 1.90
  Atorvastatin 2.11* 1.26* 1.61*
ASPEN5 Study close (mean follow- Placebo 2.91 1.21 1.59
  up Four years) Atorvastatin 2.03* 1.24* 1.80*
TNT12 Mean values during study Atorvastatin 10 mg/d 2.55 NR 2.01
  (mean follow-up =  Four Atorvastatin 80 mg/d 1.99* 1.64*
years)
HPS37 Mean values during study Simvastatin minus 2.40§ 1.09§ 1.80§
(mean follow-up =  five placebo
years)
LIPS11 Six weeks Placebo 3.46 NR 1.63
  Fluvastatin 2.29* 1.45§
GREACE38 Mean values during study Physician’s standard 4.37 1.03 1.94
(mean follow-up three years) of care
  Atorvastatin 2.51* 1.09* 1.44*

LDL: low-density lipoprotein; HDL: high-density lipoprotein; TG: triglycerides; 4S: Scandinavian Simvastatin Survival Study; CARDS: Collaborative
AtoRvastatin Diabetes Study; ASPEN: Atorvastatin Study for the Prevention of coronary heart disease Endpoints in Non-insulin dependent diabetes
mellitus; TNT: Treating to New Targets; HPS: Heart Protection Study; LIPS: Lescol Intervention Prevention Study; GREACE: GREek Atorvastatin
and CHD Evaluation; NR: not reported; *Significant versus comparator group (p≤0.05). §Statistical significance not reported.

described as ‘residual risk’.34 Therefore, although statin
therapy has helped markedly to reduce the risk of CVD,
there remains a residual risk of CV events in patients with
type 2 diabetes. In this context, it is important that the
emphasis be on the individual risk and not simply choles-
terol targets.35
Despite the demonstrated benefits of statins for the pre-
vention of CVD, further measures may be needed in the
treatment of more vulnerable cohorts such as patients with
diabetes. The objective of this review is to discuss the
mechanisms of persisting CVD risk in patients with diabe-
tes receiving statins and to investigate other interventions
that could help to reduce this risk further.
Indicators of CVD risk beyond
LDL-C
Other risk factors contribute to CVD risk in addition to
LDL-C levels. The Prospective Cardiovascular Münster
(PROCAM) score uses eight independent risk factors to
determine the risk of an acute coronary event. In order of
importance these are: age; high LDL-C levels; smoking;
low HDL-C levels; high systolic blood pressure (BP); a
family history of MI; diabetes; and high TG levels.39
Hyperglycaemia and hypertension are established risk fac-
tors for CVD in type 2 diabetes. The United Kingdom
Prospective Diabetes Study (UKPDS) found that a 1%
reduction in glycosylated haemoglobin (HbA1c) resulted in
a 21% reduction in the risk of death related to diabetes and
a 14% reduction in the risk of MI.40,41 Chronic kidney dis-
ease (CKD), in particular a reduced glomerular filtration
rate, is also associated with an increased risk of CVD, and
patients with diabetes are more likely to develop CKD than
the general population.42
The level of HDL-C (or total cholesterol: HDL-C ratio)
is included in a number of other risk scores including
QRISK,43 the UKPDS risk engine44 and the Framingham
risk score.45 However, these scores do not incorporate TG
levels. The original publication of the ESC Systematic
COronary Risk Evaluation (SCORE) did not include either
HDL-C or TG levels in the calculation of CV risk, as this
would be difficult to show on the simple charts it uses.46 A
more recent publication from the SCORE group suggested
that inclusion of HDL-C might be useful in some
settings.47
Lipid risk factors for CVD in
patients with type 2 diabetes
In patients with type 2 diabetes, low HDL-C and high TG
levels are of particular importance because these patients
often have a particular form of atherogenic dyslipidaemia
characterised by small dense LDL-C particles, low HDL-C
levels and high TG levels.34
Several studies have shown that a low level of HDL-C is
an independent risk factor for CVD in diabetes.25,41,48,49 For

Downloaded from dvr.sagepub.com by guest on February 27, 2013

104 Diabetes & Vascular Disease Research 10(2)
example, the UKPDS found that low HDL-C was an inde-
pendent risk factor for coronary artery disease (CAD) and
MI.41 However, the Justification for the Use of statins in
Prevention: an Intervention Trial Evaluating Rosuvastatin
(JUPITER) found that while there was an inverse relation-
ship between HDL-C level and CV risk in patients receiv-
ing placebo, the same was not observed for those treated
with rosuvastatin.50 Data are even less clear for the effect of
TG levels on CV risk, especially in patients with diabetes.
The UKPDS found that high levels of TG were a risk factor
for CAD but this was not independent from other risk fac-
tors.41 However, a meta-analysis of 17 studies investigating
CV risk and TG levels in the general population did find a
significant association even when results were adjusted for
HDL-C levels.49 As well as contributing to macrovascular
risk, low HDL-C levels and high TG potentially contribute
to the microvascular complications of diabetes such as
retinopathy and nephropathy.34 Both the ADA and ESC rec-
ommend that TG levels should be < 1.7 mmol/L and HDL-C
levels should be >1 mmol/L in men and >1.3 mmol/L in
women.2,24–27
Interventions to reduce CVD risk
beyond statin therapy: clinical trials
and current status
The clinical benefits of statins are believed to be principally
mediated by reductions in LDL-C levels.25 Their effects are
modest on TG and HDL-C. For example, in the PROVE-IT
study median HDL-C levels increased from baseline by
6.5% in the atorvastatin 80 mg/day group and 8.1% in the
pravastatin 40 mg/day group.13 In the TNT study, high-dose
atorvastatin (80 mg/day) significantly reduced TG levels
from baseline (p < 0.001) but had no significant effect on
HDL-C levels.12 In cases of mixed dyslipidaemias, the
ESC/EAS guidelines recommend that, in addition to statins,
patients receive drugs that influence HDL-C and TG levels
to further reduce CVD risk.27 Recent clinical trials have
investigated these agents in more than 24,000 patients with
diabetes; results are summarised below and in Tables 3 and
4. Table 5 shows the average lipid levels attained during
these studies or the final lipid levels measured at the end of
the study. Although TG levels in the intervention groups
were usually decreased to the intended range of ≤1.7
mmol/L, mean LDL-C failed to reach the intended thera-
peutic target of ≤2 mmol/L in the majority of studies.
Key trials of non-statin lipid-
lowering therapies
Fenofibrate
The Fenofibrate Intervention and Event Lowering in
Diabetes (FIELD) study investigated the effect of raising
Downloaded from dvr.sagepub.com by guest on February 27, 2013
HDL-C and lowering TG levels with fenofibrate 200 mg/
day in 9795 patients with type 2 diabetes.51 Patients were
not taking statins or other lipid-lowering drugs at the start
of the study. Over the entire trial, average use of non-study
lipid-lowering therapies, predominantly statins, was sig-
nificantly greater in the placebo group (17%) than the
fenofibrate group (8%; p < 0.0001).
Fenofibrate improved lipid parameters including total
cholesterol, LDL-C, HDL-C and TG. The combined pri-
mary endpoint of non-fatal MI or death due to CHD was
directionally positive, but not significantly different for the
fenofibrate group compared with the placebo group (RRR
11%; p =  0.16). However, there was a significant reduction
with fenofibrate for non-fatal MI (RRR 24%; p =  0.01) and
the combined secondary endpoint of CVD death, non-fatal
MI, non-fatal stroke or coronary or carotid revascularisa-
tion procedure (RRR 11%; p =  0.035) .51 Furthermore, in a
predefined subgroup analysis in fenofibrate-treated patients
with low baseline HDL-C (< 1.03 mmol/L in men and < 1.29
mmol/L in women) who seem to be a logical target group
for such therapy, there was a significant reduction in the
primary endpoint versus placebo (RRR 14%; p =  0.02) .51 In
patients who had both high TG (≥2.3 mmol/L) and low
HDL-C levels at baseline, fenofibrate reduced the relative
risk of CVD events by 27% compared with placebo
(p =  0.005) .52 Fenofibrate also reduced the number of sub-
sequent CV events in patients who had a previous asympto-
matic or ‘silent’ MI (RRR 78%; p =  0.003).53
The Action to Control Cardiovascular Risk in Diabetes
(ACCORD) study investigated the effects on CVD out-
comes of intensive control of blood glucose, BP or plasma
lipids in three separate study arms. In the ACCORD lipid
study arm, simvastatin monotherapy was compared with
simvastatin plus fenofibrate (starting dose 160 mg/day) in
patients with type 2 diabetes, 37% of whom had experi-
enced a previous CVevent.54 No significant difference in
the combined primary endpoint of MI, stroke or death due
to CVD was seen between the monotherapy and combina-
tion therapy groups. However, as in the FIELD study, there
was a benefit of combination therapy with fenofibrate for
patients with high TG and low HDL-C levels at baseline: in
this group the primary endpoint occurred in 17.3% of
patients on monotherapy versus 12.4% on combination
therapy (p =  0.057 for interaction).55
Administration of fenofibric acid, the active form of the
compound, eliminates the need for hepatic and intestinal con-
version of fenofibrate to the active acid. Clinical trials of
fenofibric acid 135 mg/day in combination with simvastatin,
atorvastatin or rosuvastatin at various doses have shown addi-
tional benefits on lipid levels compared with statins alone.56,57
Gemfibrozil
The Veterans Affairs HDL Intervention Trial (VA-HIT) inves-
tigated the efficacy of gemfibrozil 1200 mg/day in reducing
 Table 3.  Trials of non-statin lipid-modifying therapies to reduce CVD endpoints.
Standl

Study Treatments Total number Patients Primary or Primary Primary endpoint

  of patients on statins secondary endpoint
  (Number with (%) CVD Patients with diabetes Patients without diabetes Whole cohort
diabetes) prevention
Rate (%) ARR (%) RRR (%) Rate (%) ARR (%) RRR (%) Rate (%) ARR (%) RRR (%)
FIELD51 Fenofibrate 4895 None at Mixed MI or 5.2 0.7 11 NR NR NR 5.2 0.7 11
200 mg/day (4895) study start; (22% had CHD (p =  0.16) (p =  0.16)
8% by end previous CVD) death
of study
  Placebo 4900 None at 5.9 NR 5.9  
(4900) study start;
17% by end
of study
ACCORD Fenofibrate 2765 100 Mixed MI, 10.3 1.0 8 NR NR NR 10.3 1.0 8
Lipid54 160 mg/day (2765) (37% had stroke (p =  0.32) (p =  0.32)
+ simvastatin previous CVD) or CVD
(mean 22.3 death
mg/day)
  Simvastatin 2753 100 11.3 NR 11.3  
(mean 22.4 (2765)
mg/day)
VA-HIT58,59 Gemfibrozil 1264 NR Secondary MI or NR NR 32 NR NR 18 17.3 4.4 22%
1200 mg/day (303) (CHD) CHD (p =  0.004) (p =  0.07) (p =  0.006)
death
  Placebo 1267 NR NR NR 21.7  
(317)

Downloaded from dvr.sagepub.com by guest on February 27, 2013

GISSI-P71, -72 PUFA ethyl 2836 Baseline: 4.2 Secondary (MI) MI, NR NR NR NR NR NR 12.6 1.3 10
esters 1 g/ (405) After 42 stroke (p =  0.048)
day mo: or all-
35.6 cause
mortality
  Placebo 2828 Baseline: 4.9 NR NR 13.9  
(426) After 42
mo:
33.6
GISSI-HF73 PUFA ethyl 3494 22.3 Secondary All-cause NR NR NR NR NR NR 27 2 9
esters 1 g/ (992) (heart failure) mortality (p =  0.041)
day
  Placebo 3481 23.0 NR NR 29  
(982)

(Continued)
105
 106

Table 3. (Continued)

Study Treatments Total number Patients Primary or Primary Primary endpoint

  of patients on statins secondary endpoint
  (Number with (%) CVD Patients with diabetes Patients without diabetes Whole cohort
diabetes) prevention
Rate (%) ARR (%) RRR (%) Rate (%) ARR (%) RRR (%) Rate (%) ARR (%) RRR (%)
Alpha- Margarine 2404 86.3 Secondary Major 15.4 3.9 22 13.6 1.3 HR 1.10 14.0 0.2 HR 1.01
Omega75 with EPA/ (507) (MI) CV (p =  0.11) (p =  0.3) (p =  0.93)
DHA 1.8 g/ event
day
  Margarine 2433 85.7 19.3 12.3 13.8  
with placebo (507)
or ALA 3 g/
day
JELIS74 EPA 1.8 g/ 9326 100 Mixed Major NR NR NR NR NR NR 2.8 0.7 19%
day (1516) (5–6% MI, 16% coronary (p =  0.011)
AP, 5% CABG event
or PTCA)
  Placebo 9319 100 NR NR 3.5  
(1524)
OMEGA76 PUFA ethyl 1925 94.6 Secondary Sudden NR NR NR NR NR NR 1.5 0 0%
esters 1 g/ (532) (MI) cardiac (p =  0.84)
day death
  Placebo 1893 93.8 NR NR 1.5  
(500)
Total 23,824  

Downloaded from dvr.sagepub.com by guest on February 27, 2013

number of
patients
with
diabetes in
these trials

ACCORD: Action to Control Cardiovascular Risk in Diabetes; AP: angina pectoris; ARR: absolute risk reduction; CABG: coronary artery bypass graft; CHD: coronary heart disease; CV, cardiovascular;
CVD: cardiovascular disease; DHA: docosahexaenoic acid; EPA: eicosapentaenoic acid; HR: hazard ratio; MI: myocardial infarction; NR: not reported; PTCA: percutaneous transluminal coronary angio-
plasty; PUFA: polyunsaturated fatty acid; RRR: relative risk reduction; FIELD: Fenofibrate Intervention and Event Lowering in Diabetes trial; VA-HIT: Department of Veterans Affairs high-density lipopro-
tein intervention trial; GISSI-P: Gruppo Italiano per lo Studio della Sopravvivenza nell’Infarto Miocardico-Prevenzione trial; GISSI-HF: GISSI-Heart Failure; JELIS: Japan EPA Lipid Intervention Study.
Diabetes & Vascular Disease Research 10(2)
Standl 107

Table 4.  Trials of statins plus other lipid-lowering therapies that examined CIMT or CAWA.

Study Treatments Total number of Patients Primary or Primary Difference in CIMT or CAWA
patients (Number on statins secondary endpoint in treated group vs placebo or
with diabetes) (%) CVD prevention comparator group (whole cohort only)
ENHANCE61 Ezetimibe 10 mg/ 357 100 Mixed CIMT 0.0053 mm
day + simvastatin (8) (4% of treated (p =  0.29)
80 mg/day and 7% of
  Placebo + 363 100 control had  
simvastatin 80 (5) previous MI)
mg/day
ARBITER Niacin 2 g/day + 187 100 Secondary CIMT 0.0086 mm
6-HALTS66, 67 statin (73) (CHD) (p =  0.016)
  Ezetimibe 10 mg/ 176 100  
day + statin (72)
NIA-Plaque68 Niacin 2 g/day + 35 100 Secondary CAWA 1.64 mm2
statin (21) (CHD or (p =  0.03)
  Placebo + statin 36 100 athero-  
(22) sclerosis)
Total number 201  
of patients
with diabetes
in these trials

CAWA: carotid artery wall area; CHD: coronary heart disease; CIMT: carotid intima media thickness; CVD: cardiovascular disease; MI: myocardial
infarction; ENHANCE: Ezetimibe and Simvastatin in Hypercholesterolaemia Enhances Atherosclerosis Regression trial; ARBITER 6-HALTS: Arterial
Biology for the Investigation of the Treatment Effects of Reducing Cholesterol 6-HDL and LDL Treatment Strategies in Atherosclerosis trial; NIA-
Plaque: NIcotinic Acid-Plaque trial.

the combined primary endpoint of CHD death, MI and stroke
in a secondary prevention setting. One year after randomisa-
tion, mean HDL-C was 6% higher in the gemfibrozil group
than the placebo group (p < 0.001) and TG levels were 31%
lower compared with placebo (p < 0.001). The mean LDL-C
level never differed significantly between the groups.58
Gemfibrozil reduced the relative risk of the primary end-
point of non-fatal MI or death from CHD by 22% (p =  0.006
vs placebo).58 A subsequent subgroup analysis reported that
the relative risk of non-fatal MI, death from CHD or stroke
was reduced by 32% in patients with diabetes (p =  0.004 vs
placebo) and by 18% in those without diabetes (p =  0.07 vs
placebo): the difference in benefit between the two sub-
groups was not significant (p =  0.26).59 Patients with diabe-
tes also obtained significant (p < 0.05) reductions in the
relative risks of CHD and stroke compared with the placebo
group.59 As gemfibrozil had no effect on LDL-C levels, the
reductions in CVD risk may have resulted from raising
HDL-C and lowering TG levels.
The combination of fenofibric acid with a statin in these
studies was generally well tolerated.57 Concern has been
raised about rhabdomyolysis, a rare but serious adverse
effect of statin therapy that can be exacerbated by addition
of fibrates. Fibrates, especially gemfibrozil, and statins
share metabolic and elimination pathways and competition
for these increases plasma concentrations of both drugs, so
increasing the likelihood of adverse effects. The Food and
Drug Administration (FDA)’s adverse-event reporting sys-
tem suggests that a combination of fenofibrate and any
statin is associated with fewer reports of rhabdomyolysis
than when gemfibrozil is combined with statins (0.58 vs 8.6
cases per million prescriptions, respectively).60 These results
suggest that a combination of fenofibrate or fenofibric acid
and statins may be better tolerated than gemfibrozil and
statins, although there are no direct comparative trials
between the two combinations. Interestingly, the ESC/EAS
guidelines recommend avoiding the combination of gemfi-
brozil with statins because of the risk of myopathy.27
Ezetimibe
The Ezetimibe and Simvastatin in Hypercholesterolaemia
Enhances Atherosclerosis Regression (ENHANCE) trial
examined changes in carotid intima-media thickness
(CIMT) in patients with familial hypercholesterolaemia.
The patients were treated with simvastatin 80 mg/day alone
or simvastatin 80 mg/day plus ezetimibe 10 mg/day. At
study end there was no significant difference in CIMT
between treatment groups even though the reduction in
LDL-C levels and the increase in HDL-C levels were sig-
nificantly greater with combination therapy than with simv-
astatin alone (p < 0.01 and p =  0.05, respectively). However,
this study included only 13 (1.8%) patients with diabetes.61
The Study of Heart and Renal Protection (SHARP) ran-
domised patients with advanced CKD (22% with diabetes)
to ezetimibe 10 mg/day plus simvastatin 20 mg/day versus
placebo versus simvastatin 20 mg/day. The latter arm was
rerandomised at one year to ezetimibe 10 mg/day

Downloaded from dvr.sagepub.com by guest on February 27, 2013

108 Diabetes & Vascular Disease Research 10(2)

Table 5.  Concentration of plasma lipids in trials of non-statin lipid-modifying therapies.

Study Lipid data collected at: Intervention Concentration of plasma lipids at specified time point (mmol/L)

  LDL HDL TG
FIELD51 Study close (mean Placebo 2.60 1.12 1.87
  follow-up =  five years) Fenofibrate 2.43* 1.13* 1.47*
ACCORD Lipid54 Study close (mean Placebo plus 2.07 1.05 1.63
follow-up =  4.7 years) simvastatin
  Fenofibrate plus 2.10 1.07* 1.38*
simvastatin
VA-HIT58 One year Placebo 2.90 0.80 1.90
  Gemfibrozil 2.90 0.90* 1.30*
GISSI-P72 Study close (mean Statin NR NR 1.84
  follow-up =  3.5 years) PUFAs plus statin 1.75*
GISSI-HF73 Three years Placebo NR NR NR
  PUFAs 1.34*
JELIS74 Study close (mean Placebo 3.53 NR 1.67
  follow-up =  4.6 years) EPA 3.52 1.57*
OMEGA76 One year Placebo 2.46 NR 1.43
  PUFAs 2.46 1.37*
ENHANCE61 Two years Placebo plus 4.98 1.31 1.35
simvastatin
  Ezetimbe plus 3.65* 1.32 1.22*
simvastatin
ARBITER Study close (mean Ezetimbe plus statin 1.69* 1.06 1.25
6-HALTS67  follow-up =  seven Niacin plus statin 1.88 1.28* 1.03*
months)
NIA-Plaque68 One year Placebo plus statin 2.07 0.98 2.04
  Niacin plus statin 1.78* 1.25* 1.69*

LDL: low-density lipoprotein; HDL: high-density lipoprotein; TG: triglycerides; EPA: eicosapentaenoic acid; NR: not reported; PUFA: polyunsaturated
fatty acids; FIELD: Fenofibrate Intervention and Event Lowering in Diabetes trial; ACCORD Lipid: Action to Control Cardiovascular Risk in
Diabetes Lipid trial; VA-HIT: Department of Veterans Affairs high-density lipoprotein intervention trial; GISSI-P: Gruppo Italiano per lo Studio
della Sopravvivenza nell’Infarto Miocardico-Prevenzione trial; GISSI-HF: GISSI-Heart Failure; JELIS: Japan EPA Lipid Intervention Study; ENHANCE:
Ezetimibe and Simvastatin in Hypercholesterolaemia Enhances Atherosclerosis Regression; ARBITER 6-HALTS: Arterial Biology for the Investigation
of the Treatment Effects of Reducing Cholesterol 6-HDL and LDL Treatment Strategies in Atherosclerosis trial; NIA-Plaque: NIcotinic Acid-Plaque
trial;*Significant versus comparator group (p≤0.05).

plus simvastatin 20 mg/day versus placebo.62 At one year,
treatment with ezetimibe plus simvastatin was associated
with significant (p < 0.0001) reductions in total cholesterol,
LDL-C, TG and apolipoprotein B1 compared with pla-
cebo.62 These changes were numerically greater than those
seen with simvastatin alone but the differences were not
analysed statistically. The effects of the combination regi-
men on lipids were maintained at two and one-half years.62
After a median of 4.9 years of follow-up, the combination
demonstrated a 17% relative risk reduction (95% confi-
dence interval (CI) 0.74–0.94) in major atherosclerotic
events compared with placebo. It should be noted that at
this time point all patients on active treatment were receiv-
ing ezetimibe plus simvastatin and therefore this result can-
not discriminate the impact of ezetimibe independently of a
‘statin-effect’ in these patients.63
The Improved Reduction of Outcomes: Vytorin Efficacy
International Trial (IMPROVE-IT) trial is currently
investigating the effect of simvastatin (40 mg/day with the
possibility to increase to 80 mg/day) with or without the
addition of ezetimibe 10 mg/day in patients with acute cor-
onary syndrome.64 The study is expected to report the effect
of treatment on CVD death, non-fatal stoke and non-fatal
MI in 2013.65
Niacin
The ARterial Biology for the Investigation of the Treatment
Effects of Reducing cholesterol 6 – HDL and LDL
Treatment Strategies (ARBITER 6-HALTS) trial compared
ezetimibe 10 mg/day with niacin (target dose 2 g/day) in
patients with CHD and low HDL-C levels who were already
taking a statin.66,67 Compared with ezetimibe, niacin was
associated with a greater rise in HDL-C and a greater reduc-
tion in TG whereas the reductions in LDL-C and total cho-
lesterol were greater in the ezetimibe group (p≤0.01 for all

Downloaded from dvr.sagepub.com by guest on February 27, 2013

Standl 109
comparisons).66,67 The trial was terminated early because
niacin was associated with significant (p≤0.001) reductions
in mean and maximal CIMT compared with baseline
whereas these measurements did not change significantly
in the ezetimibe group. Major CV events occurred in 5% of
the ezetimibe group compared with 1% of the niacin group
(p =  0.04).66,67
The NIcotinic Acid-Plaque (NIA-Plaque) trial investi-
gated the effect of niacin 2 g/day versus placebo on carotid
artery wall area (CAWA) in patients with type 2 diabetes
and CHD and in patients with carotid/peripheral atheroscle-
rosis. Both patient groups were on stable statin therapy.
Niacin significantly increased HDL-C levels (p < 0.001)
and reduced LDL-C and TG levels (p =  0.01 and p =  0.02,
respectively) compared with placebo, and after one year
CAWA was significantly reduced in the niacin group com-
pared with the placebo group (p =  0.03).68
Atherothrombosis Intervention in Metabolic syndrome
with low HDL/high triglyceride and Impact on Global
Health outcomes (AIM-HIGH) was a placebo-controlled
trial of niacin 2 g/day added to simvastatin in patients aged
≥45 years with established vascular disease. This trial was
discontinued because of an interim analysis finding that it
was unlikely to demonstrate a difference in outcomes with
niacin, and continuation would have been futile.69 Some
safety concerns were also identified, suggesting a possible
increased stroke risk vs placebo. AIM-HIGH may have
been underpowered, but the larger Heart Protection Study
2: Treatment of HDL to Reduce the Incidence of Vascular
Events (HPS2-THRIVE) (clinicaltrials.gov identifier
NCT00461630) is comparing the effect of niacin (2 g/day)
plus laropiprant (a flush inhibitor) versus placebo on CVD
events in patients with a history of CVD and receiving sim-
vastatin 40 mg/day plus ezetimibe 10 mg/day if necessary.
It is expected to report results in 2013 (clinicaltrials.gov
identifier NCT00461630).
Omega-3 fatty acids
Omega-3 PUFAs, especially eicosapentaenoic acid (EPA)
and docosahexaenoic acid (DHA), may have a protective
effect on the vasculature, although the mechanism for this
effect remains unclear. No trial of PUFAs powered for
CVD endpoints and conducted specifically in patients with
diabetes has been reported. However, there is an ongoing
trial of PUFAs in patients with diabetes (88%), or impaired
fasting glucose levels/impaired glucose tolerance (12%).
The Outcome Reduction with an Initial Glargine
INtervention (ORIGIN) trial is investigating whether insu-
lin glargine or PUFAs, or both, have a beneficial effect on
CV events.70 Results are expected in June 2012 (clinicaltri-
als.gov identifier NCT00069784).
In the GISSI-Prevenzione (GISSI-P) trial the effect of
omega-3 PUFA ethyl esters (EPA/DHA in a ratio of 1:1.2)
on death, MI or stroke was studied in patients who had
Downloaded from dvr.sagepub.com by guest on February 27, 2013
experienced a recent MI. Omega-3 PUFA ethyl esters (1 g/
day) were found to significantly (p =  0.048) reduce the risk
of the primary endpoint compared with placebo, an effect
that was seen after three months of treatment and which
lasted until the end of the study (42 months).71,72 The
GISSI-Heart Failure (GISSI-HF) trial reported that the
same formulation significantly reduced all-cause mortality
(p =  0.041) and death or hospitalisation for CV reasons
(p =  0.009) compared with placebo in patients with heart
failure.73 In a separate randomisation, rosuvastatin 10 mg/
day had no significant benefit on clinical endpoints versus
placebo.22
The Japan EPA Lipid Intervention Study (JELIS) inves-
tigated the combination of EPA (1.8 g/day) and a statin
compared with statin monotherapy in Japanese patients
with high total cholesterol levels at baseline.74 The addition
of PUFAs reduced the relative incidence of a major coro-
nary event by 19% compared with statins alone (p =  0.011).
Two recent secondary prevention studies did not repro-
duce the benefits of PUFAs seen in the GISSI trials. Patients
in the Alpha Omega Trial with a previous MI were given
margarines supplemented with EPA/DHA (1.8 g/day),
alpha-linolenic acid (ALA) (3 g/day) or placebo marga-
rine.75 No significant change was seen in the rate of major
CV events for either margarine compared with placebo.
The OMEGA trial investigated the effect of PUFA ethyl
esters 1 g/day versus placebo on sudden cardiac death
(SCD) in patients who had experienced a previous MI and
were receiving recommended treatments including a statin
in the great majority of patients.76 Addition of PUFA ethyl
esters did not significantly alter the rate of SCD (1.5% in
both groups); this study, however, was not adequately pow-
ered to detect a change in SCD. The differences in out-
comes seen in the various PUFA studies may partly result
from differences in the omega-3 fatty acids, dose or formu-
lation administered.
Key trials of non-lipid-lowering
therapies
Intensive glycaemic control
Intensive glycaemic control was intensely debated after the
glycaemic control arm of ACCORD, in which intensive
therapy significantly increased mortality leading to early
termination of the trial.77 However, meta-analyses of this
and other trials showed a significant benefit of intensive
glycaemic control on non-fatal MI and all CHD events,
with no effect on mortality.78,79
Recently, the issue of glycaemic worsening by statin
therapy has been raised. This can be seen by an increased
number of cases of new-onset diabetes while on statins ver-
sus placebo reported in some meta-analyses of randomised
controlled trials in patients with no previous history of dia-
betes,80,81 although not in other trials that selected patients
110 Diabetes & Vascular Disease Research 10(2)
with low CV risk.82 Analysis of five trials of moderate- ver-
sus intensive-dose statin therapy reported the latter to be
associated with an increased risk of new-onset diabetes
(odds ratio (OR) 1.12; 95% CI 1.04–1.22, I2 =  0%).83
However, the number needed to harm was 489, compared
with a number needed to treat of 155 for prevention of CV
events.
In patients with diabetes, there is some glycaemic wors-
ening with statin therapy, as observed in the CARDS and
AFORRD trials.4,84 The latter study showed a placebo-cor-
rected increase in HbA1c of 0.3 %. Given the enormous
benefit of statin therapy, however, it is clear that these
adverse effects on glycaemia do not change the indication of
statin therapy. However, they do warrant regular monitoring
of patient glycaemia, and if necessary, intensification of pre-
ventive or glucose-lowering measures, as reflected in the
recent FDA changes to the labelling of statins in the US.85
Intensive blood pressure control
In the BP arm of ACCORD, intensive control had no sig-
nificant effect on the combined primary outcome of MI,
stroke or death due to CVD or on all-cause mortality com-
pared with standard control.86 In an observational subgroup
analysis of the International Verapamil SR Trandolapril
(INVEST-BP) study, patients with ‘usual’ control (SBP 130
to < 140 mmHg) had a significantly lower rate of adverse
CV events than the ‘uncontrolled’ group (SBP ≥140 mmHg)
(12.6% vs 19.8%; p < 0.001), but ‘tight’ control (SBP < 130
mmHg) conferred no further reduction in event rates
(12.6% vs 12.7%; p =  0.24)87. The Randomised Olmesartan
And Diabetes MicroAlbuminuria Prevention (ROADMAP)
study randomised patients with type 2 diabetes to olmesar-
tan or placebo, with the addition of other drugs as needed to
reduce BP to < 130/80 mmHg. After a median follow-up of
3.2 years, the onset of microalbuminuria (the primary end-
point) was delayed with olmesartan (p =  0.01) but fatal CV
events occurred more commonly in the olmesartan group
(0.7% vs 0.1%; p =  0.01).88
Conclusions
Statins clearly reduce the risk of CVD in patients with type
2 diabetes and should be prescribed for most of these
patients. However, even when receiving the most appropri-
ate statin therapy by dose and drug, patients with type 2
diabetes remain at increased risk of CVD compared with
non-diabetic individuals. Correction of other parameters of
dyslipidaemia, such as high TG and low HDL-C levels, is a
logical step to further reduce the risk of CVD. Treatments
that appear to improve some clinical endpoints (at least in
selected patients) include fibrates, niacin and PUFAs.
‘Normalisation’ of blood glucose or BP appears to be
difficult and is burdened by adverse effects. It does not
Downloaded from dvr.sagepub.com by guest on February 27, 2013
seem to greatly reduce CV endpoints and may be associated
with increased CV death, especially in patients with pre-
existing CVD. Further controlled clinical trials are needed
to establish the best add-on therapy to statins for patients
with type 2 diabetes and remaining dyslipidaemia. Clearly,
therapy should always be adapted to the risk profile and
characteristics of each individual patient.
Funding
This article was supported by an unrestricted educational grant
from Abbott Products Operations AG, Allschwil, Switzerland.
Abbott had no control over the content of this review and Prof
Standl received no payment for any part of his work on this
article.
Acknowledgements
Richard Murphy, Ph D, a professional medical writer, provided
editorial assistance for the development of this review. This assis-
tance was supported by an unrestricted educational grant from
Abbott Products Operations AG, Allschwil, Switzerland. Prof
Standl made all decisions regarding its scope and content.
Conflict of interest statement
Prof Standl:
Task force: First Joint EASD/ESC Guidelines
DSMBs: PROActive, Navigator, ACE Trials
Investigator: studies initiated by Oxford Trial Unit, Menarini,
Novartis, NovoNordisk, Sanofi-Aventis, Servier, MSD/Merck
Lecturing honoraria and consultation fees: Astra Zenica, Bayer,
BMS, GSK, Johnson & Johnson, Lilly, Menarini, Merck-Serono,
MSD/Merck, Novartis, NovoNordisk, Rambaxi, Roche, Sanofi-
Aventis, Servier, Takeda
References
 1. International Diabetes Federation. Diabetes Atlas. http://
www idf org/diabetesatlas (2009, accessed 16 August 2011).
  2. Ryden L, Standl E, Bartnik M, et al. Guidelines on diabe-
tes, pre-diabetes, and cardiovascular diseases: executive
summary. The Task Force on Diabetes and Cardiovascular
Diseases of the European Society of Cardiology (ESC)
and of the European Association for the Study of Diabetes
(EASD). Eur Heart J 2007; 28: 88–136.
 3. Juutilainen A, Lehto S, Ronnemaa T, et al. Similarity of
the impact of type 1 and type 2 diabetes on cardiovascular
mortality in middle-aged subjects. Diabetes Care 2008; 31:
714–719.
  4. Colhoun HM, Betteridge DJ, Durrington PN, et al. Primary
prevention of cardiovascular disease with atorvastatin in type
2 diabetes in the Collaborative Atorvastatin Diabetes Study
(CARDS): multicentre randomised placebo-controlled trial.
Lancet 2004; 364: 685–696.
Standl 111
 5. Knopp RH, D'Emden M, Smilde JG, et al. Efficacy and
safety of atorvastatin in the prevention of cardiovascular
end points in subjects with type 2 diabetes: the Atorvastatin
Study for Prevention of Coronary Heart Disease Endpoints in
non-insulin-dependent diabetes mellitus (ASPEN). Diabetes
Care 2006; 29: 1478–1485.
  6. Taylor F, Ward K, Moore TH, et al. Statins for the primary
prevention of cardiovascular disease. Cochrane Database
Syst Rev 2011; CD004816.
  7. Shepherd J, Barter P, Carmena R, et al. Effect of lowering
LDL cholesterol substantially below currently recommended
levels in patients with coronary heart disease and diabetes:
the Treating to New Targets (TNT) study. Diabetes Care
2006; 29: 1220–1226.
 8. Collins R, Armitage J, Parish S, et al. MRC/BHF Heart
Protection Study of cholesterol-lowering with simvastatin in
5963 people with diabetes: a randomised placebo-controlled
trial. Lancet 2003; 361: 2005–2016.
  9. Athyros VG, Papageorgiou AA, Symeonidis AN, et al. Early
benefit from structured care with atorvastatin in patients
with coronary heart disease and diabetes mellitus. Angiology
2003; 54: 679–690.
10. Pyorala K, Pedersen TR, Kjekshus J, et al. Cholesterol
lowering with simvastatin improves prognosis of diabetic
patients with coronary heart disease. A subgroup analysis of
the Scandinavian Simvastatin Survival Study (4S). Diabetes
Care 1997; 20: 614–620.
11. Arampatzis CA, Goedhart D, Serruys PW, et al. Fluvastatin
reduces the impact of diabetes on long-term outcome after
coronary intervention—a Lescol Intervention Prevention
Study (LIPS) substudy. Am Heart J 2005; 149: 329–335.
12. LaRosa JC, Grundy SM, Waters DD, et al. Intensive lipid
lowering with atorvastatin in patients with stable coronary
disease. N Engl J Med 2005; 352: 1425–1435.
13. Cannon CP, Braunwald E, McCabe CH, et al. Intensive ver-
sus moderate lipid lowering with statins after acute coronary
syndromes. N Engl J Med 2004; 350: 1495–1504.
14. Cannon CP, Steinberg BA, Murphy SA, et al. Meta-analysis
of cardiovascular outcomes trials comparing intensive ver-
sus moderate statin therapy. J Am Coll Cardiol 2006; 48:
438–445.
15. Major outcomes in moderately hypercholesterolemic, hyper-
tensive patients randomized to pravastatin vs usual care: The
Antihypertensive and Lipid-Lowering Treatment to Prevent
Heart Attack Trial (ALLHAT-LLT). JAMA 2002; 288:
2998–3007.
16. Armitage J, Bowman L, Wallendszus K, et al. Intensive
lowering of LDL cholesterol with 80 mg versus 20 mg
simvastatin daily in 12,064 survivors of myocardial infarc-
tion: a double-blind randomised trial. Lancet 2010; 376:
1658–1669.
17. Sever PS, Dahlöf B, Poulter NR, et al. Prevention of coronary
and stroke events with atorvastatin in hypertensive patients
who have average or lower-than-average cholesterol con-
centrations, in the Anglo-Scandinavian Cardiac Outcomes
Downloaded from dvr.sagepub.com by guest on February 27, 2013
Trial - Lipid Lowering Arm (ASCOT-LLA): a multicentre
randomised controlled trial. Lancet 2003; 361: 1149–1158.
18. Fellstrom BC, Jardine AG, Schmieder RE, et al. Rosuvastatin
and cardiovascular events in patients undergoing hemodialy-
sis. N Engl J Med 2009; 360: 1395–1407.
19. Holdaas H, Holme I, Schmieder RE, et al. Rosuvastatin in
diabetic hemodialysis patients. J Am Soc Nephrol 2011; 22:
1335–1341.
20. Wanner C, Krane V, Marz W, et al. Atorvastatin in patients
with type 2 diabetes mellitus undergoing hemodialysis. N
Engl J Med 2005; 353: 238–248.
21. Kjekshus J, Apetrei E, Barrios V, et al. Rosuvastatin in older
patients with systolic heart failure. N Engl J Med 2007; 357:
2248–2261.
22. Tavazzi L, Maggioni AP, Marchioli R, et al. Effect of rosu-
vastatin in patients with chronic heart failure (the GISSI-HF
trial): a randomised, double-blind, placebo-controlled trial.
Lancet 2008; 372: 1231–1239.
23. Cholesterol Treatment Trialists' (CTT) Collaboration.
Efficacy and safety of more intensive lowering of LDL cho-
lesterol: a meta-analysis of data from 170,000 participants in
26 randomised trials. Lancet 2010; 376: 1670–1681.
24. American Diabetes Association. Standards of medical care
in diabetes—2010. Diabetes Care 2010; 33(Suppl 1): S11–
S61.
25. Brunzell JD, Davidson M, Furberg CD, et al. Lipoprotein
management in patients with cardiometabolic risk: consen-
sus statement from the American Diabetes Association and
the American College of Cardiology Foundation. Diabetes
Care 2008; 31: 811–822.
26. Graham I, Atar D, Borch-Johnsen K, et al. European guide-
lines on cardiovascular disease prevention in clinical prac-
tice: executive summary. Fourth Joint Task Force of the
European Society of Cardiology and other societies on cardi-
ovascular disease prevention in clinical practice (constituted
by representatives of nine societies and by invited experts).
Eur J Cardiovasc Prev Rehabil 2007; 14(Suppl 2): E1-E40.
27. Reiner Z, Catapano AL, De BG, et al. ESC/EAS Guidelines
for the management of dyslipidaemias: the Task Force for
the management of dyslipidaemias of the European Society
of Cardiology (ESC) and the European Atherosclerosis
Society (EAS). Eur Heart J 2011; 32: 1769–1818.
28. Chapman MJ, Ginsberg HN, Amarenco P, et al.
Triglyceride-rich lipoproteins and high-density lipoprotein
cholesterol in patients at high risk of cardiovascular dis-
ease: evidence and guidance for management. Eur Heart J
2011; 32: 1345–1361.
29. van Diener S, Peelen LM, Nothlings U, et al. External vali-
dation of the UK Prospective Diabetes Study (UKPDS) risk
engine in patients with type 2 diabetes. Diabetologia 2011;
54: 264–270.
30. van der Heijden AA, Ortegon MM, Niessen LW, et al.
Prediction of coronary heart disease risk in a general, pre-
diabetic, and diabetic population during 10 years of follow-
up: accuracy of the Framingham, SCORE, and UKPDS
112 Diabetes & Vascular Disease Research 10(2)
risk functions: The Hoorn Study. Diabetes Care 2009; 32:
2094–2098.
31. Kengne AP, Patel A, Colagiuri S, et al. The Framingham and
UK Prospective Diabetes Study (UKPDS) risk equations do
not reliably estimate the probability of cardiovascular events
in a large ethnically diverse sample of patients with diabetes:
the Action in Diabetes and Vascular Disease: Preterax and
Diamicron-MR Controlled Evaluation (ADVANCE) Study.
Diabetologia 2010; 53: 821–831.
32. Preis SR, Hwang SJ, Coady S, et al. Trends in all-cause and
cardiovascular disease mortality among women and men
with and without diabetes mellitus in the Framingham Heart
Study, 1950 to 2005. Circulation 2009; 119: 1728–1735.
33. Kearney PM, Blackwell L, Collins R, et al. Efficacy of cho-
lesterol-lowering therapy in 18,686 people with diabetes in
14 randomised trials of statins: a meta-analysis. Lancet 2008;
371: 117–125.
34. Fruchart JC, Sacks F, Hermans MP, et al. The Residual Risk
Reduction Initiative: a call to action to reduce residual vas-
cular risk in patients with dyslipidemia. Am J Cardiol 2008;
102(10 Suppl): 1K–34K.
35. Hayward RA and Krumholz HM. Three reasons to abandon
low-density lipoprotein targets: an open letter to the Adult
Treatment Panel IV of the National Institutes of Health. Circ
Cardiovasc Qual Outcomes 2012; 5: 2–5.
36. Randomised trial of cholesterol lowering in 4444 patients
with coronary heart disease: the Scandinavian Simvastatin
Survival Study (4S). Lancet 1994; 344: 1383–1389.
37. Heart Protection Study Collaborative Group. MRC/BHF
Heart Protection Study of cholesterol lowering with simvas-
tatin in 20,536 high-risk individuals: a randomised placebo-
controlled trial. Lancet 2002; 360: 7–22.
38. Athyros VG, Papageorgiou AA, Mercouris BR, et al.
Treatment with atorvastatin to the National Cholesterol
Educational Program goal versus 'usual' care in secondary
coronary heart disease prevention. The GREek Atorvastatin
and Coronary-heart-disease Evaluation (GREACE) study.
Curr Med Res Opin 2002; 18: 220–228.
39. Assmann G, Cullen P and Schulte H. Simple scoring
scheme for calculating the risk of acute coronary events
based on the 10-year follow-up of the prospective cardio-
vascular Munster (PROCAM) study. Circulation 2002;
105: 310–315.
40. Stratton IM, Adler AI, Neil HA, et al. Association of gly-
caemia with macrovascular and microvascular complications
of type 2 diabetes (UKPDS 35): prospective observational
study. BMJ 2000; 321: 405–412.
41. Turner RC, Millns H, Neil HA, et al. Risk factors for coro-
nary artery disease in non-insulin dependent diabetes mel-
litus: United Kingdom Prospective Diabetes Study (UKPDS:
23). BMJ 1998; 316: 823–828.
42. Di Angelantonio E, Chowdhury R, Sarwar N, et al. Chronic
kidney disease and risk of major cardiovascular disease and
non-vascular mortality: prospective population based cohort
study. BMJ 2010; 341: c4986.
Downloaded from dvr.sagepub.com by guest on February 27, 2013
43. Hippisley-Cox J, Coupland C, Vinogradova Y, et al.
Derivation and validation of QRISK, a new cardiovascular
disease risk score for the United Kingdom: prospective open
cohort study. BMJ 2007; 335: 136.
44. Stevens RJ, Kothari V, Adler AI, et al. The UKPDS risk
engine: a model for the risk of coronary heart disease in
Type II diabetes (UKPDS 56). Clin Sci (Lond) 2001; 101:
671–679.
45. D'Agostino RB Sr, Vasan RS, Pencina MJ, et al. General
cardiovascular risk profile for use in primary care: the
Framingham Heart Study. Circulation 2008; 117: 743–753.
46. Conroy RM, Pyorala K, Fitzgerald AP, et al. Estimation of
ten-year risk of fatal cardiovascular disease in Europe: the
SCORE project. Eur Heart J 2003; 24: 987–1003.
47. Cooney MT, Dudina A, De Bacquer D, et al. How much does
HDL cholesterol add to risk estimation? A report from the
SCORE Investigators. Eur J Cardiovasc Prev Rehabil 2009;
16: 304–314.
48. Lehto S, Ronnemaa T, Haffner SM, et al. Dyslipidemia
and hyperglycemia predict coronary heart disease events
in middle-aged patients with NIDDM. Diabetes 1997; 46:
1354–1359.
49. Hokanson JE and Austin MA. Plasma triglyceride level is a
risk factor for cardiovascular disease independent of high-
density lipoprotein cholesterol level: a meta-analysis of pop-
ulation-based prospective studies. J Cardiovasc Risk 1996;
3: 213–219.
50. Ridker PM, Genest J, Boekholdt SM, et al. HDL cholesterol
and residual risk of first cardiovascular events after treatment
with potent statin therapy: an analysis from the JUPITER
trial. Lancet 2010; 376: 333–339.
51. Keech A, Simes RJ, Barter P, et al. Effects of long-term
fenofibrate therapy on cardiovascular events in 9795 people
with type 2 diabetes mellitus (the FIELD study): randomised
controlled trial. Lancet 2005; 366: 1849-1861.
52. Scott R, O'Brien R, Fulcher G, et al. Effects of fenofibrate
treatment on cardiovascular disease risk in 9,795 individu-
als with type 2 diabetes and various components of the
metabolic syndrome: the Fenofibrate Intervention and Event
Lowering in Diabetes (FIELD) study. Diabetes Care 2009;
32: 493–498.
53. Burgess DC, Hunt D, Li L, et al. Incidence and predictors of
silent myocardial infarction in type 2 diabetes and the effect
of fenofibrate: an analysis from the Fenofibrate Intervention
and Event Lowering in Diabetes (FIELD) study. Eur Heart J
2010; 31: 92–99.
54. Ginsberg HN, Elam MB, Lovato LC, et al. Effects of combi-
nation lipid therapy in type 2 diabetes mellitus. N Engl J Med
2010; 362: 1563–1574.
55. Elam M, Lovato LC, Byington RP, et al. Hypertriglyceridemia
and low HDL-C predicts fenofibrate response in the
ACCORD-lipid trial. American Heart Association 2010;
122: A19724.
56. Bays HE, Roth EM, McKenney JM, et al. The effects of
fenofibric acid alone and with statins on the prevalence
Standl 113
of metabolic syndrome and its diagnostic components in
patients with mixed dyslipidemia. Diabetes Care 2010; 33:
2113–2116.
57. Mohiuddin SM, Pepine CJ, Kelly MT, et al. Efficacy and
safety of ABT-335 (fenofibric acid) in combination with
simvastatin in patients with mixed dyslipidemia: a phase 3,
randomized, controlled study. Am Heart J 2009; 157: 195–
203.
58. Rubins HB, Robins SJ, Collins D, et al. Gemfibrozil for the
secondary prevention of coronary heart disease in men with
low levels of high-density lipoprotein cholesterol. Veterans
Affairs High-Density Lipoprotein Cholesterol Intervention
Trial Study Group. N Engl J Med 1999; 341: 410–418.
59. Rubins HB, Robins SJ, Collins D, et al. Diabetes, plasma
insulin, and cardiovascular disease: subgroup analysis from
the Department of Veterans Affairs high-density lipoprotein
intervention trial (VA-HIT). Arch Intern Med 2002; 162:
2597–2604.
60. Jones PH and Davidson MH. Reporting rate of rhabdomyol-
ysis with fenofibrate + statin versus gemfibrozil + any statin.
Am J Cardiol 2005; 95: 120-122.
61. Kastelein JJ, Akdim F, Stroes ES, et al. Simvastatin with or
without ezetimibe in familial hypercholesterolemia. N Engl J
Med 2008; 358: 1431–1443.
62. Sharp Collaborative Group. Study of Heart and Renal
Protection (SHARP): randomized trial to assess the effects
of lowering low-density lipoprotein cholesterol among 9,438
patients with chronic kidney disease. Am Heart J 2010; 160:
785–794.
63. Baigent C, Landray MJ, Reith C, et al. The effects of low-
ering LDL cholesterol with simvastatin plus ezetimibe in
patients with chronic kidney disease (Study of Heart and
Renal Protection): a randomised placebo-controlled trial.
Lancet 2011; 377: 2181–2192.
64. Cannon CP, Giugliano RP, Blazing MA, et al. Rationale
and design of IMPROVE-IT (IMProved Reduction of
Outcomes: Vytorin Efficacy International Trial): compari-
son of ezetimbe/simvastatin versus simvastatin monotherapy
on cardiovascular outcomes in patients with acute coronary
syndromes. Am Heart J 2008; 156: 826–832.
65. Califf RM, Lokhnygina Y, Cannon CP, et al. An update
on the IMProved reduction of outcomes: Vytorin Efficacy
International Trial (IMPROVE-IT) design. Am Heart J 2010;
159: 705–709.
66. Taylor AJ, Villines TC, Stanek EJ, et al. Extended-release
niacin or ezetimibe and carotid intima-media thickness. N
Engl J Med 2009; 361: 2113–2122.
67. Villines TC, Stanek EJ, Devine PJ, et al. The ARBITER
6-HALTS Trial (Arterial Biology for the Investigation of the
Treatment Effects of Reducing Cholesterol 6-HDL and LDL
Treatment Strategies in Atherosclerosis): final results and the
impact of medication adherence, dose, and treatment dura-
tion. J Am Coll Cardiol 2010; 55: 2721–2726.
68. Lee JM, Robson MD, Yu LM, et al. Effects of high-dose mod-
ified-release nicotinic acid on atherosclerosis and vascular
Downloaded from dvr.sagepub.com by guest on February 27, 2013
function: a randomized, placebo-controlled, magnetic reso-
nance imaging study. J Am Coll Cardiol 2009; 54: 1787–1794.
69. National Institutes of Health. NIH stops clinical trial on com-
bination cholesterol treatment. National Institutes of Health
2011.
70. Gerstein H, Yusuf S, Riddle MC, et al. Rationale, design,
and baseline characteristics for a large international trial
of cardiovascular disease prevention in people with dys-
glycemia: the ORIGIN Trial (Outcome Reduction with
an Initial Glargine Intervention). Am Heart J 2008; 155:
26–32, 32.
71. GISSI-Prevenzione Investigators. Dietary supplementation
with n-3 polyunsaturated fatty acids and vitamin E after
myocardial infarction: results of the GISSI-Prevenzione
trial. Gruppo Italiano per lo Studio della Sopravvivenza
nell'Infarto miocardico. Lancet 1999; 354: 447–455.
72. Marchioli R, Barzi F, Bomba E, et al. Early protection
against sudden death by n-3 polyunsaturated fatty acids after
myocardial infarction: time-course analysis of the results
of the Gruppo Italiano per lo Studio della Sopravvivenza
nell'Infarto Miocardico (GISSI)-Prevenzione. Circulation
2002; 105: 1897–1903.
73. Tavazzi L, Maggioni AP, Marchioli R, et al. Effect of n-3
polyunsaturated fatty acids in patients with chronic heart
failure (the GISSI-HF trial): a randomised, double-blind,
placebo-controlled trial. Lancet 2008; 372: 1223–1230.
74. Yokoyama M, Origasa H, Matsuzaki M, et al. Effects of
eicosapentaenoic acid on major coronary events in hyper-
cholesterolaemic patients (JELIS): a randomised open-label,
blinded endpoint analysis. Lancet 2007; 369: 1090–1098.
75. Kromhout D, Giltay EJ, Geleijnse JM, et al. n-3 Fatty acids
and cardiovascular events after myocardial infarction. N
Engl J Med 2010; 363: 2015–2026.
76. Rauch B, Schiele R, Schneider S, et al. OMEGA, a rand-
omized, placebo-controlled trial to test the effect of highly
purified omega-3 fatty acids on top of modern guideline-
adjusted therapy after myocardial infarction. Circulation
2010; 122: 2152–2159.
77. Gerstein HC, Miller ME, Byington RP, et al. Effects of inten-
sive glucose lowering in type 2 diabetes. N Engl J Med 2008;
358: 2545–2559.
78. Ray KK, Seshasai SR, Wijesuriya S, et al. Effect of intensive
control of glucose on cardiovascular outcomes and death
in patients with diabetes mellitus: a meta-analysis of ran-
domised controlled trials. Lancet 2009; 373: 1765–1772.
79. Turnbull FM, Abraira C, Anderson RJ, et al. Intensive glu-
cose control and macrovascular outcomes in type 2 diabetes.
Diabetologia 2009; 52: 2288–2298.
80. Culver AL, Ockene IS, Balasubramanian R, et al. Statin use
and risk of diabetes mellitus in postmenopausal women in
the Women's Health Initiative. Arch Intern Med 2012; 172:
144–152.
81. Sattar N, Preiss D, Murray HM, et al. Statins and risk of inci-
dent diabetes: a collaborative meta-analysis of randomised
statin trials. Lancet 2010; 375: 735–742.
114 Diabetes & Vascular Disease Research 10(2)

82. Tonelli M, Lloyd A, Clement F, et al. Efficacy of statins for
primary prevention in people at low cardiovascular risk: a
meta-analysis. CMAJ 2011; 183: E1189–E1202.
83. Preiss D, Seshasai SR, Welsh P, et al. Risk of incident diabe-
tes with intensive-dose compared with moderate-dose statin
therapy: a meta-analysis. JAMA 2011; 305: 2556–2564.
84. Holman RR, Paul S, Farmer A, et al. Atorvastatin in Factorial
with Omega-3 EE90 Risk Reduction in Diabetes (AFORRD):
a randomised controlled trial. Diabetologia 2009; 52: 50–59.
85. US Food and Drug Administration (US FDA).
FDA announces changes in safety labeling for some
cholesterol-reducing drugs. http://www.fda.gov/NewsEvents/
Newsroom/PressAnnouncements/ucm293623.htm (2012,
accessed 7 March 2012).
86. Cushman WC, Evans GW, Byington RP, et al. Effects of
intensive blood-pressure control in type 2 diabetes mellitus.
N Engl J Med 2010; 362: 1575–1585.
87. Cooper-DeHoff RM, Gong Y, Handberg EM, et al. Tight
blood pressure control and cardiovascular outcomes among
hypertensive patients with diabetes and coronary artery dis-
ease. JAMA 2010; 304: 61–68.
88. Haller H, Ito S, Izzo JL Jr, et al. Olmesartan for the delay or
prevention of microalbuminuria in type 2 diabetes. N Engl J
Med 2011; 364: 907–917.

Downloaded from dvr.sagepub.com by guest on February 27, 2013