Review

Potential Drug Combinations

to Reduce Cardiovascular
Disease Burden in Diabetes
Sivaram Pillarisetti1,2,*
The major cause of death and complications in patients with type 2 diabetes
Trends
(T2DM) is cardiovascular disease (CVD). More than 60% of all patients with
Lowering plasma TG or increasing
T2DM die of CVD, and an even greater percentage have serious complications. high-density lipoprotein (HDL) do not
The impact of glucose lowering on cardiovascular complications is a hotly seem to offer benefits above the stan-
dard of care in diabetics.
debated issue and recent large clinical trials reported no significant decrease
in cardiovascular events with intensive glucose control. Risk remains high even Therapeutic targets that prevent glu-
after correcting diabetes-associated dyslipidemia with drugs such as fibrates cose and lipid absorption appear to
be promising in reducing CVD burden
and niacin. Data from several clinical studies show that postprandial glucose in patients with diabetes.
and lipids have a strong predictive value on myocardial infarction (MI) and
Emerging data suggest that mechan-
mortality. However, strategies to reduce postprandial hyperglycemia and/or
isms that promote glucose removal
lipemia through increased utilization of glucose and/or triglycerides (TG) have through the kidney appear to show
been shown to not be effective in reducing the CVD burden. In this review, I cardiovascular and mortality benefits
in patients with diabetes.
discus the preferred ways to reduce postprandial glucose and TG with combi-
nations of currently marketed drugs with potential benefit in CVD. Reducing sustained vascular stress
under postprandial conditions is a pro-
mising therapeutic approach to reduce
Diabetes and CVD cardiovascular disease burden in
Adults with T2DM are two to four times more likely to have heart disease or a stroke than adults patients with diabetes.

without diabetes, and approximately 65% of patients with T2DM will die from CVD [1]. Risk of MI,
stroke, microvascular events, and mortality are all strongly associated with hyperglycemia
[hemoglobin A1c (HbA1c)] and epidemiologic analyses suggest that each 1% increase in HbA1c
increases the risk for CVD by approximately 18% [2]. In addition to hyperglycemia, patients with
T2DM often present with additional risk factors that predispose them to CVD. These include
insulin resistance, obesity, hypertension, and dyslipidemia. Although patients with diabetes in
general do not have high low-density lipoprotein (LDL), the results of statin trials support the
importance of the intensive control of LDL in patients with T2DM [3]. However, CVD remains high
and the event rates in the statin-treated subgroups of patients with diabetes are generally higher
than those in the treated subgroups of patients without diabetes.

Although HbA1c levels are strongly associated with CVD, it is not clear whether hyperglycemia
per se promotes CVD. While trials such as the Diabetes Control and Complications Trial (DCCT)
and UK Prospective Diabetes Study (UKPDS) showed that tight control of blood glucose
reduces the development of the microvascular disease (nephropathy and retinopathy) [4,5], 1
Kareus Therapeutics SA, La Chaux-
the relations between blood glucose control, cardiovascular events, and all-cause mortality are de-Fonds, Switzerland
controversial. While The Veterans Affairs Diabetes Trial (VADT) showed no significant effect of 2
NeuroPn Therapeutics, GA,
intensive glucose control on cardiovascular outcomes [6], intense glucose lowering in the Action Alpharetta, USA

to Control Cardiovascular Risk in Diabetes (ACCORD) trial showed an unexpected increase in

all-cause mortality [7]. What is also interesting is that intensive multifactorial risk factor manage- *Correspondence: pillarisetti@live.com
ment (i.e., lifestyle interventions, blood glucose, blood pressure, and cholesterol control, as well (S. Pillarisetti).

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as the prescription of daily low-dose aspirin) also does not seem to significantly reduce the risk of
first, second, or third cardiovascular events, compared with standard diabetes care, according
to a subanalysis of the ADDITION-Europe trial [8]. A Cochrane systematic review [9] of intensive
glycemic control versus conventional glycemic control involving 20 randomized clinical trials that
included 29 986 participants with T2DM did not show significant differences for all-cause
mortality and cardiovascular mortality. Similarly, another analysis that included 13 studies
and 34 533 patients showed no significant benefits of intensive glucose-lowering treatment
on all-cause mortality and deaths from cardiovascular causes [10].

The experience was similar with lipid trials, in that several recent trials addressing diabetic
dyslipidemia (high TG and low high-density lipoprotein; HDL) also did not show encouraging
data. Fibrates (gemfibrozil and fenofibrate) belong to a class of drugs that exert their effects by
activating peroxisome proliferator-activated receptor (PPAR)-/. These drugs reduce the
concentration of plasma TG by 30–50% and raise the level of HDL cholesterol (HDL-C) by
2–20%. In earlier trials, such as the Veterans Affairs High-Density Lipoprotein Intervention Trial
(VA-HIT) and Helsinki heart study, subgroup analysis showed that, in men with coronary heart
disease (CHD) and a low HDL, gemfibrozil use was associated with a reduction in major
cardiovascular events in persons with diabetes and in nondiabetic subjects with a high fasting
plasma insulin level [11,12]. However, more recent trial data (FIELD and ACCORD trials) show
no benefit of dyslipidemia treatment on CVD in patients with diabetes [13,14]. In the ACCORD-
Lipid trial involving 5518 patients over 4.7 years, fenofibrate treatment showed no significant
benefit on total cardiovascular events or mortality. As a result, information from the trial was
added to the physician label and patient medication guide for fenofibrate, which is currently
marketed in the USA as Trilipix. In the AIM-HIGH trial [15], which involved 3414 patients
(approximately 30% of whom had diabetes), adding niacin (1500–2000 mg/day) had no
beneficial effect over simvastatin therapy alone despite significant improvements in TG and
HDL. Moreover, there was a trend toward increased risk of ischemic stroke in the niacin-treated
group. Thus, it is inconclusive whether treating dyslipidemia will reduce CVD in patients with
diabetes.

Postprandial Phenomena
It is clear that addressing fasting plasma glucose (FPG), or dyslipidemia did not provide
convincing evidence for CVD protection. In this review, I focus on postprandial glycemia and
lipemia and discuss their relation to CVD and ways to reduce the postprandial burden.

Postprandial Glucose
The phenomenon of postprandial glucose (PPG) was addressed in detail by Schrot [16].
Postprandial hyperglycemia is one of the earliest abnormalities observed in patients with
T2DM and is defined as a plasma glucose level exceeding 7.8 mM glucose (140 mg/dl).
Changes in PPG, as determined by a 2-h glucose tolerance test (GTT), often precede FPG
changes in the natural history of T2DM. Studies showed that PPG elevations ( > 200 mg/dl)
occurred in approximately 39% of patients whose HbA1c levels were optimal ( < 7%) [17,18]. In
patients using oral agents, PPG elevation occurred in 63% of those with HbA1c < 7%. In
patients with normal or near-normal FPG and a HbA1c that remained high, the 2-h PPG
becomes a good index of glycemic control. Thus, PPG elevation is a frequent finding even
when HbA1c goals are achieved [19]. Controlling PPG at this point would likely lead to a
reduction in HbA1c to further below 7%.

Elevated PPG has long been considered an independent risk factor for CVD and death [20–24].
Earlier studies that used 1-h post-meal numbers predicted a relation between PPG and CVD. A
study involving Hawaiian Japanese subjects showed that death from all causes, CVD, and
coronary heart disease were significantly higher in men with glucose intolerance [25]. Similarly,

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the Chicago Peoples Gas Company study, which also looked at 1-h glucose levels, found a
significant relation between asymptomatic hyperglycemia on repeat examinations and coronary
and cardiovascular mortality, independent of other factors [26]. The predictive power of PPG on
cardiovascular events was also investigated in the Diabetes Intervention Study (DIS [27]). The
DIS study was carried out in relatively young patients with newly diagnosed T2DM who were
followed for 11 years. It focused only on PPG and did not consider HbA1c; results showed that
PPG predicted MI and mortality. The first strong evidence between PPG and CVD came from the
DECODE study, which analyzed data from 13 prospective European cohort studies that
included 18 048 men, 7316 of whom were followed for 7.3 years [20]. This study used 2-h
post-glucose numbers as per WHO criteria. This analysis showed that a high blood glucose
concentration 2 h after glucose load was associated with an increased risk of death, indepen-
dently of fasting blood glucose, and that fasting blood glucose was not as satisfactory as 2-h
blood glucose for the prediction of mortality. The most recent study that further highlights the
importance of PPG in CVD is the San Luigi Gonzaga Diabetes Study [28]. This study examined
the relation between cardiovascular events and HbA1c and blood glucose measured: (i) after an
overnight fast; (ii) after breakfast; (iii) after lunch; and (iv) before dinner. The study found that PPG,
but not FBG, is an independent risk factor for cardiovascular events in patients with T2DM, with a
stronger predictive power in women than in men. A long-term follow-up of this study further
confirmed these findings [29].

Several factors may contribute to impaired PPG in diabetes (Figure 1) [30–33]. The most
important of these may be insulin resistance and impaired glucagon production, which may
also contribute to one another. Insulin resistance is characterized by the inability of insulin to

Insulin resistant

Glucagon
Adipose
Liver Muscle

Pancreas

(D)

(B,C) (E)

Glucose Prolonged PPG under an

Insulin
insulin-resistant state
(A)
(F)

Intesne Vascular endothelium

Kidney

Figure 1. Postprandial Glycemia (PPG): Causes and Different Classes of Drugs That Are Known to Reduce
PPG. Insulin resistance develops in multiple tissues under increased energy intake, leading to reduced glucose disposal
and increased insulin secretion. Pancreas may also produce excess glucagon, which in turn affects glucose output from
liver. The vascular endothelium is exposed to elevated glucose and insulin, leading to vascular inflammation, oxidative
stress, and atherosclerosis. Drugs that affect PPG are shown in purple boxes: (A) /-glycosidase inhibitors (acarbose and
miglitol) reduce glucose absorption; (B) agents that enhance pancreatic insulin secretion via glucose-independent (e.g.,
sulfonylureas) or dependent [glucogen-like peptide 1 (GLP-1) agonists and dipeptidyl peptidase 4 (DPP4) inhibitors)
mechanisms; (C) biguanides (metformin) reduce liver glucose output; (D) thiazolidinediones (TZDs; pioglitazone, and
rosiglitazone) enhance glucose uptake in adipose; and (E) sodium-glucose cotransporter type 2 (SGLT2) inhibitors promote
glucose clearance through kidney. Although (D) and (E) are effective in reducing fasting plasma glucose, they have a weaker
effect on PPG compared with (A–C).

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activate its tyrosine kinase receptor and downstream signaling pathways that regulate glucose
disposal and lipid metabolism in target tissues. Multiple prospective studies have documented
an association between insulin resistance and accelerated CVD in patients with T2DM, as well as
in nondiabetic individuals [34,35]. For a long time, abnormalities in glucagon secretion from
pancreatic / cells have been implicated in the development of fasting and postprandial
hyperglycemia in T2DM [36]. In the fasting state, inappropriately high plasma glucagon levels
have been observed in patients with impaired glucose tolerance and T2DM [37,38]. In the
postprandial state, the decrease in plasma glucagon concentrations after a glucose load is less
pronounced in these patients than in healthy subjects. These abnormalities in pancreatic / cell
function are evident several years before the diagnosis of impaired glucose tolerance. Several
mechanisms [37,38] have been proposed to explain these alterations in glucagon kinetics, such
as insulin resistance at the level of pancreatic / cells, / cell desensitization by prolonged
hyperglycemia, and postprandial lipemia (PPL). Elevated glucagon in turn may contribute to
abnormalities in postprandial lipids [39].

Postprandial Lipemia
PPL represents the state of lipid metabolism between food intake and the postabsorptive state
(Figure 2) [40–42]. Dietary fat is absorbed mainly as free fatty acids (FFA), which are packaged
into large TG-rich particles (TRL) together with apo B48, a truncated form of apo B synthesized in
the intestinal cells and secreted into the bloodstream as chylomicrons. Two enzymes, lipoprotein

Adipose
Liver

(C,D)

(E)
FFA
Lipolysis
VLDL
B48-chilomicrons
Prolonged PPL

(A,B) Lipolysis
LPL
Vascular endothelium
Intesne

FFA

Heart

Figure 2. Postprandial Lipemia (PPL): Causes and Different Classes of Drug That Are Known to Reduce PPL.
At least three factors contribute to abnormal PPL in diabetics: (i) increased intestinal production of apoB48 particles; (ii)
increased very low-density lipoprotein (VLDL) production by liver, which may be due in part to the release of free fatty acids
(FFAs) from adipose tissue, which drives the production of triglycerides in the liver; and (iii) decreased lipoprotein lipase
(LPL)-mediated lipolysis and/or clearance in circulation. Although overall lipolysis rates are reduced in diabetes, because
glucose uptake and oxidation are impaired, LPL lipolysis is increased in heart and the heart is compelled to use fatty acids
exclusively for ATP generation. Drugs that affect PPL are shown in purple boxes: (A,B) drugs that inhibit triglyceride
absorption (e.g., orlistat) or cholesterol absorption (ezetimibe) reduce lipoprotein secretion from the gut; (C,D) drugs such as
fibrates inhibit the secretion of triglycerides from the liver and stimulate the clearance of triglycerides by activating LPL; and
(E) niacin has two mechanisms by which it reduces triglyceride levels. It blocks the release of FFAs from adipose tissue,
which also results in a reduced rate of secretion of VLDL particles.

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lipase (LPL) and hepatic lipase (HL), regulate the lipolytic rate of TRLs. LPL hydrolyzes the TG in
chylomicrons to FAs, which are taken either by muscle cells for oxidation or by adipocytes for
storage. FAs are also a major source of energy for heart. LPL is synthesized primarily by
adipocytes and myocytes and is transferred to the luminal side of the capillary endothelial cells
[43]. PPL is a normal physiological phenomenon that reflects the aforementioned metabolic
pathway. The postprandial alterations in TG and lipoprotein metabolism are transitory; however,
postprandial alterations are abnormal in patients with T2DM [40], resulting in exaggerated
magnitude and duration of TRL response after a fatty meal, which results in the accumulation
of TRLs and their remnants in the circulation. At least three factors contribute to abnormal
postprandial lipemia in patients with diabetes: (i) increased intestinal production of apoB48
particles; (ii) increased very LDL (VLDL) production by liver; and (iii) decreased lipolysis and/or
clearance in circulation. Although overall lipolysis rates are reduced in diabetes, because glucose
uptake and oxidation are impaired, LPL lipolysis is increased in heart and the heart is compelled
to use FAs exclusively for ATP generation [44]. Zilversmit [45] was the first to propose the
possibility that PPL has an important role in the pathogenesis of chronic heart disease (CHD),
and later studies provided substantial support for this hypothesis [46–48]. Two prospective
population cohorts, Women's Health Study [49] and Copenhagen City Heart Study [50],
reported that elevated nonfasting TG rather than fasting TG is associated with cardiovascular
events independent of conventional cardiovascular risk factors. Furthermore, the incremental
area under the response curve (AUC) rather than fasting TG or total TG AUC accurately
described the TG response to an oral fat load in both healthy subjects and those with T2DM.

Reducing the Postprandial Burden: Limitations and Advantages of Current

Drugs
PPL alone or together with PPG can cause significant damage to the vascular wall. As discussed
above, there is a large body of evidence correlating PPG and PPL with CVD. There are several
studies on the potential mechanisms by which elevated glucose and FAs can contribute to
endothelial dysfunction, inflammation, insulin resistance, and atherosclerosis, the underlying
cause of CVD [51–56]. It should be noted that insulin resistance, which precedes diabetes, is
considered to be a way for the organism to handle a great imbalance in energy intake versus
energy expenditure. The initial response to such an imbalance is to store excess energy in the
form of fat, resulting in fat and/or weight gain. However, if the imbalance continues, the system
turns off insulin-signaling pathways, leading to insulin resistance and hyperinsulinemia. If energy
influx continues, a sustained postprandial phenomena ensues, resulting in a situation where
vascular endothelium is exposed to hyperglycemia, hypertriglyceridemia, and hyperinsulinemia
(Figures 1 and 2), creating a constant insult to vascular endothelium.

Drugs that Reduce PPG/PPL without CV Benefits or with Adverse CV Effects

Most current drugs try to overcome PPG by bringing more insulin to the system or by targeting
excess glucose to adipose (the exhausted original body defense). As discussed in this review,
data on the cardiovascular safety of these agents so far has been discouraging. The reader is
referred to two recent reviews on currently marketed drugs [57,58].

Sulfonylureas
The sulfonylureas (glyburide, glipizide, and glimepiride) and glinides (repaglinide and nateglinide)
stimulate insulin secretion from pancreatic b cells and are one of the most effective drugs in
reducing PPG. The main adverse effects of these drugs are hypoglycemia and weight gain. First
insights into the potential adverse effects of sulfonylureas came from the University Group
Diabetes Program (UGDP) study, which showed that patients treated with the sulfonylurea
tolbutamide experienced excess cardiac deaths compared with placebo or insulin treatments
[59]. Compared with metformin, glipizide treatment was associated with a significant increase in
nonfatal cardiovascular events and death [60]. Glibenclamide was shown to be harmful to

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patients with diabetes and CVD; thus, such patients are suggested to avoid this drug. A meta-
analysis of 72 randomized controlled trials involving sulfonylurea monotherapy for 24 weeks or
more in patients with T2DM found that all-cause mortality, cardiovascular mortality, and a
composite of MI, stroke, and cardiovascular mortality were increased in patients treated with
glibenclamide, glipizide, and tolbutamide [61]. In the Left Ventricular Dysfunction in Type 2
Diabetes Mellitus (DYDA) study, repaglinide therapy was found to be an independent predictor of
left ventricular dysfunction [62]. In summary, although all secretagogs may not have similar
adverse effects, it is unclear whether any of them have significant protective effects.

Glucagon-Like Peptide 1 Agonists and Dipeptidyl Peptidase 4 inhibitors

Glucagon-like peptide 1 (GLP-1) is an enteroendocrine peptide that induces insulin secretion in
response to elevated plasma glucose. Given that GLP-1 promotes insulin secretion from pancreas,
GLP-1 agonists are, similar to sulfonylureas, effective in reducing postprandial glycemia. While
exenatide, exenatide extended-release, liraglutide, and albiglutide are analogs of GLP-1, dipeptidyl
peptidase 4 (DPP-4) inhibitors inhibit endogenous GLP-1 degradation. Although several preclinical
studies suggest that GLP-1 has positive effects on certain cardiovascular parameters independent
of the effects on plasma glucose [63], data from different trials [EXAMINE (alogliptin), SAVOR-TIMI
(saxagliptin) and TECOS (sitagliptin)] examining the effects of DPP-4 inhibitors neither reduced nor
increased the risk of major cardiovascular events compared with placebo [64–66]. Moreover,
saxagliptin treatment was associated with an increased risk for hospitalization for heart failure.
Other major long-term prospective clinical trials involving other DPP-4 inhibitors are currently
underway to determine their effects on cardiovascular risk (e.g., CAROLINA with linagliptin).
Results from these studies will hopefully further elucidate the cardiovascular safety of DPP-4
inhibitors in patients with diabetes. While meta-analysis of albiglutide trials revealed no significant
effect on cardiovascular events in placebo versus albiglutide, a retrospective database review of
exenatide trials showed a 20% decrease in CVD risk [67–69]. Liraglutide is currently being
evaluated in the Liraglutide Effect and Action in Diabetes: Evaluation of cardiovascular outcome
Results (LEADER) trial to assess its cardiovascular safety.

Thiazolidinediones
Pioglitazone and rosiglitazone, which are the only insulin sensitizers in the market, exert their
metabolic effects via activation of PPARg. They target excess plasma glucose to adipose and
also lower TG by increasing LPL mass and activity. Thus, they have an effect on both PPG and
PPL. Thiazolidinediones (TZDs) have had their ups and downs with respect to clarity on safety.
Initial meta-analysis studies suggested an increased cardiovascular risk with rosiglitazone, which
was called into question by subsequent studies [70,71]. Based on these studies, the US FDA
ultimately lifted some of the restrictions it had imposed on rosiglitazone. In the large prospective
study (PROactive) involving 5238 patients with diabetes, pioglitazone increased the incidence of
serious congestive heart failure [72]. PPARg is expressed in human heart, and its activation in the
heart by TZDs triggers abnormal accumulation of intracellular lipids that may in part contribute to
heart failure [73,74]. Pioglitazone did not significantly affect the composite primary endpoint
(mortality, nonfatal MI, silent MI, stroke, acute coronary syndrome and leg revascularization) in
the PROactive trial; however, subsequent meta-analysis of all trials involving pioglitazone
suggested a 25% decrease in the incidence of CVD with pioglitazone. From a mechanistic
standpoint, targeting excess energy to adipose should give an overall protective effect. How-
ever, the effects of TZD in heart may in part negate their otherwise beneficial effects. It should
also be noted that TZD treatment is associated with a modest but clinically significant increase in
the risk of bladder cancer related to PPARg activation in the target tissue [75].

Fibrates and Niacin

Both fibrates and niacin are effective in reducing fasting TG as well as postprandial TG. Fibrates
exert their metabolic effects via activation of PPAR/. Fibrates stimulate LPL activity by lipolysis of

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TG in lipoproteins. While the net effect is lowering of TG, endothelium is constantly exposed to
lipolysis products, which compromise barrier function and induce inflammation in endothelial
cells [53–56]. PPAR/ is expressed in the insulin-resistant and diabetic heart [76,77]. Activation
of PPAR/ in the heart exhibited a phenotype similar to that of the human diabetic heart (i.e.,
ventricular dysfunction associated with increased FA uptake and oxidation, myocyte TG depo-
sition, and reduced glucose utilization), which was further exacerbated by a high-fat diet [78]. In
both the FIELD and ACCORD lipid trials, fenofibrate significantly lowered TG as well as PPL.
However, as discussed above, this did not translate into benefits on overall cardiovascular end
points or mortality.

The molecular mechanism by which niacin shows its lipid-lowering effects is mostly unknown
[79]. The niacin receptor HCA2 (GPR109A) on adipose tissue has been shown to have an
important role in acute anti-lipolytic effects, but is not required for the long-term lipid-lowering
effects. By inhibiting lipolysis, niacin reduces FFA release from adipocytes, thus making less
substrate available for VLDL-TG production in the liver. Niacin is the only drug in the market that
favorably affects all lipoproteins (i.e., lower LDL, TG, lipoprotein a, and increased HDL). Con-
sidering such effects, it is hard to understand why the two cardiovascular outcome trials with
niacin [Atherothrombosis Intervention in Metabolic Syndrome with Low HDL/High Triglycerides
(AIM-HIGH) and Impact on Global Health trial and HPS2-THRIVE] were both negative [80]. It
should be noted that several large studies suggest minimal to modest long-term effects of niacin
on blood glucose levels in patients with T2DM [80]. This was evident in earlier phases of the study
and then returned toward baseline, suggesting titration of medication would control the negative
effects of niacin on plasma glucose. Considering the lack of protective effect on CVD, it may be ill
advised to prescribe niacin for patients with diabetes.

From the above discussion, it is clear that pathways that enhance glucose and/or lipid utilization,
although they reduce the postprandial burden, may in the process subject vascular endothelium
to sustained insults. I believe that the optimal way to address PPL and/or PPG is to reduce their
influx into the blood either by slowing and/or blocking their absorption or inhibiting endogenous
production, or rapidly removing them from bloodstream without increasing tissue uptake and/or
utilization. This would be the ideal way to address the imbalance in energy intake and utilization.
Pathways that can be addressed with current drugs are presented in Figure 3.

Pathways Targeting the Gut

Alpha-glucosidase inhibitors
The alpha-glucosidase inhibitors (AGIs) acarbose and miglitol inhibit alpha-glucosidase in the
proximal small bowel and prevent complex carbohydrate digestion, resulting in reduced post-
prandial hyperglycemia [57]. There are no long-term studies examining the effect of AGIs on
CVD. The Study to Prevent Non-Insulin Dependent Diabetes Mellitus (STOP-NIDDM, with 1429
subjects) showed a 49% reduction of cardiovascular events, as well as a 36% risk reduction of
developing T2DM [81]. However, the total number of events was small, and the study was not
powered to draw any conclusion about CVD protection. The Acarbose Cardiovascular Evalua-
tion (ACE) trial is a secondary-prevention trial that is currently underway to assess the CV effects
of acarbose [82]. Overall, acarbose seems to be a reasonable agent for reducing CVD risk in
addition to lowering HbA1c levels in patients with diabetes.

Ezetimibe
Ezetimibe is an inhibitor of Niemann-Pick C1-Like 1 (NPC1L1) in the intestine and prevents
cholesterol absorption and lowers plasma cholesterol and LDL [83]. Ezetimibe decreases LDL
by approximately 20% and also improves both hypertriglyceridemia and HDL levels. Several
preclinical and clinical studies suggest that ezetimibe, by inhibiting cholesterol absorption, also
affects PPL and PPG in normal and insulin-resistant conditions [84–88]. Ezetimibe significantly

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 Liver Figure 3. Preferred Approaches to
Reduce Postprandial Elevations of
Glucose and Lipids. (A,B) Reduce glu-
cose absorption by /-glucosidase inhibi-
tors (acarbose and miglitol); (C) inhibit
(C) endogenous glucose production (metfor-
min); (D) remove glucose through kidney
(A,B) [sodium-glucose cotransporter type 2
(SGLT2) inhibitors]; and (E,F) reduce fat
and cholesterol absorption (orlistat or eze-
Glucose timibe). Such mechanisms reduce the
postprandial burden on vascular endothe-
lium and reduce the incidence of
(D) atherosclerosis.
Lipids
Kidney
(E,F)
Intesne

Less vascular stress

Atherosclerosis

decreased 4-h and 6-h TG after a high-fat and high-glucose meal. Similar results were also seen
in patients with diabetes, where ezetimibe treatment was associated with significant decrease in
postprandial chylomicron particles. Ezetimibe appears to modulate the expression of different
proteins in intestinal cells and blocks both the absorption of cholesterol and the intracellular
trafficking and metabolism of long-chain FAs in enterocytes, resulting in the reduction of the
formation of ApoB-48 particles [89,90]. Thus, ezetimibe is suggested to not only improve
circulating lipid levels, but also modify glucose and fat metabolism by alleviating various PPL
abnormalities and improving insulin sensitivity. The cardiovascular safety of ezetimibe has been
studied in multiple trials [91]. Although initial studies cast doubt on whether ezetimibe offers any
cardiovascular protection over statins, more recent clinical trials show protection from cardio-
vascular events with ezetimibe. The results of IMPROVE-IT were first presented at the American
Heart Association Scientific Sessions in November, 2014 [92]. In IMPROVE-IT, patients taking
Vytorin (a combination of simvastatin with ezetimibe) experienced significantly fewer major
cardiovascular events (as measured by a composite of cardiovascular death, nonfatal MI,
nonfatal stroke, rehospitalization for unstable angina, or coronary revascularization). The effect
was significant across subgroups, in particular for patients with diabetes, who had a consider-
ably larger benefit than nondiabetics [92]. In the Assessing Lipophilic vs. hydrophilic Statin
therapy for Acute MI study (ALPS-AMI; a retrospective analysis), major adverse cardiac and
cerebrovascular events (MACCE), including all-cause death, recurrence of MI, stroke, and heart
failure requiring hospitalization, and MACCE with revascularization were compared between
statin alone or statin plus ezetimibe [93]. Ezetimibe and statin combination therapy improved
MACCE compared with statin monotherapy. In the PRECISE-IVUS (a prospective, randomized,
controlled, multicenter study) trial [94], the combination of statin plus ezetimibe showed greater
coronary plaque regression compared with standard statin monotherapy. A population-based
dynamic cohort study using data from the Taiwan National Health Insurance Database (20 485
patients) showed that, compared with high-potency statins alone, simvastatin–ezetimibe ther-
apy was associated with a lower incidence of MACE in patients with T2DM [95]. Taken together,
these data suggest that, by reducing postprandial burden, ezetimibe may offer greater cardio-
vascular benefit in patients with diabetes.

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Orlistat
Orlistat is an inhibitor of pancreatic lipase and blocks fat digestion in the intestine, thereby
slowing its absorption. Orlistat has been shown to reduce the absorption of dietary fat by an
average of 30% at a dose of 120 mg. It has been on the market for many years and is currently
available over the counter for obesity treatment. Orlistat is effective in reducing PPL, remnant-like
particles, and FFAs after meals in obese patients with or without diabetes [96–98]. Moreover,
treatment of obese individuals without diabetes with orlistat resulted in a significant 37%
decrease in the incidence of diabetes [99]. Although the long-term cardiovascular safety of
orlistat has not been examined, by reducing PPL and weight gain it appears to reduce
inflammatory cytokines and blood pressure [100].

Targeting Endogenous Production of Glucose

Biguanides (Metformin)
Metformin is the first-line of therapy for diabetes. It is effective in lowering glucose, causes
minimal hypoglycemia, and is mostly weight neutral. Although several molecular mechanisms
have been proposed for the actions of metformin [101], the net result is a decrease in liver
glucose production. Metformin alters cell energy metabolism and inhibits hepatic gluconeogen-
esis. It also decreases plasma TG levels, by lowering hepatic lipoprotein secretion. Metformin
also favorably modulates both PPL and PPG when added on to other hypoglycemic agents.
Several studies suggest that metformin has a protective effect against CVD. In the UKPDS study,
metformin showed a significantly greater effect than chlorpropamide, glibenclamide, or insulin on
any diabetes-related end point, all-cause mortality, and stroke [102]. A meta-analysis of 35
clinical trials showed a significant benefit of metformin versus placebo and/or no therapy [103].
Meta-regression showed a significant correlation of the effect of metformin on cardiovascular
events with trial duration and with minimum and maximum age for inclusion, meaning that the
drug appeared to be more beneficial in longer trials enrolling younger patients [57].

Targeting Clearance
Sodium-Glucose Cotransporter Type 2 Inhibitors
Sodium-glucose cotransporter type 2 (SGLT2) inhibitors (canagliflozin, dapagliflozin, and empa-
gliflozin) are new glucose-lowering agents that exert their effect by decreasing glucose reab-
sorption by the kidneys and by increasing urinary glucose excretion through the kidneys [104].
They are effective in reducing plasma glucose and improving insulin sensitivity. In the case of
canagliflozin, because of low-potency SGLT1 (a glucose transporter in the intestinal cells)
inhibition, it can reduce intestinal glucose absorption, which may contribute to better control
of postprandial hyperglycemia [105]. A meta-analysis of cardiovascular outcomes (including
cardiovascular death, MI, stroke, and hospitalization for unstable angina) based on 14 clinical
trials involving 6300 subjects treated with dapagliflozin showed an odds ratio of 0.73 (95% CI
0.46–1.16) compared with the control group, suggesting a benefit [106]. The long-term effects
of these agents on cardiovascular outcomes and mortality remain to be seen. Adverse effects of
SGLT2 treatment include genital tract infections and, less commonly, ketoacidosis.

Nondiabetic Drugs with Potential Utility in Diabetic CVD

Cilostazol
Cilostazol (Pletal) is an orally available generic drug approved for intermittent claudication in
individuals with peripheral vascular disease. By inhibiting phosphodiesterase (PDE3), cilostazol
increases intracellular cAMP levels, blocks platelet aggregation, and promotes arterial vasodila-
tion. Recent studies in animals and humans show that cilostazol has beneficial effects beyond its
original indication. It reduces plasma glucose and HbA1c [107–111]. It improves postprandial
lipemia in patients with diabetes and increases HDL [107,108]. Most importantly, cilostazol
protects vessels against hyperglycemic injury and accelerates healing [109]. A recent analysis of
patients with diabetes on different platelet therapies showed that the composite disease-free

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survival rate for the cilostazol monotherapy group was similar to the aspirin subgroup [110]. In Outstanding Questions
patients with T2DM, treatment with cilostazol for 1 year resulted in a significant decrease in What are the appropriate models to
carotid intima media thickness [111]. Tissue-specific effects of cilostazol may independently study diabetic heart disease in ani-
mals? Currently, there are no suitable
contribute to its glucose-lowering and vascular and cardioprotective effects. PDE3 levels are models and those that are available use
elevated in diabetic pancreas and inhibition by cilostazol results in increased b cell viability and a hypercholesterolemia background,
improved secretory response to glucose [112]. In vascular cells and heart, elevation of cAMP by which is often absent in patients with
diabetes.
cilostazol has been shown to have many antiatherosclerotic effects. These include improving
barrier function, reducing glucose-induced cell adhesion, and smooth muscle cell proliferation What are the factors contributing to
[113–115]. With its long safety record in patients with vascular disease and diabetes, cilostazol elevated cardiovascular risk in patients
could be positioned to meet the unmet need in patients with T2DM. with diabetes?

Mechanistic studies to understand the

Concluding Remarks contribution of postprandial phenom-
In summary, based on the data reviewed here, agents that reduce PPL and PPG by enhancing ena to atherosclerosis are warranted
their tissue utilization may be less attractive for CVD protection in diabetes compared with agents
Is balancing energy intake and output a
that reduce postprandial stress by decreasing absorption or facilitate removal from the system
better approach than overcoming insu-
by kidney (Figure 3). I would like to call the former ‘endothelial stress agents’ (E-stress: insulin, lin resistance with excess insulin?
sulfonyl ureas, GLP-1/DPP4 inhibitors, fibrates, etc.) and the latter ‘endothelial-sparing agents’
(E-spare: metformin, acarbose, ezetimibe, orlistat, SGLT1/2 inhibitors, and cilostazol). Such
E-spare agents would cause the least stress to vascular endothelium, prevent atherogenic
events, and reduce overall cardiovascular burden. Since metformin is the first-line therapy for
diabetes, one or more E-spare agents may be added on to achieve optimal control of
postprandial stress and reduce CVD burden in patients with diabetes (see Outstanding Ques-
tions). Data from the CVD outcome study of empagliflozin (SGLT2 inhibitor) have recently been
published [116]. These data show that patients taking empagliflozin had a lower rate of the
primary composite cardiovascular outcome and of death from any cause when the study drug
was added to standard care, supporting the hypothesis presented here. Future strategies to
reduce PPL and PPG influx into the blood either by slowing and/or blocking their absorption, by
inhibiting their endogenous production, or by rapidly removing them from the bloodstream, may
prove valuable in reducing CVD burden in diabetes.

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