1. review article
Diabetes, Obesity and Metabolism 13: 313–325, 2011.
© 2011 Blackwell Publishing Ltd
article
review
Therapies for diabetic dyslipidaemia
D. S. H. Bell1 , F. Al Badarin2 & J. H. O’Keefe, Jr2
1 Department of Endocrinology, University of Alabama, Birmingham, AL, USA
2 Saint Luke’s Cardiovascular Consultants/Mid America Heart and Vascular Institute, University of Missouri-Kansas City, Kansas City, MO, USA
Correction of diabetic dyslipidaemia in diabetic patients is the most important factor in reducing cardiac risk. Diabetic dyslipidaemia is
characterized by elevated triglycerides, low total high-density lipoprotein (HDL) and small dense low-density lipoprotein (LDL) particles. The
most important therapeutic goal in diabetic dyslipidaemia is correction of the non-HDL-cholesterol (HDL-C) level. Glycaemic control with
particular attention to postprandial glucose control plays a role not only in improving dyslipidaemia but also in lowering cardiac events.
Pioglitazone is particularly effective for improving the manifestations of diabetic dyslipidaemia, in addition to its favorable effects on systemic
inflammation and hyperglycaemia. Use of statins in addition to lifestyle change is recommended in most if not all type 2 diabetic patients
and the goal should be to lower the LDL to a level recommended for the patient with existing cardiovascular disease (CVD) (non-HDL-C level
<100 mg/dl). In addition, therapies for normalization of HDL and triglyceride levels should be deployed. Most patients with type 2 diabetes
(T2D) will require combining a lipid-lowering therapy with therapeutic lifestyle changes to achieve optimal lipid levels. Combinations usually
include two or more of the following: a statin, nicotinic acid, omega-3 fats and bile acid sequestrants (BASs). Fibrates may also be of use
in diabetic patients with persistently elevated triglycerides and depressed HDL-C levels, although their role in lowering adverse CV events is
questionable.
Keywords: cardiovascular disease, diabetes mellitus, dyslipidaemia, lipid-lowering therapy, thiazolidinediones, type 2 diabetes
Date submitted 6 July 2010; date of first decision 16 August 2010; date of final acceptance 17 November 2010
Modifiable Cardiac Risk Factors in the Diabetic Dyslipidaemia
Diabetic Patient Data from the Framingham study indicate that a low HDL
Diabetes mellitus (DM) is a major risk factor for cardiovascular level accompanied by an elevated triglyceride level is twice
disease (CVD). According to the National cholesterol education as common among patients with type 2 diabetes (T2D)
program (NCEP) and adult treatment panel III (ATPIII) compared to non-diabetic patients, while concentrations of
recommendations, patients with diabetes are in a high- calculated LDL and total cholesterol do not differ [10]. The
risk category for cardiovascular (CV) events [1,2] and lowering of total HDL levels in patients with T2D is mainly
diabetes is now considered a coronary heart disease (CHD) because of a decrease in the concentration of the larger more
equivalent [3]. cardioprotective HDL particles, with the smaller more dense
Diabetic patients have high prevalence of concomitant and less cardioprotective HDL particles predominating [11].
CV risk factors (hypertension, smoking and truncal obe- The low HDL, high triglyceride pattern is also characteristic
sity) [4]. In addition, the biochemical and metabolic derange- of individuals with prediabetes or the metabolic syndrome
ments that accompany DM lead to abnormal oxidative (MetSyn), regardless of race, ethnicity and gender. It should
stress, impaired endothelial function, increased fibrinogen be noted that in the Framingham study, the diabetic African
and platelet activation and chronic low-grade inflamma- Americans’ lipid pattern was more commonly that of a low
tion, all of which are known to promote plaque for- HDL accompanied by a high calculated LDL level with only
mation and atherogenesis [5–7]. Furthermore, DM predis- 19% (compared with 50% of those of European origin) having
poses to atherogenic lipid abnormalities including elevated hypertriglyceridaemia [12].
low-density lipoprotein-cholesterol (LDL-C), greater num- Because of resistance to the action of insulin on the adipocyte
ber of smaller LDL particles, low high-density lipoprotein- (particularly the peritoneal adipocyte), free fatty acid (FFA)
cholesterol (HDL-C) and high triglycerides [8,9]. There- levels are elevated [13]. Increased delivery of FFAs to the
fore, an aggressive approach to controlling CVD risk fac- liver promotes hepatic production of triglycerides which are
tors, especially dyslipidaemia, is essential in all diabetic packaged in ApoB-containing very low-density lipoproteins
subjects. (VLDLs). The presence of increased VLDL increases the
available substrate for cholesterol ester transfer protein (CETP)
which enhances the exchange of triglycerides for cholesterol
Correspondence to: Dr. David S. H. Bell, University of Alabama and Southside
Endocrinology, 1020 26th Street South, Room 204, Birmingham, AL 35205, USA. from the HDL to the LDL particles increasing the triglyceride
E-mail: dshbell@yahoo.com; davidshbellmd@charter.net content of both particles.

2. review article DIABETES, OBESITY AND METABOLISM
The increased triglyceride content of both the LDL and addition, non-HDL-C is also more convenient for the patient
HDL particles causes increased activity of the enzyme hepatic because it can be measured in the non-fasting state. The goals
lipase which results in an increased production of both small for non-HDL-C are 30 mg/dl higher than those of the calcu-
dense LDL and small dense HDL particles. Small dense LDL lated LDL, so that if the goal for LDL is 100 mg/dl then the
particles are more atherogenic because these particles, especially goal for non-HDL-C is 130 mg/dl and if the goal for LDL is
when glycated, are more easily oxidized and ‘picked up’ 70 mg/dl then the goal for non-HDL-C is 100 mg/dl [1].
by the scavenger receptor on the macrophage which has a Recently, it has been proposed that in the general population
much greater affinity for oxidized LDL than for non-oxidized lipid screening should be performed in the non-fasting state
LDL [14]. Macrophages therefore facilitate the transportation with only a total cholesterol and HDL being measured. This
of these particles through the intima to the subintimal space opinion is based on a study of a European population where
and media of the artery where the process of atherogenesis is it was shown that independent of the calculated LDL levels,
initiated and accelerated by these highly atherogenic particles. patients with higher non-HDL-C levels were at an increased
The concentration of small dense LDL particles is increased risk of CHD [20]. In addition, two large trials of statin
not only with diabetes and the MetSyn but also with cigarette therapy, treating to new targets (TNT) [21] and incremental
smoking, hypertension and the presence of a low HDL-C level. decreases in endpoints through aggressive lipid-lowering
In addition to facilitating the passage of monocytes through (IDEAL) trial [22], have also shown that levels of non-HDL-C
the arterial wall, oxidized LDL is also cytotoxic and damages and ApoB are more closely associated with CV outcomes
the endothelium [15]. than calculated LDL levels. However, data documenting that
Small dense HDL particles are more easily cleared by the targeting non-HDL-C leads to better outcomes than targeting
kidney with more apo-A being filtered and metabolized renally, LDL-C levels is still lacking.
which results in a shorter life span of this particle, and
accounts for the lower HDL levels typically seen in patients Therapy of Diabetic Dyslipidaemia
with insulin resistance and/or diabetes [16]. Small dense HDL
Based on the UK prospective diabetes study (UKPDS), the
particles are also twofold to threefold less effective than the
most powerful risk factor for cardiac events in the diabetic
larger HDL particle in reverse cholesterol transport. This
patient is an elevated LDL, closely followed by a decreased
is mainly attributed to the lower concentrations of ApoE
HDL level. These lipid risk factors are followed in order by the
and lecithin-cholesterol acyltransferase (LCAT) in small dense
other independent risk factors including HbA1c, systolic blood
HDL particles. Furthermore, these particles have decreased
pressure and cigarette smoking [23].
anti-inflammatory and antioxidant properties [17]. Therefore,
Thus, while the therapy of diabetic dyslipidaemia is extremely
small dense HDL particles are potentially less cardioprotective
important, it should not be performed in isolation and should
than larger HDL particles which are inferred almost entirely
be accompanied by aggressive therapy of both hyperglycaemia
from epidemiological and clinical associations.
and hypertension, using evidence-based therapies such as drugs
and therapeutic lifestyle changes (diet, weight loss, exercise,
smoking cessation, etc).
Goals of the Lipid-lowering Therapy
in the Diabetic Patient Glycaemic Control and Diabetic Dyslipidaemia
Calculated LDL Glycaemic control is the first and most important step in
The Friedewald calculation for serum LDL-C levels is almost controlling dyslipidaemia, which can result in a significant
universally utilized. However, in the insulin-resistant or improvement in lipid levels particularly in patients with
diabetic patient this calculation may be inaccurate because hypertriglycaeridemia, where lowering of the triglyceride level
it underestimates the number of LDL particles as well as the is usually accompanied by an increase in the HDL level. In
atherogenic potential of these particles. addition, with correction of hyperglycaemia the LDL particle
The most logical solution to the problem of an underes- size may be increased, and if pioglitazone or insulin is utilized,
timated LDL level, utilizing the Friedewald calculation, is to a decrease in the number of LDL particles may occur as well.
directly measure the ApoB levels (one per LDL particle) or Of more importance than overall glycaemic control is the
to directly measure the number of LDL particles. However, control of postprandial hyperglycaemia. Varying degrees of
measurement of ApoB is preferable because ApoB is also a postprandial hyperglycaemia are invariably present in diabetic
component of the other important atherogenic particles (inter- patients, especially when treated with drugs with minimal
mediate density lipoproteins, remnant lipoproteins and small effect on postprandial hyperglycaemia, such as basal insulin
dense VLDL particles). and metformin.
The use of non-HDL-C, a surrogate for the number of Triglyceride-rich lipoproteins (TRLs) derived from the
ApoB-containing atherogenic particles, was shown to be a bet- intestine have been shown to be increased with insulin
ter predictor of cardiac events than LDL-C [18], particularly resistance not only in the preprandial state but importantly
in patients with DM, insulin resistance and/or hypertriglyceri- also in the postprandial state. Elevated TRLs are also associated
daemia [19]. The non-HDL-C level is recommended by ATPIII with increased cardiac events. In particular, the production
to be utilized as a secondary target in the hypertriglyceridaemia rate of ApoB 48 containing particles is increased with both
subject where the calculated LDL is invariably falsely low [1]. In insulin resistance and T2D. Enterocytes, which are similar
314 Bell et al. Volume 13 No. 4 April 2011

3. DIABETES, OBESITY AND METABOLISM review article
to hepatocytes, overproduce ApoB 48 which facilitates the
absorption of ingested fat thereby enriching the assembly
and secretion of TRLs which contributes to postprandial
hyperlipidemia [24].
Postprandial hyperglycaemia is accompanied by postpran-
dial hyperlipidemia (characterized by elevated postmeal levels
of triglycerides and fatty acids) and the combination of post-
prandial hyperglycaemia and postprandial hyperlipidemia has
been labelled ‘postprandial dysmetabolism’ [25]. Postprandial
dysmetabolism is an insulin-resistant inflammatory state char-
acterized by increased cytokine levels, decreased fibrinolysis
because of increased PAI1 activity and increased oxidative
stress leading to endothelial dysfunction [26]. The increased
inflammation within the plaque that occurs with postpran- Figure 2. Postprandial glucose and athero progression—patients with
dial dysmetabolism increases the risk of a cardiac event and normal glucose tolerance who had a postprandial glucose level of <87 mg/dl
it has been shown that postprandial glucose fluctuations are had coronary regression. The remaining patients had coronary progression
in proportion to the increase in postprandial glucose. Adapted with
more likely to trigger oxidative stress than chronic sustained
permission from Ref. [28].
hyperglycaemia (figure 1) [27,28].
In multiple population studies, postprandial glucose levels
have been associated with CHD and mortality. In the increased cardiac events and mortality [31]. In the Honolulu
HOORN [29], DECODE [30], Whitehall, Helsinki policemen study of over 6000 men, the 1-h postprandial glucose level was
and Paris protective studies, which in aggregate included over associated with cardiac events and mortality [32].
45 000 subjects, an elevated 2-h glucose was associated with In a study of non-diabetic females with normal glucose
tolerance and coronary artery disease, coronary angiography
was performed at baseline after 3 years [33]. The lower the
2-h glucose level on a baseline glucose tolerance test, the less
the progression of coronary atherosclerotic burden over the
course of the 3-year study. Indeed, if the 2-h glucose was
lesser than 86 mg/dl there was regression in the coronary
atheroma volume (figure 2) [33]. Therefore, even in this study
of individuals with postmeal glucose excursions within the
normal range, the higher the postprandial glucose rose, the
greater was the rate of atheroma formation. Similarly, in a
study of individuals with normal fasting and 2-h glucose levels,
higher CV mortality was seen among those with higher 2-h
glucose levels (closer to 140 mg/dl) [34].
The DECODE study showed that mortality could not be
predicted from the fasting glucose level but could be predicted
from the postprandial glucose level, which was also shown to
be an independent risk factor for mortality [30]. The STOP-
NIDDM study, a blinded placebo-controlled study of 1429
individuals with impaired glucose tolerance, assessed whether
the α-glucosidase inhibitor, acarbose, could slowdown the
progression to T2D [35]. While conversion to diabetes was
significantly decreased by 25%, the relative risk of a CV
event decreased by 49%. Subsequently, the phase 3 studies
of acarbose were re-examined for CV events and it was found
that compared to placebo and other diabetic medications the
risk of having a myocardial infarction (MI) was decreased
by 64% and the risk of any CV event decreased by 35% with
acarbose [36]. Additionally, acarbose decreased carotid intima-
medial thickening (CIMT) by 50%—a benefit that dissipated
Figure 1. Postprandial—the immediate deleterious effects of a meal when acarbose was discontinued [37]. Acarbose, though its
containing 75 g of glucose and 700 kcal/m2 of whipping cream in 20
effects on α-glucosidase and lipase, reduces both postprandial
diabetic subjects. Within 2–4 h glucose and triglyceride levels double,
causing immediate oxidant stress (nitrotyrosine), inflammation C-reactive glucose and lipid levels. Thiazolidinediones (TZDs), by
protein (CRP), resulting in deterioration in endothelial function (FMD limiting intestinal lipid absorption, which is increased in
% = percent flow-mediated dilatation). Adapted with permission from the MetSyn, also reduce both postprandial hyperglycaemia
Ref. [28]. and hyperlipidemia. While postprandial glucose is not
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4. review article DIABETES, OBESITY AND METABOLISM
lowered by metformin or basal insulin, it is lowered by
sulfonylureas, incretin mimetics, DPP4 inhibitors, pramlintide
and short-acting insulin [38]. However, to date, only the
α-glucosidase inhibitors and TZDs have been shown to
reduce both postprandial hyperglycaemia and postprandial
hyperlipidemia [39].
The nateglinide and valsartan in impaired glucose tolerance
outcomes research (NAVIGATOR) trial showed that nateglin-
ide, a sulfonylurea-like agent that lowers postprandial glucose,
proved ineffective at halting progression from impaired glucose
tolerance to overt T2DM and also had no significant impact
on reducing CV events. However, nateglinide, for uncertain
reasons, did not lower the postglucose challenge glucose levels
for the patients in the NAVIGATOR trial [40]. Figure 3. Proactive trial—PROactive: significant difference in principal
secondary endpoint (death, MI or stroke; pioglitazone vs. placebo: HR 0.84;
95% CI 0.72–0.98). HR, heart rate; MI, myocardial infarction. Adapted
TZDs and Diabetic Dyslipidaemia with permission from Ref. [124].
A head-to-head randomized clinical trial comparing maximal
doses of pioglitazone and rosiglitazone showed that while towards less CV events could have become significant with
both of these drugs were equally effective at lowering the a longer duration of the study because the termination of
HbA1c, pioglitazone was superior to rosiglitazone in increasing the study was based on the number of events which was
both the HDL and the LDL particle sizes [41]. Paradoxically, surprisingly high and resulted in the study lasting for only
while pioglitazone decreased triglycerides by 12%, rosiglitazone 3.4 years. In addition, a retrospective subanalysis of the study
increased triglycerides by 14.9%. However, a finding of much showed that there was no significant improvement in CV events
greater importance was that pioglitazone reduced the number when statins or β-blockers were being utilized. However, for
of LDL particles by 51% while rosiglitazone increased this any study to show an additional improvement in cardiac
number by 111%, resulting in lesser increases in calculated events in the diabetic patient who was utilizing maximal
LDL and ApoB levels with pioglitazone. Rosiglitazone has risk-reducing therapies would entail the inclusion of very
been shown to be ineffective at lowering atherosclerotic plaque large numbers of subjects and would therefore be impractical
burden in the carotid and coronary arteries and has been and cost-prohibitive. The major side effect of pioglitazone in
effectively removed from the US and European markets due to PROACTIVE, especially when used with insulin, was fluid
concerns about its CV safety [42]. retention and non-fatal heart failure [49].
These differences in lipid levels, especially the difference
in LDL particle numbers, could explain the differences in
accumulation of coronary artery atheroma and cardiac events Lifestyle Changes and Diabetic Dyslipidaemia
seen with these drugs. However, other factors may be involved Lifestyle factors including dietary changes, increased physical
because a total of 23 genes have been shown to be expressed activity, weight loss and smoking cessation may help diabetic
with either rosiglitazone or pioglitazone; of these, 5 genes are patients reach their therapeutic goals. Cessation of smoking,
exclusively expressed by rosiglitazone and 12 genes exclusively exercise and weight loss is particularly beneficial in elevating
by pioglitazone [43]. HDL levels.
In contrast, in the pioglitazone effect on regression of The benefits of regular exercise, in addition to an improved
intravascular sonographic coronary obstruction retrospective lipid profile, include weight loss, decreased abdominal fat,
evaluation (PERISCOPE) study, pioglitazone when compared reduced inflammation, increased insulin sensitivity, decreased
with glimepiride significantly reduced the percentage of blood pressure levels and improved endothelial function. The
atheroma volume (the primary endpoint) as well as atheroma ADA recommends 150 min of aerobic physical activity per
thickness [44]. Of note, the reduction in the atheroma volume week accompanied by resistance training up to three times per
achieved with pioglitazone in PERISCOPE compared favorably week [50]. Exercise duration correlates strongly with reductions
with that achieved by the strongest of the statin cholesterol- in triglycerides and weight and increases in HDL levels.
lowering drugs [45]. Significant improvements in HDL require at least 20 min of
In the PROACTIVE study, the addition of pioglitazone to daily exercise; 40–60 min of exercise daily will produce better
existing diabetic therapies resulted in significant decreases in results. Aerobic exercise appears to raise HDL better than
the principle secondary combined endpoint of MI, stroke and strength training or stretching exercises [51,52].
death (figure 3). Furthermore, decreases in the recurrence
of MI and stroke were also shown [46,47]. The primary
composite endpoint which included criteria for peripheral Diet
vascular disease was not significantly decreased, probably The ADA recommends weight loss in overweight patients, a
because of the inclusion of subjects with peripheral vascular saturated fat intake of less than 7% of total calories, minimal
disease who showed no improvement in cardiac events with trans-fat intake, reduced cholesterol intake, a carbohydrate
pioglitazone [47,48]. However, even in this group, the trend intake limited to 130 g/day and fiber intake of at least 14 g
316 Bell et al. Volume 13 No. 4 April 2011

5. DIABETES, OBESITY AND METABOLISM review article
per thousand calories [50]. ATPIII also focuses on weight loss, • Low-to-moderate amounts of non-fat or low-fat dairy
reduced fat intake, reduced carbohydrate intake in addition • Light-to-moderate daily consumption of wine, typically with
to an increase in calories derived from monounsaturated or meals
polyunsaturated fats [1]. • Preference for local, seasonal, produce
Investigators from the Framingham Heart study found that • Physically active lifestyle, usually incorporated into activities
a diet consistent with the fundamentals of the Mediterranean- of daily life
style diet appears to prevent development of the T2D and
MetSyn. Specifically, a diet high in vegetables, fruits, nuts, Testosterone Replacement Therapy and Diabetic
omega-3 fatty acids, olive oil and whole grains but low Dyslipidaemia
in refined carbohydrates, saturated fats and trans fats was
associated with reduced risks for T2D, including lower It has been estimated that as many as 50% of type 2
levels of insulin resistance, abdominal obesity, fasting glucose diabetic males have hypogonadotropic hypogonadism [57].
and triglycerides, and improvements in HDL-C levels and This is because the excess peritoneal fat associated with the
endothelial function [53]. MetSyn and T2D is associated with increased activity of the
A more recent epidemiological study of 23 500 Greek adults enzyme aromatase which results in an increased conversion of
reported that the intake of vegetables, fruits, nuts, legumes, and testosterone to estrogen (mainly estradiol). Increased estrogen
olive oil, and drinking light-to-moderate amounts of alcohol, levels at the level of the hypothalamus suppress the release of
while minimizing the consumption of fatty meats and avoiding gonadotropin-releasing hormone which in turn decreases the
excessive alcohol intake was linked to improved longevity. The release of gonadotropins (particularly luteinizing hormone)
proportion of the overall improvement in longevity attributable from the anterior pituitary gland resulting in a decreased
to each of the specific components of the Mediterranean production of testosterone from the Leydig cells of the testicles.
diet was as follows: moderate ethanol consumption 24%, low Low testosterone levels have been associated with insulin
consumption of meat 17%, high vegetable consumption 16%, resistance, higher PAI1 and fibrinogen levels, increased FFA
high fruit and nut consumption 11%, high monounsaturated and triglyceride levels and lower HDL levels [58]. Increased
to saturated lipid ratio 11% and high legume consumption oxidative stress, endothelial dysfunction, increased CIMT and
10% [54]. Overall, those individuals who adhered to the increased CV events and mortality have also been associated
Mediterranean dietary principles most closely were 25% less with low testosterone levels.
likely to die during the course of the study [54]. Testosterone replacement therapy in testosterone-deficient
A trial of patients with newly diagnosed T2D randomized subjects lowers insulin resistance and results in lowering of
them to either a Mediterranean diet or a low-fat American triglyceride and elevation of HDL levels and improved oxidative
Heart Association (AHA) diet. After 4 years, only 44% of newly stress and endothelial function [59]. It has been estimated that
diagnosed diabetic patients randomized to the Mediterranean for each 5.3 nmol/l elevation in serum testosterone levels the
diet vs. 70% of those randomized to the low-fat AHA diet risk of an MI may decrease by 57% [60]. However, the safety
required glucose-lowering drug therapy for control of their and clinical benefit of routine testosterone replacement in
diabetes. Individuals following the Mediterranean diet also hypogonadal men with MetSyn are currently unknown. Indeed,
showed greater improvement in several CV risk factors [55]. a recent randomized study of testosterone dermal gel to assess
An epidemiological study of over 13 000 people found that leg strength which improved with testosterone was abandoned
those who followed a Mediterranean-style diet were less likely because of a greater number of cardiac adverse events in the
to develop new-onset diabetes. The benefits were especially testosterone group [61,62]. Routine testosterone replacement
pronounced in those who were at higher risk of developing in hypogonadal men with MetSyn cannot be recommended
T2D because of issues such as MetSyn, excess weight, family and further prospective studies evaluating the safety and clinical
history and blood pressure. Study participants with the best benefit of testosterone replacement are needed.
adherence to the Mediterranean dietary principles had >50%
decrease in the risk of developing diabetes during 4.4 years Therapies that may Worsen Diabetic Dyslipidaemia
follow-up [56].
Drugs commonly utilized for hormone replacement therapy
In summary, following the traditional Mediterranean-style
and hypertension may worsen hyperlipidemia. Hypertrigly-
diet results in a lower risk of developing T2D, better control
caeridemia, often at levels that may cause pancreatitis and
of blood glucose in individuals with T2D and a substantially
enough pancreatic damage to cause diabetes, is associated with
lower need to resort to glucose-lowering drug therapy. The
the utilization of oral postmenopausal estrogen replacement
Mediterranean-style diet has also been shown to improve
therapy in vulnerable individuals [63]. Drugs that increase
multiple CV risk factors.
insulin resistance not only result in an increase in triglycerides
but also a lowering of HDL levels and the development of
Principles of the Mediterranean Diet smaller more dense and more atherogenic LDL particles. Use of
• A high intake of fruits, vegetables, beans, nuts, seeds and thiazide diuretics, first and second generation β-blockers (but
cereal grains not vasodilating β-blockers such as carvedilol and nebivolol)
• Olive oil preferred for cooking and dressings increases insulin resistance and adversely affect the lipid profile
• Moderate amounts of fish and seafood but modest intake of of the insulin-resistant or diabetic patient. However, ethanol
meat and drugs such as blockers of the renin-angiotensin system
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6. review article DIABETES, OBESITY AND METABOLISM
(RAS), both of which reduce insulin resistance, have been daily achieved a 25% reduction in CV events. In PROVE-IT,
shown to increase total HDL (mainly smaller HDL particles) only 38% of diabetic patients achieved the combined goal of
and increase the LDL particle size [64]. The use of bile acid an LDL lesser than 70 mg/dl and an hsCRP level of lesser than
sequestrants (BASs) may induce hypertriglyceridaemia [65]. 2 mg/l, but if both these goals were achieved there was a further
However, with colesevelam it does not appear to cause signifi- reduction in CV events of 34% [74].
cant hypertriglyceridaemia [66]. In the JUPITER trial, where patients with diabetes were
excluded, 41% of the subjects had the clinical features of
MetSyn. With rosuvastatin 20 mg daily, a similar reduction in
Statin (HMG-CoA-Reductase Inhibitor) Therapy CV events was achieved in MetSyn subjects as was achieved in
in the Diabetic Patient non-MetSyn subjects [67]. In addition, subjects with impaired
Statins are recommended by the ADA as an addition to lifestyle fasting glucose had similar reductions in CV events with
therapy for all diabetic patients with CVD and for those without rosuvastatin as those with normal fasting glucose levels.
known CVD who are over the age of 40 and have an additional Importantly, the development of new T2D did not negate
CV risk factor (family history of heart disease, cigarette smoking the statin-conferred reduction in adverse CV events noted in
or hypertension) [50]. Even without risk factors, statins should those patients randomized to rosuvastatin in the JUPITER
be considered for those diabetic patients without known CVD trial [67].
who are under the age of 40 and who have a calculated LDL of There have been three large-blinded and placebo-controlled
over 100 mg/dl [50]. Statins mainly lower LDL levels but also studies with atorvastatin 10 mg daily, which have been
raise HDL levels and may increase LDL particle size. In addition, restricted to diabetic subjects. Neither the die deutsche diabetes
statins lower highly sensitive C-reactive protein (hsCRP) (a dialyse studies (4D) of hemodialysis patients with diabetes [75]
marker of inflammation which is strongly associated with the nor the atorvastatin for prevention of CHD endpoints in
MetSyn, diabetes and CV disease). non-insulin-dependent DM (ASPEN) [76] showed significant
In the diabetic patient, statins may worsen glycaemic control reductions in CV events because of the advance stages of
and in the prediabetic patient increase the risk of development atherosclerosis in these subjects. In contrast, the collaborative
of T2D. Rosuvastatin has, in the JUPITER trial [67], been shown atorvastatin diabetes study (CARDS) showed not only a
to increase both the HbA1c and the incidence of reported decrease in LDL and an increase in HDL, but also an increase
new-onset diabetes. Alternatively, in the West of Scotland in LDL particle size and a 37% reduction in CV events [77]
study [68] the incidence of diabetes was decreased by 30% with (figure 4).
pravastatin. A meta-analysis of mega trials suggested that, with Prior to the availability of statins, the POSCH study
the exception of pravastatin, the statins appear to modestly of subjects with familial hypercholesterolemia showed that
increase the risk of new diabetes (approximately by 9%), with the LDL level was significantly lowered by small bowel
simvastatin showing the highest risk [69]. A more recent meta- bypass surgery [78]. In spite of significant LDL lowering,
analysis showed that treating 255 patients with a statin for an improvement in CV events did not occur over the first
4 years would result in one extra case of diabetes [70]. Because 5 postsurgical years, but after 5 years positive differences in
in the JUPITER trial the HbA1c but not the fasting glucose was cardiac events began to appear and by 12 years these differences
increased [67], it is likely that statins (with the exception of became statistically significant with a 35% reduction. Because
pravastatin) increase postprandial glucose. Indeed, atorvastatin the protective effect of statins on cardiac events in most
has been shown to both increase insulin levels and HbA1c [69]. clinical trials begins to appear within 3–6 months, this earlier
Overall, the risk (6–13%) of developing diabetes with the use
of statin is not a major liability when compared with the potent
cardioprotective effects of statins, even in those who develop
new diabetes while on the statin [71].
Subgroup analyses of several major statin trials have
examined whether statins had as much of an effect on
improving CV outcomes in the diabetic patient compared with
the non-diabetic patient. In the Heart Protection study [72],
daily administration of 40 mg of simvastatin resulted in a
22% reduction of CV events in all diabetic subjects and in
diabetic subjects without known CVD a 33% reduction. A
meta-analysis of 14 statin trials which included 18 686 diabetic
subjects showed that with an average 39 mg/dl reduction in
LDL, over 4.3 years all-cause mortality was decreased by 9%
and major cardiac events by 21% [73].
Figure 4. The CARDS Trial, significant reduction in the primary endpoint
Subgroup analyses of major statin trials have also shown that
(acute CHD events, coronary revascularization or stroke). Atorvastatin also
achieving lower LDL levels in diabetic subjects was associated resulted in a 48% relative risk reduction for stroke, p = 0.016, and a 47%
with a greater lowering of CV events. In the pravastatin or relative risk reduction for non-fatal MI, p = 0.0178. CHD, coronary
atorvastatin evaluation and infection therapy (PROVE-IT) and heart disease; MI, myocardial infarction. Adapted with permission from
the TNT trials, diabetic subjects treated with atorvastatin 80 mg Ref. [77].
318 Bell et al. Volume 13 No. 4 April 2011

7. DIABETES, OBESITY AND METABOLISM review article
improvement cannot be related to LDL lowering and is Niacin
probably because of the pleiotropic effects of statins. The key components of diabetic dyslipidaemia are improved
The pleiotropic effects of statins include lowering of with niacin therapy with both LDL and triglyceride levels being
plasma viscosity, decreased generation of thrombin and lowered and both total HDL levels and HDL and LDL particle
decreased platelet aggregation [79]. Most importantly, statins sizes being increased. In addition, niacin (2 g/day) can lower
also decrease inflammation, both systemically and within the lipoprotein (a) levels by 25% [89–91]. In practice, the use of
atheromatous plaque [80]. The decrease in systemic inflamma- niacin is limited by its side effects, particularly that of cutaneous
tion lowers oxidative stress and improves endothelial function. flushing. This side effect is mediated through the interaction of
Within the atheromatous plaque a decrease in inflammation prostaglandin D2 with the DP1 receptor in the skin [92].
promotes a more stable fibrous plaque by reducing the elabo- The use of extended-release preparations and/or patient
ration of collagenases and metalloproteinase’s by white blood education may improve compliance. Taking an extended-
cells, thereby lowering the likelihood of plaque rupture. Statins release preparation with apple sauce or psyllium (metamucil)
also increase angiogenesis and the formation of collateral ves- and an aspirin can decrease the frequency and severity
sels and thus reduce ischaemia severity in the setting of acute of flushing. Combining niacin with laropiprant, a potent
and chronic coronary artery occlusions [81]. prostaglandin receptor antagonist, is a safe and promising
Subjects with diabetes and/or the MetSyn almost invari- option to improve patients’ tolerability of niacin [93] and is
ably have elevated hsCRP levels because excess macrophage- being tested in a large outcome-based clinical trial [94].
infiltrated peritoneal fat produces Interleukin 6 which stim- Another side effect of niacin is an increase in insulin
ulates hepatic production of CRP. In the setting of bacterial resistance, which is usually short-lived, so that over the long
infections, CRP is protective by adhering to the wall of the term the effect on glycaemic control is minimal. For example,
pneumococcus bacteria where it combined with complement in the arterial disease multiple intervention trial (ADMIT) [95]
to damage the bacterial cell membrane and activate the immune and the assessment of diabetes control and evaluation of the
system [82]. While CRP is beneficial during an acute infection, efficacy of niaspan trial (ADVENT) [96], niacin was utilized
chronically elevated CRP levels are detrimental, mainly because without significant long-term increases in glucose levels.
CRP binds to oxidized LDL particles. Therefore, when oxidized Niacin was utilized in the double-blind coronary drug
LDL levels are high, as occurs in both the diabetic and insulin- project (CDP) which was a study of men who had had an
resistant patients, CRP not only accelerates the growth of the MI and of whom 40% had impaired fasting glucose and/or
atheromatous plaque but also increases inflammation within impaired glucose tolerance [97]. In this study, while the primary
the atheroma and increases the risk of plaque rupture and CV endpoint of all-cause mortality was not significantly reduced
events. with niacin, after 6.2 years non-fatal MI was decreased by
Lowering of inflammation, with drugs other than statins, has 26% and transient ischemic attacks or strokes by 24%, in
been shown to decrease CV events, and decreasing inflamma- spite of a poor adherence due to troublesome side effects.
tion as a result of statin therapy has been associated with reduced However, 9 years after the termination of the study there was a
risks for some non-cardiac diseases. For example, the use of residual 10.2% decrease (58.2 vs. 52.0%) in all-cause mortality
methotrexate in patients with rheumatoid arthritis has been which was largely because of a decrease in death from CVD,
shown to decrease cardiac events by as much as 40–60% and suggesting that niacin therapy may have residual long-lasting
veterans admitted to hospital with septicemia have a higher sur- benefits [98].
vival rate if they have been taking a statin [83]. In the PROVE-IT While the use of niacin in the CDP study resulted in modest
study, lowering of LDL and hsCRP to goal were equally effective increases in both fasting and 1-h postprandial glucose levels,
in lowering cardiac events, and when both goals were achieved the need for initiation of insulin or the addition of an oral
the reduction in CV events was maximized [84]. In the PROVE- antidiabetic agent was no greater in the niacin group than it
IT, subjects with the higher CRP levels had all the characteristics was in the placebo group [97]. In addition, in those who did
of the MetSyn, i.e. higher levels of glucose, triglyceride and develop a fasting glucose of more than 126 mg/dl, there was a
blood pressures with a higher BMI and a lower HDL [85]. significant 57% reduction in MI after 6 years, which was similar
Therefore, in the type 2 diabetic patient where hsCRP is almost to those whose fasting glucose remained in ranges lesser than
invariably elevated, statins and doses of statins that maximally 126 mg/dl, suggesting that niacin may be even more effective
lower both LDL and hsCRP should be utilized. In the JUPITER in the insulin-resistant or diabetic subject, probably because
trial, those subjects on rosuvastatin who achieved LDL levels of niacin’s ability to elevate HDL levels. Therefore, in spite
<70 mg/dl and CRP levels <1.0 experienced a 79% reduction of poor compliance and short-term worsening of glycaemic
in adverse CV events during the randomized trial [67]. control, niacin significantly reduces cardiac events in both the
However, it may be that rather than being a treatment target, diabetic and insulin-resistant patients and thus should be used
CRP may simply be another risk factor that strengthens the more frequently utilized in these cohorts [99].
case for statin therapy. If indeed this is the case, then the use of
CRP is superfluous in a diabetic patient where statin therapy
is generally indicated regardless. Because of the expected high Fibrates
levels of inflammation and CV risk in diabetic patients, maximal Fibrates, through stimulating the activity of lipoprotein lipase,
statin therapy as utilized in the REVERSAL [86], TNT [87], reduce both triglyceride levels and the levels of the TRLs
PROVE-IT [88] and JUPITER [67] trials should be utilized. through decreased hepatic production of VLDL [100]. As a
Volume 13 No. 4 April 2011 doi:10.1111/j.1463-1326.2010.01342.x 319

8. review article DIABETES, OBESITY AND METABOLISM
result, there is an increase in HDL levels and an increase in LDL
particle size [101]. Other cardioprotective properties of fibrates
include the ability to lower hsCRP and inflammation [102].
This, in conjunction with an improvement in the level of the
atherogenic TRLs and HDL levels, might result in a reduction
in CV events.
The Helsinki Heart study [103] utilized gemfibrozil at a
dose of 1200 mg daily, in men who had a non-HDL-C level
of more than 200 mg/dl. The greatest lowering of cardiac
events occurred when the baseline triglyceride level exceeded
200 mg/dl and was accompanied by a low LDL-to-HDL
ratio. Compared with placebo, cardiac events were decreased
by 71% in this group who had all the characteristics of
the insulin resistance (metabolic) syndrome. The veterans
affairs high-density lipoprotein-cholesterol intervention trial
(VA-HIT) [104] also utilized gemfibrozil at a dose of 1200 mg
daily in men with known CVD, an HDL lesser than 40 mg/dl Figure 5. In the ACCORD lipid trial, fenofibrate did not significantly
and a calculated LDL lesser than 140 mg/dl. In a subgroup improve the primary outcome. Adapted with permission from Ref. [108].
analysis of the VA-HIT of those subjects with diabetes,
gemfibrozil reduced cardiac events by 32% and in those with
2.2 and 2.4 events per year, respectively, in the two treatment
insulin resistance (defined as non-diabetic subjects with an
arms (p-value 0.32). Also, there was no statistically significant
elevated fasting hyperinsulinemia) by 35% [105].
difference between the two treatments among the secondary
In prospective placebo-controlled studies of diabetic endpoints.
subjects, fibrates have been shown to be inconsistent in their
ability to decrease the progression of coronary atherosclerosis
and/or decrease cardiac events. With fenofibrate being Omega-3 Fatty Acids
administered in a dose of 200 mg daily, in the diabetes Omega-3 fatty acids at high doses, 3–5 g of eicosapentanoic
atherosclerosis intervention study (DIAS) [106] there was, acid (EPA) + docasahexanoic acid (DHA) per day, effectively
after 3 years, significantly less progression of coronary artery lower triglyceride levels [109], while concurrently increasing
disease as measured by the minimal coronary artery lumen calculated LDL levels which is probably because of an increase in
diameter. In the DIAS study, however, the primary endpoint of particle size rather than an increase in particle numbers [110].
a decrease in mean segment diameter did not reach statistical The decrease in mortality that has been shown with omega-
significance. Similarly, in the fenofibrate intervention and event 3 fats appears to be in part because of an antiarrhythmic
lowering in diabetes (FIELD) study [107], daily administration effect. Recently, omega-3 fats have also been shown to
of 200 mg fenofibrate did not significantly change the primary decelerate telomere shortening which is a marker of biological
endpoint of non-fatal MI or death related to CHD. However, aging [111].
in the FIELD study, there was a significant 24% reduction In diabetic subjects, daily administration of 3.6 g of
in non-fatal MI and a significant 11% decrease in CV EPA + DHA has been shown to decrease triglyceride levels
events as well as improvements in albuminuria and diabetic by 28%, increase HDL levels by 7% and not to have an
retinopathy as was later documented with fenofibrate in the effect on ApoB or LDL-concentrations in spite of decreases in
ACCORD study of type 2 diabetic subjects. Fenofibrate also the ApoB component of VLDL and an increased conversion
non-significantly increased total mortality, mortality related to of VLDL to LDL [112]. In the COMBOS trial, the use of
coronary artery disease and the incidence of acute pancreatitis omega-3 fats (3.6 g of EPA + DHA) was tested in subjects
and pulmonary embolism. The FIELD study was confounded with hypertriglyceridaemia. In this randomized trial, the
by a greater use of statins in the placebo group which may non-HDL-C was decreased by an additional 9% when omega-3
account for the less than expected improvement in CV events. fats were added to simvastatin 40 mg compared with 2.2%
Again, the greatest CV benefit of fenofibrate was seen in patients when placebo was added to 40 mg of simvastatin daily [113].
who had the characteristic lipid profile (high triglyceride and In addition, triglycerides were lowered by 30% with the
low HDL) of the MetSyn. combination compared to 6% with simvastatin alone and
In the action to control cardiovascular risk in diabetes HDL-C was increased by 3.4% with the combination.
(ACCORD) trial [108], the investigators examined the effects A subgroup analysis of the Gruppo Italiano per lo Studio
of combination lipid therapy in 5518 patients with T2D. The della Infarto Miocardico (GISSI-Prevenzione) showed that
addition of fenofibrate to simvastatin vs. simvastatin plus total mortality was decreased by 28% with 1 g of omega-3
placebo did not reduce the risk CV events (fatal CV events, fats in diabetic subjects which compared favorably with non-
non-fatal MI or non-fatal stroke) (figure 5). There was a trend diabetic subjects where omega-3 fats decreased mortality by
towards the benefit of fenofibrate in the cohort of patients with 18% [114]. In another subgroup analysis from the Japan
high triglyceride and low HDL levels. After a mean follow-up EPA lipid intervention study (JELIS), subjects who had the
of 4.7 years, the annualized rates of the primary endpoint were characteristics of the MetSyn (defined as a high triglyceride
320 Bell et al. Volume 13 No. 4 April 2011

9. DIABETES, OBESITY AND METABOLISM review article
LDL levels, BASs, at least in one trial, may be equally effective
at lowering cardiac events. This is because for every 1% the
LDL is lowered by a statin there is a 1% lowering of car-
diac events, whereas for every 1% the LDL is lowered with
a BAS there is a 2% decrease in cardiac events [119]. Addi-
tional advantages of BASs are their beneficial effects on glucose
metabolism (improvement in fasting, postprandial glucose
as well as HbA1c) and reductions in systemic inflammation
(BASs lower CRP by about 20–25%). Because many statins
may modestly increase the risk of new T2D, the combina-
tion of a well-tolerated BAS such as colesevelam and a statin
could potentially prevent the development of diabetes in those
who are at the highest risk (subjects with the MetSyn or
prediabetes) and improve glycaemic control in subjects with
Figure 6. In the JELIS trial, supplementation with omega-3 fatty acids established diabetes [69]. In the setting of T2D, colesevelam at
reduced the primary endpoint of major coronary events particularly well
a daily dose of 3.75 g has been shown to lower the HbA1c by
in those patients with impaired glucose metabolism (IGM) as compared
to those with normal glucose (NG) levels. Adapted with permission from
0.5% and the postprandial glucose by 32 mg/day [120], mak-
Ref. [116]. ing colesevelam a logical add-on to statin therapy in diabetic
patients [69].
to HDL ratio) had a 71% increased risk of a CV event
which was decreased by 53% with the daily combination of Ezetimibe
EPA (1800 mg) and a statin [115,116] (figure 6). In addition,
Another lipid-lowering agent, ezetimibe, acts at the brush
even with the lower daily intake of 250 mg of omega-3 fats
border of the small intestine by blocking the absorption of both
daily, diabetic subjects showed a 17% reduction in mortality
dietary and biliary cholesterol and plant sterols. Consequently,
and a 36% reduction in mortality related to coronary artery
this leads to the depletion of intracellular cholesterol and
disease [116].
increased clearance of circulating LDL by the liver, resulting in
In addition, to their beneficial effects on lipid levels, omega-
the reduction of both LDL and total cholesterol levels [121].
3 fats have other non-LDL-dependent benefits, including
However, no data currently exist to document that ezetimibe
reduced heart rate and blood pressure and antithrombotic
(despite its beneficial effects on LDL levels) reduces CV events
effects which protect against ischemic stroke and non-fatal MI.
or atherosclerosis progression in the overall population or in
However, the most important cardioprotective effect of omega-
diabetic or insulin-resistant subjects.
3 fats may be their antiarrhythmic properties, protecting from
both atrial and ventricular fibrillation, the incidences of which
are increased in the diabetic patient [117]. Combination Therapies
Often, to achieve goals in the diabetic patient, combinations of
Bile Acid Sequestrants different lipid-lowering agents with different modes of action
Historically, BASs have been used where statins are not need to be utilized. Better results can usually be obtained by
tolerated or untested and/or associated with safety concerns adding a BASs, omega-3 fats or niacin to a statin rather than
(fertile women and children). These agents have a non- by increasing the dose of the statin, because doubling of the
systemic action; BASs are not absorbed out of the lumen dose of statin only results in a further 6% reduction in the
of the intestine. They work to lower cholesterol, by decreasing LDL. The combination of a statin with omega-3 or niacin will
the reabsorption of bile acids resulting in a compensatory also result in a greater increase in HDL-C levels and more
increase in the hepatic production of bile acids, decreasing robust decreases in triglycerides and non-HDL-C levels. The
intracellular cholesterol and increasing the utilization of potential for adverse events is increased when gemfibrozil and
cholesterol and depletion of the LDL pool. However, BASs to a lesser extent other fibrates are utilized with a statin because
can also increase triglyceride levels, cause gastrointestinal the combination of a statin and a fibrate increases the risk of
symptoms (particularly constipation) and are associated with myalgias, myositis and rhabdomyolysis.
an increased prevalence of cholelithiasis. A more modern A secondary analysis of diabetic subjects in the SANDS trial,
BAS, colesevelam, has been chemically altered to improve the where the goals for LDL were less than 100 mg/dl or 70 mg/dl
relative affinity of binding of bile acids and thus has a much and goals for non-HDL-C lesser than 100 or 130 mg/dl, showed
lower incidence of these side effects [66,118]. While it carries that irrespective of whether these goals were reached with a
a warning of induction of severe hypertriglyceridaemia, this is high statin dose or the combination of a statin with ezetimibe
generally only an issue for patients with elevated triglycerides or fenofibrate, those subjects with the lower goals had a
at baseline [66,118]. statistically significantly greater decrease in the CIMT [122].
BASs are considered as second-line therapy for lowering As detailed above, in the ACCORD study, the effect of a
LDL levels and are most commonly utilized in combination combination of a statin and fenofibrate did not improve CV
therapy. While not as potent as statins in the lowering of outcome [123].
Volume 13 No. 4 April 2011 doi:10.1111/j.1463-1326.2010.01342.x 321

10. review article DIABETES, OBESITY AND METABOLISM
Conclusions treatment of high blood cholesterol in adults (adult treatment panel III).
JAMA 2001; 285: 2486–2497.
In this article, we emphasize that the correction of diabetic dys-
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that may also have a beneficial effect on dyslipidaemia. Lifestyle 319–324.
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Conflict of Interest 21: 312–318.
All authors contributed to the entire writing of the manuscript, 18. Cui Y, Blumenthal RS, Flaws JA et al. Non-high-density lipoprotein
corrections and updates. cholesterol level as a predictor of cardiovascular disease mortality.
J. H. O. is the speaker for AstraZeneca, GlaxoSmithKline, Arch Intern Med 2001; 161: 1413–1419.
Takeda and Merck. F. A. B. has nothing to declare and D. S. 19. Lu W, Resnick HE, Jablonski KA et al. Non-HDL cholesterol as a predictor
H. B. is the consultant and speaker for Bristol Myers-Squibb, of cardiovascular disease in type 2 diabetes: the strong heart study.
AstraZeneca, Novo Nordisk and Takeda. Diabet Care 2003; 26: 16–23.
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