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Wilsonetal. Cardiovascular Diabetology (2022) 21:23
https://doi.org/10.1186/s12933-022-01460-5
REVIEW
Diabetes andrestenosis
Scott Wilson1, Pasquale Mone1,2, Urna Kansakar1,2, Stanislovas S. Jankauskas1,2, Kwame Donkor1,
Ayobami Adebayo1, Fahimeh Varzideh1,2, Michael Eacobacci1, Jessica Gambardella2,3, Angela Lombardi1 and
Gaetano Santulli1,2,3*
Abstract
Restenosis, defined as the re-narrowing of an arterial lumen after revascularization, represents an increasingly impor-
tant issue in clinical practice. Indeed, as the number of stent placements has risen to an estimate that exceeds 3
million annually worldwide, revascularization procedures have become much more common. Several investigators
have demonstrated that vessels in patients with diabetes mellitus have an increased risk restenosis. Here we present
a systematic overview of the effects of diabetes on in-stent restenosis. Current classification and updated epidemiol-
ogy of restenosis are discussed, alongside the main mechanisms underlying the pathophysiology of this event. Then,
we summarize the clinical presentation of restenosis, emphasizing the importance of glycemic control in diabetic
patients. Indeed, in diabetic patients who underwent revascularization procedures a proper glycemic control remains
imperative.
Keywords: ACS, BMS, CABG, DES, Diabetes, Endothelial dysfunction, Epidemiology, Hyperglycemia, PCI, Restenosis,
STEMI, Stent, VSMC
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Introduction
e global burden of cardiovascular disease is dispro-
portionately borne by patients with diabetes mellitus
(DM) [1–4]. Hyperglycemia, insulin-resistance, and the
increased presence of advanced glycation end products
(AGEs) represent a handful of the conditions that con-
tribute to a 2 to fourfold increased risk of both coro-
nary and peripheral artery disease (CAD & PVD) in DM
[5–10]. e deleterious effects of these components on
the vascular endothelium have been shown in the litera-
ture to be closely associated with macrovascular disease
including diffuse atherosclerosis [11–13]. However, it is
the complications of diabetes-associated heart disease—
including vascular occlusion, restenosis, and in-stent
restenosis (ISR)—that make diabetics a particularly com-
plex population to treat.
Restenosis, defined as re-narrowing of an arterial
lumen after corrective vascular intervention like percu-
taneous intervention (PCI) and coronary artery bypass
graft surgery (CABG), is an increasingly important issue
in clinical practice. Indeed, as the number of stent place-
ments has risen to an estimate of over 3 million annually
worldwide, revascularization procedures have become
much more common. Unsurprisingly, it has been con-
sistently shown that vessels in patients with DM have
an accelerated rate of late loss of lumen diameter and
increased ISR [14–16]. In fact, DM is an independent
predictor of recurrent restenosis [17–19].
As we have come to realize, the progression of reste-
nosis can be affected by our treatment choices: both for
the underlying DM and in the type of intervention in the
occluded vessel. With the advent of newer therapies and
second-generation drug-eluting stents (DES), restenosis
can be better managed than ever before. Herein, we will
present a systematic overview of the effects of DM on
Open Access
Cardiovascular Diabetology
*Correspondence: gsantulli001@gmail.com
1 Department of Medicine, Einstein Institute for Aging Research,
Einstein-Mount Sinai Diabetes Research Center (ES-DRC), The Fleischer
Institute for Diabetes and Metabolism (FIDAM), Albert Einstein College
of Medicine, New York, NY, USA
Full list of author information is available at the end of the article
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Page 2 of 14
Wilsonetal. Cardiovascular Diabetology (2022) 21:23
ISR after coronary angioplasty. We searched in PubMed
original clinical studies presenting in the title the words
diabetes, in-stent restenosis, restenosis; studies not in
English and abstractswere not included.
Eects ofdiabetes onthecardiovascular system
Despite the widespread use of hypoglycemic agents
and greater awareness, diabetic patients experience sig-
nificantly higher all-cause and cardiovascular mortality
rates than subjects without diabetes after adjustment
for other risk factors (16% and 18%, respectively in
2019) [20, 21]. Macrovascular complications mediated
by atherosclerosis prove to be the leading cause of pre-
mature death in this population [22–24]. Nonetheless,
microvascular complications can often present clini-
cally in the form of diabetic nephropathy, neuropathy,
and retinopathy [25–32]. A major contributor to both
types of vasculopathy is endothelial damage, mediated
in part by the actual glycemic control of each patient
[33]. Hyperglycemia can contribute to oxidative stress
through the production of mitochondrial superoxide,
NADPH reduction through polyol accumulation, and
AGE synthesis through the nonenzymatic oxidation of
glycoproteins—all of which are capable to cause dam-
age to the endothelial cells; the vascular endothelium
is particularly sensitive to the effects of hyperglycemia
since endothelial cells do not adaptively downregulate
their GLUT-mediated uptake of glucose [34–37].
Diabetic cardiomyopathy represents the direct effect of
diabetes on both the structure and function of the heart
[7, 38, 39]. Even after adjustment for conventional risk
factors (like age, CAD, dyslipidemia, and hypertension),
those with diabetes have a markedly higher risk for the
development of heart failure [7]. is cardiomyopathy
typically presents left ventricular hypertrophy and dias-
tolic dysfunction at the echocardiographic examination,
often leading to heart failure with preserved ejection
fraction (HFpEF, ejection fraction ≥ 50%) [40, 41]. e
mechanisms behind these changes are not fully under-
stood but likely involve many of the processes common
to those implicated in vascular endothelial damage, in
addition to impaired mitochondrial calcium handling
and autonomic neuropathy—all of which have been func-
tionally linked to hyperglycemia [42, 43].
Pathophysiology ofrestenosis
Denition
ISR, based on its traditional definition, is a ≥ 50% luminal
re-narrowing of an artery within or directly adjacent to
the stented region after PCI, determined through angi-
ography. e clinical definition of ISR includes the same
angiographic criteria along with signs of ischemia and/or
acute coronary syndrome (ACS); often requiring target
lesion revascularization (TLR) [44]. Finally, recurrent ISR
is defined as two or more revascularization failures at the
same vascular segment.
Overview
e progression of restenosis is gradual, already start-
ing in the early hours after intervention. Using PCI to
restore blood flow in atherosclerotic vessels can result
in the disruption of the target vessel’s integrity. An
intact endothelial lining is an important factor in pre-
venting thrombosis, inflammation, and intimal hyper-
plasia. ISR occurs as a result of this endothelial damage
and subsequent neointimal and vascular smooth mus-
cle cell (VSMC) proliferation [45]. As early as 30min
after endothelial injury, proto-oncogenes have already
begun to be upregulated in VSMC nuclei in response
to growth factor signaling [46]. ese processes form
the basis of using pharmacologic agents to reduce cel-
lular growth and migration in a stented vessel. If a stent
is not used, however, like in the case of simple balloon
angioplasty (BAP), restenosis is primarily mediated by
the vessel elastic recoil followed by adverse remodeling
[47–49].
Neointimal hyperplasia in patients with diabetes looks
phenotypically different to the one observed in non-
diabetic patients. VSMC specimens from patients with
type 2 DM (T2DM) are phenotypically abnormal and
behave in a more aggressive manner (greater adhesion
and migration) in cell culture [50, 51]. is process may
be partly dependent on the adipokine resistin, which is
upregulated in human aortic VSMCs in patients DM
[52]. Furthermore, several studies have shown that pro-
inflammatory cytokines (like IL-1β, which is chronically
activated in T2DM [53]) are able to induce the change in
VSMCs into a secretory state, whereas both glucose and
insulin could increase VSMC mitogenesis [54, 55]. ese
findings are consistent with accelerated rates of coronary
narrowing and thrombosis in T2DM and highlight the
importance of a tight glycemic control in these patients.
De novo neo-atherosclerosis may also be present in
the site of the lesion, the progression of which—mainly
mediated by chronic inflammation and low-density lipo-
protein (LDL) cholesterol uptake by macrophages [56]—
might explain the presentation of unstable angina and
thrombotic events in patients years after PCI [57]. More-
over, remnant-like particle cholesterol was shown to be
an independent risk factor for ISR [58], whereas high-
density lipoprotein (HDL) cholesterol levels are known to
be inversely associated with ISR in diabetic patients [59].
Other predictors of ISR include levels of soluble receptor
for advanced glycation end products (sRAGE), uric acid,
and platelet distribution width [60–63].
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Wilsonetal. Cardiovascular Diabetology (2022) 21:23
Neo-atherosclerosis is suggested to play a critical role
in restenosis after the placement of a DES especially if
compared to bare-metal stents (BMS) [64, 65]. Indeed,
when comparing the two types of intervention, patients
given a first-generation DES experienced a significantly
earlier and more frequent onset of in-stent neo-athero-
sclerosis than those with BMS placement [66].
Patients with DM are subject to a unique, rapidly pro-
gressive, and widespread form of atherosclerosis, result-
ing in a higher rate of restenosis after simple BAP [67,
68]. ese events increase the chance that a patient with
DM will undergo repeated revascularizations, a proce-
dure that has been shown to increase the risk of cardio-
vascular death fourfold (HR = 4.22; 95% CI, 2.10–8.48) in
the 2020 Evaluation of XIENCE versus Coronary Artery
Bypass Graft Surgery for Effectiveness of Left Main
Revascularization (EXCEL) trial [69].
Impaired endothelial function and increased plasmino-
gen activator inhibitor 1 (PAI-1) activity in patients with
DM result in a greater risk of late in-stent thrombotic
events after PCI, which is already more common with
first-generation DES compared to BMS intervention [70].
Moreover, insulin-resistance contributes to increased
P2Y-receptor-pathway signaling, leading to greater plate-
let aggregation in DM [71]. ese factors underscore the
importance of adherence to dual antiplatelet therapy
(DAPT, comprising of P2Y-inhibitors and aspirin) in
patients with DM undergoing PCI. In fact, patients who
comply poorly with or cannot tolerate DAPT are likely to
benefit more from alternatives to PCI including CABG,
BAP, or medical therapy [72].
A major concern in modern stents is delayed failure in
the form of late in-stent thrombosis, which is a throm-
botic event occurring between 1month and 1year after
PCI [73]. Although the incidence of late in-stent throm-
bosis is low (~ 0.35%-0.7% in cases with DES), the out-
comes are poor, with a fatality rate of 45% reported
in 2005 and a fourfold increase in all-cause mortality
(HR = 4.9, 95% CI 1.1–21.4) in 2009 [74–76]. Pathological
studies of sirolimus and paclitaxel-eluting stents revealed
that localized hypersensitivity against the stent polymer
is a major thrombotic factor. Moreover, coronary arter-
ies exhibit a longer delay in healing after DES implanta-
tion compared to BMS, consistent with reports of higher
rates of very late (> 1 year) in-stent thrombosis in DES
[77–79]. Chronic inflammation in response to the DES
has shown to be a cause of this phenomenon, evidenced
by persistent fibrin deposits and incomplete endotheli-
zation, particularly in patients with additional risk fac-
tors like DM. In this case, the suppression of neointimal
expansion by sirolimus and paclitaxel may be detrimen-
tal—impairing the normal healing process of the vascu-
lar wall [80]. ankfully, newer second-generation DES
(including zotarolimus and everolimus-eluting stents) are
associated with significantly lower rates of early and late
in-stent thrombosis compared to sirolimus-eluting coun-
terparts [81]. On top of these thromboresistant proper-
ties, everolimus-eluting stents were ranked as the most
effective treatment for ISR according to a 2015 meta-
analysis of 27 clinical trials in comparison to all other
major modalities (in order of effectiveness: drug-coated
balloons, first-generation DES, vascular brachytherapy,
BMS, BAP, and rotablation) [82].
ISR classication andrisk factors
ere are three main categories of ISR defined by the
Mehran System through angiographic classification: Pat-
tern I (focal, ≤ 10mm length), pattern II (diffuse, > 10mm
length), pattern III (proliferative, > 10 mm, extending
beyond the confines of the stent), and pattern IV (totally
occluded ISR) [44]. ese classifications can be regarded
as a measure of a vessel’s intrinsic proliferative response
to stent placement. A study published in 1999 found that
the long-term need for TLR increases with the higher
classes of ISR (HR = 1.7; P = 0.0380) and with the pres-
ence of diabetes (HR = 2.8; P = 0.0003) [83]. Taken
together with other evidence, DM is suggested to be a
strong determinant of neointimal hyperplasia [84, 85].
Other risk factors for ISR include pre-operative variables
like vessel diameter, stent length, number of prior stents,
age, hypertension, and kidney disease [86–89]. However,
post-operative levels of inflammatory markers (including
high-sensitivity C-reactive protein, matrix metallopro-
teinase 2, tumor necrosis factor, and chemokine ligand 2)
also serve as potential risk criteria [90–93].
e distribution of neointimal proliferation is most
often uniform along the length of the stent but may be
focal, as shown by intravascular ultrasound [94]. Various
studies have shown that the lesion’s appearance can vary
significantly with the type of stent used: notably, reste-
nosis in BMS is generally more diffuse than in DES [95].
On the other hand, in-stent neointimal proliferation in
patients with DM tends to be located more towards the
edges of the stent [44].
Lastly, immunologic, genetic and epigenetic mecha-
nisms have been proposed to partakes in the pathophysi-
ology of ISR in diabetic patients [96–124].
Epidemiology
e incidence of restenosis varies significantly across
studies. Rates have dropped markedly with technologi-
cal advances in angioplasty. e occurrence of resteno-
sis is estimated to be at about 32–55% in the pre-stent
era, 17–41% in the BMS era (after their implementation
in the 1980s), compared to less than ~ 18% with the use
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Page 4 of 14
Wilsonetal. Cardiovascular Diabetology (2022) 21:23
of second-generation DES [47]. In support of these esti-
mates, there has been a greatly decreased incidence of
TLR and cardiovascular mortality in patients using DES
over BMS. is estimate includes the use of first-gener-
ation sirolimus-eluting stent, in which the occurrence of
ISR is comparably low following the procedure but more
common in diabetic patients [125–127].
Karl Haase and collaborators determined that the small
size of the vessel and the presence of DM were independ-
ent predictors for the occurrence of ISR [128]. Although
the risk factors for ISR in the general population are well-
defined, there have been fewer studies dedicated to the
differences between diabetic patients that fall victim to
restenosis versus those that do not. A recent prospective
study of 920 diabetic patients found that serum VLDL-
C and uric acid were associated with a relative risk of
ISR after coronary DES implantation of 1.85- and 1.19,
respectively [129]. In this study, LDL-C and HDL-C levels
were not significantly different between the two groups.
Clinical presentation
ISR may present as recurrent signs of myocardial
ischemia—often beginning with stable angina pectoris
as shown through patient history, stress tests, and ECG
modifications [130, 131]. ough, this presentation may
be a result of incomplete revascularization or the pro-
gression of CAD at a separate site [44]. Rather, the defini-
tive diagnosis of ISR is normally made through coronary
angiography [132–135].
Symptoms have been found to develop on an average
of about 6 months after PCI in patients with ISR of a
BMS. ose with DES generally develop symptoms later,
but often between 3 and 12 months and have a more
stable symptomatology [44, 136]. Nonetheless, resteno-
sis cannot be seen as a benign condition. ACS arising
from ISR is well documented and associated with more
adverse cardiac outcomes [137, 138]. A 2014 retrospec-
tive study found that of 909 patients undergoing TLR
from prior PCI with all generations of stents—including
second-generation DESs— the majority presented with
ACS at 66–71% [139]. Yet, statistics on the presentation
of ISR can vary greatly between studies with many find-
ing that patients with ISR are most commonly asympto-
matic or present with stable angina in the DES era [140].
Notably, approximately 50% of patients with restenosis
determined initially by angiography have no ISR-related
symptoms [141].
Clinical data
Stent ecacy
Ever since Eric Van Belle and colleagues reported no sig-
nificant increase in ISR risk in diabetic patients in 1997
[142], a preponderant evidence has emerged showing
that there is indeed an increased rate of ISR, TLR, ST,
and major adverse cardiovascular events (MACE) due to
DM when using BAP, BMS, and first-generation DES [68,
143]. Moreover, diabetic patients showed a more heter-
ogenous pattern of the neointima after BMS, resulting
in longer high-grade obstruction segments [144]. How-
ever, in the second-generation DES era, it remains some-
what controversial [145–151] whether DM (particularly
T2DM) is still a statistically significant predictor of long-
term adverse outcomes—including ISR, MACE, and late
in-stent thrombosis after PCI (Table1). is uncertainty
may reflect the fact that the use of second-generation
DES suppresses the difference in outcomes between
those with and without DM. ough, the variability may
be partly caused by differences in clinical variables (such
as secondary prevention), study design, and stent compo-
nents (including alloy and drug delivery vehicle).
In any case, there is a clear benefit of using newer-gen-
eration stent technology over first-generation DES on ISR
when looking exclusively at patients with DM. is find-
ing was shown initially in the Everolimus-Eluting Stent
Versus Sirolimus-Eluting Stent Implantation for De Novo
Coronary Artery Disease in Patients with Diabetes Mel-
litus (ESSENCE-DIABETES) prospective trial in 2011
and confirmed by lengthier studies that followed [152,
153]. Notably, four years later, the Taxus Element versus
Xience Prime in a Diabetic Population (TUXEDO)–India
study demonstrated that there was a significantly greater
incidence of TLR (3.4% vs. 1.2%, P = 0.002), in-stent
thrombosis (2.1% vs. 0.4%, P = 0.002), and spontaneous
myocardial infarction (MI, 3.2% vs. 1.2%, P = 0.004) after
1year in diabetic patients randomized to the paclitaxel-
eluting stent intervention [154]. A more recent retro-
spective study stratified 13,895 patients with prior MI
into normoglycemic, pre-diabetic, and diabetic groups
to compare outcomes between first and second-genera-
tion DES intervention. e authors found a significantly
higher incidence of cardiovascular endpoint and in-stent
thrombosis in those treated with first-generation in com-
parison to second-generation DES within all three glyce-
mic groups [155]. is confirmation is important since
prior evidence of the relative benefits of newer DES gen-
erations in DM patients post-MI was limited.
When comparing first-generation paclitaxel- and siroli-
mus-eluting stents specifically in patients with DM, data
diverge on the relative risk of MACE of each; these two
stent types tend to be comparable in safety profile with
sirolimus-eluting stent intervention likely resulting in
slightly lower ISR rates over paclitaxel-eluting counter-
parts according to meta-analyses [156, 157].
Drug-coated balloons (DCBs) and bioabsorbable vas-
cular scaffolds (BVSs) are two modern interventions sim-
ilar in that they deliver an anti-proliferative agent to the
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Wilsonetal. Cardiovascular Diabetology (2022) 21:23
vascular endothelium without permanently adding addi-
tional scaffolds. DCBs have proven non-inferior to (and
occasionally favorable over) first-generation DES, par-
ticularly in coronary small vessel disease. For example, a
reduction in TLR was found only in diabetic patients in
last year’s Long-term Efficacy and Safety of Drug-Coated
Balloons versus Drug-Eluting Stents for Small Coronary
Artery Disease (BASKET-SMALL 2) trial [158, 159].
Meta-analysis of the limited studies on DCB in de-novo
lesions in diabetic patients presented neutral findings
over the use of DES [160]. However, the Restenosis Intra-
stent of Bare Metal Stents: Paclitaxel-eluting Balloon vs.
Everolimus-eluting Stent (RIBS-IV) trial found that PCI
with second-generation DES was associated with lower
percent diameter stenosis over DCB (mean follow up
of 1year) [161]; still, the overall need for TLR in both
groups was low and comparable, suggesting second-gen-
eration DES may be marginally preferable in the context
of large vessel disease [161].
e Drug-Eluting Balloon for In-Stent Restenosis
(DARE) trial was designed to investigate the relative
performance of the paclitaxel-eluting balloon compared
with the everolimus-eluting stent (XIENCE) in the treat-
ment of any ISR [162]. In patients with ISR and DM, the
Paclitaxel-eluting Balloon resulted in similar 6-months
in-segment minimal lumen diameter and comparable
rates of major adverse events compared to Xience, and
in-segment late loss at 6months was significantly lower
in the Paclitaxel-eluting Balloon arm [163].
Despite the comprehensive evidence for using DES,
BMS is still widely used for diabetic patients in the United
States [164–167]. is fact may be attributed to both high
prices and increased duration of DAPT needed for DES,
despite beneficial cost–benefit analysis [168]. Both global
and local gaps in access to these new therapies should be
viewed as drivers in disparate cardiovascular outcomes
between socioeconomic and ethnic groups as demon-
strated by countless studies [169–173]. is aspect repre-
sents a considerable a problem for patients with diabetes,
since they are at a significantly higher risk for revascular-
ization with BMS over DES and tend to be stratified into
lower socioeconomic groups [174, 175]. Indeed, these
factors must be considered in advocating for patients and
informing areas of research in the future.
Table 1 Relative risk of major adverse cardiac events (MACE), target lesion revascularization (TLR), and stent thrombosis (ST) in
patients with and without DM undergoing PCI with second-generation drug-eluting stent (DES)
Early TLR and late LTR were determined angiographically at the rst (325 ± 90days) follow-up and between the rst and second (772 ± 133days) follow-ups,
respectively, in the Zheng etal. study. In the Kuramitsu etal. study, Early ST was classied as occurring within 30days, Late ST was between 31 and 365days, and Very
Late ST referred to events after 1year. * = Multivariate analysis used. Bold text = statistical signicance at p < 0.05
Study Study design Number
of diabetic
patients
Total patients T1DM
and/or
T2DM
Outcome Relative risk
(95% condence
interval)
P-value References
Konishi et al. (2016) Observational cohort
study
Mean follow-up:
958 days
575 1667 T1DM MACE 1.18 (0.74–1.82)* 0.48 [145]
199 1291 T2DM MACE 1.07 (0.77–1.49)* 0.67
575 1667 T1DM TLR 1.92 (1.10–3.29)* 0.02
199 1291 T2DM TLR 1.52 (0.97–2.35)* 0.06
D’Ascenzo et al.
(2017) Retrospective multi-
center study
Mean follow-up:
650 days
485 1270 T1DM TLR 2.0 (1.1–3.6) 0.04 [146]
Honda et al. (2015) Retrospective single
center study
Mean follow-up:
23.1 months
713 1669 Both TLR 1.23 (0.89–1.69) 0.21 [147]
Zheng et al. (2019) Retrospective single
center study
Mean follow-up:
325 days and
772 days
133 394 Both Early TLR 2.58 (1.29–5.15) 0.007 [148]
Late TLR 1.56 (0.47–5.21) 0.472
Pi et al. (2018) Retrospective multi-
center study
Mean follow-up:
3 years
1786 4812 Both TLR 1.70 (1.22–2.36) 0.002 [149]
ST 1.55 (0.75–3.21) 0.242
Kuramitsu et al.
(2019) Retrospective multi-
center study
Mean follow-up:
4 years
695 1541 Both Early ST 1.20 (0.81–1.77) 0.36 [150]
Late ST 1.02 (0.52–1.99) 0.95
Very late ST 0.93 (0.51–1.71) 0.83
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Wilsonetal. Cardiovascular Diabetology (2022) 21:23
Glycemic control
Glycemic control at the time of PCI plays an essential role
in preventing TLR [176–178]. Of note, fasting blood glu-
cose and hemoglobin A1c (HbA1c) have been thoroughly
investigated as clinical biomarkers for ISR risk [179].
Results between studies often vary regarding the degree
to which HbA1c and fasting blood glucose correlated with
restenosis in DM and/or metabolic syndrome. However,
most authors present evidence that supports the impor-
tance of proper pre- and post-operative glycemic control.
Recently, in a 2020 cohort study, 420 T2DM patients with
DES were given follow-up coronary angiographies and
routine HbA1c measurements [180]. In this study, insu-
lin resistance (known risk factor in ISR [181–188]) was
correlated with higher tertiles of HbA1c variability and,
therefore, may have played a confounding role. Most
recently, our group has demonstrated that hyperglycemia
plays a decisive role in ISR, also in non-diabetic patients
[189]. Indeed, we showed that admission hyperglycemia
increased the risk of ISR at one year follow-up, both in
BMS and 2nd generation DES [189]. Intriguingly, this
effect was independent from glycemic control.
Hyperglycemia does also affect restenosis in vessels
other than the coronary arteries [190–210]. For instance,
a retrospective study of 322 patients undergoing carotid
artery stenting reported that patients with elevated peri-
operative fasting blood glucose had significantly less free-
dom from restenosis at 5years compared to those with
normal fasting blood glucose [211].
Hyperinsulinemia andrestenosis
Considering the other components of T2DM phenotype,
insulin resistance and hyperinsulinemia are likely key
players in the increased incidence of restenosis [212]. It
is worth noting that multiple studies have linked meas-
ures of insulin resistance to the rate of ISR after coronary
DES intervention [181, 184, 213, 214]. A 2015 cohort
study revealed that the Homeostatic Model Assessment
for Insulin Resistance (HOMA-IR)—a model using fast-
ing plasma insulin and glucose [215–218]—could predict
the risk of ISR in both diabetic and non-diabetic patients
(HR 1.5, 95% CI 1.2–1.8; p < 0.001) [213, 219]. Several
studies reported hyperinsulinemia as an independent
risk factor for restenosis, even in patients in absence of
DM or treatment with insulin [110, 220–222]. Further-
more, restenosis rates are found to be higher in diabetic
populations with greater percentages of patients treated
with insulin [223]. One explanation for these results is
that high insulin levels are directly associated with both
increased PAI-1 expression, which increases thrombosis
and VSMC proliferation (characteristics of restenosis and
late ST) [224].
e importance of strict glycemic control on car-
diovascular complications in patients with T2DM is
well-understood by the biomedical community. A 2009
meta-analysis of five large retrospective studies reported
a 15% reduction in events related to CAD (HR = 0.85,
95% CI 0.77–0.93) in patients following a more intensive
glucose-lowering regimen [225].
Various studies have suggested that using insulin-sen-
sitizing (IS) strategies like metformin and thiazolidin-
ediones have a more beneficial effect on restenosis than
insulin-providing regimens using insulin therapy and sul-
fonylureas [50]. Moreover, the favorable effects of thiazo-
lidinediones on the progression of restenosis have been
demonstrated to be independent of glycemic control; this
finding may be explained through their agonistic effect
on PPARγ, including the reduction of proinflammatory
cytokines, VSMC migration, and neointimal hyperplasia
(as measured by carotid arterial intima-media thickness)
[226–228].
Clinical data on the effects of IS therapy are somewhat
mixed. Numerous small studies have shown that trogl-
itazone, pioglitazone, and rosiglitazone result in reduced
restenosis compared to conventional therapy for DM
[229–232]. Yet, in 2010, a major randomized control trial
of 2368 patients found that those with stable ischemic
heart disease and T2DM had a significant reduction in
MI only with IS regimens (but not insulin-preserving reg-
imens) post-CABG, with a decreased but non-significant
reduction post-PCI [233]. A large retrospective study
found that although metformin and thiazolidinediones—
individually—did not significantly reduce mortality over
the standard of care, co-prescription of the two IS treat-
ments was able to reduce cardiac endpoint (HR = 0.52,
95% CI 0.34–0.82) within 1year [234]. Further investiga-
tion on the clinical efficacy of IS therapy is merited and
treatment strategies using combinations of agents may be
a promising direction.
Pharmacological prevention
Beyond general glycemic control, DAPT and lipid-lower-
ing therapy form the pillars of treatment after the place-
ment of a stent in diabetic patients [235]. Some studies
have indicated that the addition of cilostazol to these
agents (sometimes referred to as ‘triple antiplatelet ther-
apy’) may decrease the risk of ISR [236–238]. Cilostazol
is a vasodilator that suppresses cAMP degradation, a
substance whose anti-mitogenic properties have been
found to maintain VSMC quiescence in damaged vessels
[239]. Reassuringly, a reduction in both late lumen loss
and 9-month TLR was observed in cilostazol-treated dia-
betic patients receiving DES in a recent prospective study
[240]. For diabetic patients that cannot receive DES,
Content courtesy of Springer Nature, terms of use apply. Rights reserved.
Page 7 of 14
Wilsonetal. Cardiovascular Diabetology (2022) 21:23
administration of colchicine has proven to be very effec-
tive in reducing the rate of ISR in BMS [241].
e use of antioxidants in ISR has been evaluated for
over a decade, taking into account that restenosis is
partly mediated by oxidative stress to the vascular
endothelium—particularly in presence of hyperglyce-
mia [242–249]. Substances that reduce free radicals like
probucol have shown promise invitro, but are marred by
side-effects, including prolongation of QT-interval [250].
While the results of related clinical trials come in, per-
haps the most straightforward path to prevention is ade-
quate management of DM itself.
Conclusions
Available evidence indicates that a tight glycemic control
is crucial in diabetic patients who underwent revasculari-
zation procedures. Current treatment paradigms for DM
should not be cast aside to better manage alterations in
insulinemia, but it should be noted that the choice of glu-
cose-lowering agent may affect the chances of developing
ISR.
Acknowledgements
We thank Dr. Wang for helpful discussion. We apologize to the authors whose
contributions were not directly cited.
Authors’ contributions
All authors wrote the main manuscript text and reviewed the manuscript. All
authors fully contributed to this research. All authors read and approved the
final manuscript.
Funding
The Santulli laboratory is supported in part by the National Institutes of Health
(R01-HL146691, R01-DK123259, R01-DK033823, R01-HL159062, R56-AG066431,
and T32-HL144456 to G.S.), by the Irma T. Hirschl and Monique Weill-Caulier
Trusts (to G.S.), by the Diabetes Action Research and Education Foundation (to
G.S.), by the New York Academy of Medicine (NYAM, Glorney-Raisbeck Grant
in Cardiovascular Medicine to S.W.), and by the American Heart Association
(AHA-21POST836407 to S.J.J., and AHA-22POST915561 to F.V., and AHA-
20POST35211151 to J.G.).
Availability of data and materials
Not applicable.
Declarations
Ethics approval and consent to participate
Not applicable.
Consent for publication
All authors gave the consent for the publication of the article. All data and
materials are available.
Competing interests
The authors declare no competing interests.
Author details
1 Department of Medicine, Einstein Institute for Aging Research, Ein-
stein-Mount Sinai Diabetes Research Center (ES-DRC), The Fleischer Institute
for Diabetes and Metabolism (FIDAM), Albert Einstein College of Medicine,
New York, NY, USA. 2 Department of Molecular Pharmacology, Wilf Family
Cardiovascular Research Institute, Institute for Neuroimmunology and Inflam-
mation (INI),, Albert Einstein College of Medicine, New York, NY, USA.
3 International Translational Research and Medical Education (ITME) Consor-
tium, Department of Advanced Biomedical Sciences, “Federico II” University,
Naples, Italy.
Received: 16 December 2021 Accepted: 21 January 2022
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