Canadian Journal of Cardiology 34 (2018) 575e584

Review
Diabetes, Hypertension, and Cardiovascular Disease:
Clinical Insights and Vascular Mechanisms
John R. Petrie, MD, PhD, Tomasz J. Guzik, MD, PhD, and Rhian M. Touyz, MD, PhD
Institute of Cardiovascular and Medical Sciences, University of Glasgow, United Kingdom

ABSTRACT 
RESUM 
E
Hypertension and type 2 diabetes are common comorbidities. L’hypertension et le diabète de type 2 sont des affections con-
Hypertension is twice as frequent in patients with diabetes compared comitantes fre quentes. L’hypertension est deux fois plus fre quente
with those who do not have diabetes. Moreover, patients with chez les patients atteints de diabète que chez ceux qui n’en sont pas
hypertension often exhibit insulin resistance and are at greater risk of atteints. De plus, les patients atteints d’hypertension sont souvent
diabetes developing than are normotensive individuals. The major sistants à l’insuline et sont plus susceptibles de souffrir de diabète
re
cause of morbidity and mortality in diabetes is cardiovascular que les personnes normotendues. Chez les diabe tiques, la principale
disease, which is exacerbated by hypertension. Accordingly, diabetes cause de morbidite  et de mortalite est la maladie cardiovasculaire, qui
and hypertension are closely interlinked because of similar risk fac- est exacerbe e par l’hypertension. En conse quence, le diabète et l’hy-
tors, such as endothelial dysfunction, vascular inflammation, arterial pertension sont e troitement interrelies en raison de facteurs de risques
remodelling, atherosclerosis, dyslipidemia, and obesity. There is also similaires, comme la dysfonction endothe liale, l’inflammation vascu-
substantial overlap in the cardiovascular complications of diabetes laire, le remodelage arte riel, l’athe
roscle
rose, la dyslipide mie et
and hypertension related primarily to microvascular and macro- site
l’obe . On observe un chevauchement important entre les compli-
vascular disease. Common mechanisms, such as upregulation of the cations cardiovasculaires du diabète et celles de l’hypertension lie es
renin-angiotensin-aldosterone system, oxidative stress, inflammation, principalement à des maladies microvasculaires et macrovasculaires.
and activation of the immune system likely contribute to the close Des me canismes communs, comme une stimulation du système
relationship between diabetes and hypertension. In this article we nine-angiotensine-aldoste
re rone, un stress oxydatif, une inflammation
discuss diabetes and hypertension as comorbidities and discuss the et une activation du système immunitaire, sont susceptibles de con-
pathophysiological features of vascular complications associated troite entre le diabète et l’hypertension. Dans cet
tribuer à la relation e
with these conditions. We also highlight some vascular mechanisms article, nous abordons le diabète et l’hypertension comme des affec-
that predispose to both conditions, focusing on advanced glycation tions concomitantes et nous parlons des caracte ristiques physio-
end products, oxidative stress, inflammation, the immune system, pathologiques des complications vasculaires associe es à ces
and microRNAs. Finally, we provide some insights into current ther- affections. Nous soulignons e galement certains me canismes vascu-
apies targeting diabetes and cardiovascular complications and laires qui predisposent à ces deux affections, en mettant l’accent sur
introduce some new agents that may have vasoprotective therapeutic les produits finaux de glycation avance e, le stress oxydatif, l’in-
potential in diabetes. flammation, le système immunitaire et les micro-ARN. Finalement,
nous pre sentons certaines connaissances sur les traitements actuels
ciblant le diabète et les complications cardiovasculaires et nous
presentons de nouveaux agents qui pourraient avoir un pouvoir vaso-
protecteur chez les patients diabe tiques.

Type 2 Diabetes Mellitus and Hypertension adopted, particularly in lower-income and developing coun-
The prevalence of obesity and type 2 diabetes (T2D) tries. It is predicted that the number of cases of T2D will rise
continues to rise worldwide as lifestyles associated with low from 415 million to 642 million by 2040.1 Hypertension is
energy expenditure and high caloric intake are increasingly even more common, rising in prevalence in the same coun-
tries, with a recent worldwide estimate of 1.39 billion cases.2
Although T2D and hypertension can be simply diagnosed
Received for publication November 11, 2017. Accepted December 7, 2017. at the bedside, they are each complex and heterogeneous
Corresponding author: Dr Rhian M. Touyz, Institute of Cardiovascular phenotypes associated with an elevated risk of life-threatening
and Medical Sciences, University of Glasgow, 126 University Place, Glasgow cardiovascular disease (CVD). Their frequent coexistence in
G12 8TA, United Kingdom. Tel.: þ44-141-330-7775; fax: þ44-141-330-
3360. the same individual is not a coincidence, because aspects of
E-mail: [email protected] the pathophysiology are shared by both conditions, particu-
See page 581 for disclosure information. larly those related to obesity and insulin resistance. For

https://doi.org/10.1016/j.cjca.2017.12.005
0828-282X/Ó 2017 The Authors. Published by Elsevier Inc. on behalf of the Canadian Cardiovascular Society. This is an open access article under the CC BY
license (http://creativecommons.org/licenses/by/4.0/).
576 Canadian Journal of Cardiology
Volume 34 2018

example, in the San Antonio Heart Study, 85% of those with highlighted. We also discuss how some of the newer agents
T2D had hypertension by the fifth decade of life, whereas used in the treatment of T2D can influence blood pressure
50% of those with hypertension experienced impaired glucose (BP) regulation and the risk of CVD, with an eye to future
tolerance or T2D.3 developments more specifically targeting vascular protection.
In health, insulin maintains glucose homeostasis by inte-
grated actions on carbohydrate, protein, and lipid metabolism.
Loss of sensitivity to aspects of insulin action (insulin resis- Macrovascular Disease
tance) principally affects the liver, muscle, and adipose tissues
and is selective for glucose and lipid metabolism, eg, sparing Clinical features
insulin’s action to retain sodium in the distal tubule.4,5 Macrovascular (or cardiovascular) disease of larger conduit
Reduction in insulin-mediated glucose disposal leads to arteries is a complex inflammatory process leading to
compensatory hypersecretion of insulin to maintain homeo- myocardial infarction, stroke, and peripheral artery disease.
stasis: Glucose intolerance ensues if this endocrine pancreas The primary pathologic process associated with macrovascular
response is inadequate, although some obese individuals avoid disease is atherosclerosis, which in diabetes is accelerated with
T2D by virtue of a supranormal B-cell response.6 Recently, extensive distribution of vascular lesions.10 T2D confers an
the role of adipose tissue in these associations has been approximate 2-fold elevation in CVD risk, equivalent to that
increasingly appreciated.7 of a previous myocardial infarction.11,12 Moreover, patients
Diabetes is associated with both macrovascular (involving with T2D have poorer outcomes after an acute coronary
large arteries such as conduit vessels) and microvascular syndrome and higher rates of reinfarction and heart failure.13
(involving small arteries and capillaries) disease. Chronic Elevation of CVD risk begins at the stage of prediabetes in
hyperglycemia and insulin resistance play an important role in association with insulin resistance and impaired glucose
the initiation of vascular complications of diabetes and involve tolerance.14 As well as being the diagnostic hallmark of T2D,
a number of mechanisms including (1) increased formation of hyperglycemia is the principal determinant of microvascular
advanced glycation end products (AGEs) and activation of the complications of T2D and plays an important role in the
receptor for advanced glycation end products (RAGE) pathogenesis of CVD. However, in established T2D, it is a
AGE-RAGE axis, (2) oxidative stress, and (3) inflammation.8 relatively weak modifiable risk factor compared with hyper-
In addition, emerging evidence suggests a role for microRNAs tension, dyslipidemia, and (unfortunately in many pop-
(miRNAs) in the vasculopathy of diabetes (see further on).9 ulations) cigarette smoking.15,16
Hypertension is an important risk factor for diabetes-
associated vascular complications, because hypertension itself
Pathophysiological features
is characterized by vascular dysfunction and injury (Fig. 1).
In this review, we focus on vascular complications of dia- Insulin resistance is detectable for several years before
betes and discuss the impact of comorbidities, specifically the onset of T2D. It is associated with obesity, particularly
hypertension. The role of oxidative stress and inflammation as central obesity, but may be present in lean individuals with
“common soil” for metabolic and vascular disease are hypertension.17 During calorie excess, adipocytes in
obese humansdwhether in subcutaneous or visceral
areasdundergo hypertrophy. Visceral adipocytes are more
Common Risk factors susceptible to cellular death as they begin to enlarge and
Insulin
Dyslipidemia
their stromal vascular fraction becomes infiltrated with
resistance
macrophages.18
These macrophages around dead adipocytes form “crown-
Genes Obesity
like structures,” a histologic appearance that is associated with
expression of cytokines (including tumor necrosis factor-a
[TNF-a], interleukin-6 [IL-6]), and inducible nitric oxide
Diabetes Hypertension
synthase.19 These changes have been shown to coincide with
the onset of insulin resistance and provide a pathophysiolog-
ical link between metabolic and vascular disease.20
Endothelial Vascular Vascular Arterial
In addition to these proinflammatory changes, adipocyte
Atherosclerosis dysfuncƟon inflammaƟon fibrosis remodeling hypertrophy is associated with larger triglyceride stores, a
higher lipolytic rate, and an atherogenic lipid profile: elevated
concentrations of small dense low-density lipoprotein
Macrovascular disease Microvascular disease cholesterol, high concentrations of triglycerides, triglyceride-
Cardiovascular disease
rich remnants, very low-density lipoprotein cholesterol, and
apolipoprotein B, usually in combination with low levels of
high-density lipoprotein cholesterol.7 This profile is associated
Figure 1. Vascular processes whereby diabetes and hypertension
predispose to cardiovascular disease. Common risk factors promote
with increased production of leptin, decreased production of
diabetes and hypertension, which are associated with atheroscle- adiponectin, higher circulating levels of nonesterified fatty
rosis, vascular inflammation, endothelial dysfunction, and structural acids (NEFAs), and activation of mitochondrial oxidative
remodelling, which lead to macrovascular and microvascular disease. stress pathways in vascular endothelial cells.7
Vascular damage and endothelial dysfunction is amplified when dia- These proinflammatory and metabolic consequences
betes and hypertension coexist. of obesity and insulin resistance result in endothelial
Petrie et al. 577
Diabetes, Hypertension, and Vascular Complications

dysfunction, a key antecedent and modulator of atheroscle- muscle cell dysfunction. Hyperglycemia is the key stimulus for
rosis that has been demonstrated not only in hypertension but these processes by stimulating vasoinjurious signalling path-
also in prediabetes,21 first-degree relatives of individuals with ways, activating the polyol pathway, increasing oxidative
T2D,22 and even insulin-resistant healthy individuals.22,23 It stress, stimulating proinflammatory transcription factors, and
is characterized by disruption of the intricate physiological activation of immune responses. Similar processes are induced
balance between vasoconstrictors (endothelin, angiotensin II) by hypertension.39
and vasodilators (nitric oxide, prostacyclin), growth promot-
ing and inhibitory factors, proatherogenic and antiatherogenic
factors, and procoagulant and anticoagulant factors.24,25 A Mechanisms of Vascular Complications in
substantial body of evidence suggests that impaired Diabetes and the Impact of Hypertension
endothelium-dependent vasodilation may in turn contribute A number of interacting mechanisms are in play as sum-
to or exacerbate insulin resistance by limiting the delivery of marized in the following sections (Fig. 2).
substrate (glucose) to key target tissues.26
AGE-RAGE axis
In addition to these functional changes, an associated
low-grade inflammation in endothelial and smooth muscle AGEs are compounds that have undergone irreversible
cells of the vascular wall causes cell proliferation, hypertrophy, posttranslational modifications because of reactions between
remodelling, and apoptosis.27 This accelerates disruption of sugars and amino groups on proteins and nucleic acids.
the balance between the arterial wall scaffolding proteins Hyperglycemia accelerates formation of AGEs, which accu-
elastin and collagen that determine vascular compliance, a mulate in the extracellular matrix of vessels and contribute to
form of “vascular aging,” which is a characteristic phenotype vascular damage in diabetes.40 AGEs stimulate production of
in hypertension.28-31 Vascular stiffening leads to widening of reactive oxygen species (ROS), which in turn further enhance
arterial pulse pressure and increased pulsatile shear, exacer- AGE formation. AGEs are also antigenic and hence induce
bating endothelial dysfunction and vascular disease.32 immune responses.40 In addition to AGEs, dicarbonyl
methylglyoxal, a by-product of glycolysis, accumulates in tis-
sues and contributes to diabetes-associated vascular damage.41
Microvascular Disease AGEs interact with 2 main types of cell surface receptors:
(1) scavenger receptors, which remove and degrade AGEs, and
Clinical features (2) receptors for AGEs (RAGE), which trigger specific cellular
Microvascular disease leads to retinopathy, nephropathy, and signalling responses on AGE binding. RAGE is a member of
neuropathy, which are major causes of morbidity and mortality the immunoglobulin family and binds many ligands besides
in patients with diabetes. In the United States, diabetic reti- AGEs, such as high mobility group protein B1, S100 calcium-
nopathy affects about 28% of individuals with established binding proteins (including calgranulin), amyloid-b-protein,
T2D.33 Worldwide it is responsible for 10,000 cases of blind- and amphotericin. AGE-RAGE signals through transforming
ness every year.34,35 Diabetic nephropathy affects about 25% of growth factor (TGF)-b, NF-kB, mitogen-activated protein
individuals with T2D and is the most common cause of renal kinases (MAPK; ERK1/2, p38MAPK), and nicotinamide
failure in the United States.36 Neuropathy affects about 20% of adenine dinucleotide phosphate (NADPH) oxidases (Nox)
these individuals, although it is estimated that about 50% have and induces expression of vascular adhesion molecule 1, E-
neuropathy at some point in their lives.36 Each of these organ- selectin, vascular endothelial growth factor, and proin-
specific microvascular complications has its own unique clin- flammatory cytokines (IL-1b, IL-6, TNF-a).42 In diabetes,
ical and histologic features, but all are common with increasing activation of these signalling pathways is increased in vascular
duration of hyperglycemia and are driven by its downstream smooth muscle cells, leading to vascular fibrosis, calcification,
cellular effects, including polyol accumulation (resulting from inflammation, prothrombotic effects, and vascular damage,
saturation of the hexokinase pathway and consequent increased processes underlying diabetic nephropathy, retinopathy,
activity of aldose reductase), AGE-induced injury, increased neuropathy, and atherosclerotic CVD.43 Coexisting hyper-
vascular permeability, and oxidative stress.8 tension amplifies these complications and contributes to the
Follow-up of the Action in Diabetes and Vascular Disease:
Preterax and Diamicron Controlled Evaluation (ADVANCE)
trial cohort has confirmed that the presence of microvascular Diabetes Hypertension

complications increases the risk of cardiovascular complica-

tions in individuls with T2D.37 Moreover, the coexistence of
hypertension and retinopathy is a risk factor for the progres- Immune OxidaƟve InflammaƟo
Hyperglycemia RAAS InflammaƟon miRNA
sion of nephropathy. There is evidence that treatment of acƟvaƟon stress n

hypertension with angiotensin II receptor blockers can reduce

the progression of retinopathy in addition to well-known AGEs Macrovascular and
effects on nephropathy.38 RAGE Microvascular disease

Pathophysiological features Figure 2. Putative mechanisms whereby diabetes and hypertension

cause vascular disease. Immune cell activation and inflammation are
Pathognomonic alterations of diabetic microangiopathy mediated through oxidative stress. AGEs, advanced glycation end
include capillary basement membrane thickening, increased products; RAAS, renin-angiotensin-aldosterone system; RAGE, recep-
endothelial permeability, and endothelial and vascular smooth tor AGE.
578 Canadian Journal of Cardiology
Volume 34 2018

accelerated vasculopathy in diabetes.44 Patients with diabetes phosphatases, transcription factors, Ca2þ channels, ion
have increased tissue and circulating concentrations of AGEs transporters, and proinflammatory genes.52 In diabetes and
and soluble RAGE, which is predictive of cardiovascular hypertension, oxidative stress (increased ROS bioavailability)
events and all-cause mortality. As such, urinary and plasma promotes vascular inflammation, fibrosis, and injury, pro-
AGE levels and soluble RAGE may act as biomarkers for cesses that are normalized by Nox inhibitors or ROS scav-
vascular disease in diabetes.45 engers, or both. Nox1, but not Nox4, seems to be important
Targeting AGE-RAGE has been considered a potential in atherosclerosis in diabetes, as we demonstrated in Nox1-
therapeutic strategy to reduce or prevent CVD in diabetes. A deficient mice on the atherosclerosis-prone ApoE/ back-
number of large clinical trials investigating cardiovascular ground made diabetic with streptozotocin.53 Nox4 has been
benefits of alagebrium (ALT-711), which reduces accumula- implicated in renal injury in mouse models of diabetes, effects
tion of AGEs by cleaving AGE cross-links, have been that are ameliorated with Nox1/4 inhibitors and in mice
undertaken. They include Distensibility Improvement and deficient in Nox4.54,55 Nox5 may also be important in
Remodeling in Diastolic Heart Failure (DIAMOND; diabetes-associated vascular injury and nephropathy. We
NCT00043836), Systolic and Pulse Pressure Hemodynamic demonstrated that renal Nox5 expression is increased in pa-
Improvement By Restoring Elasticity (SAPPHIRE; tients with diabetic nephropathy. Moreover, in transgenic
NCT00045981), Systolic Hypertension Interaction With Left mice with podocyte-specific expression of human Nox5, renal
Ventricular Remodeling (SILVER; NCT00045994), Systolic injury was amplified by diabetes.56 Similar findings were
Pressure Efficacy and Safety Trial of Alagebrium (SPECTRA; observed in mice expressing human Nox5 in a vascular
NCT00089713), Beginning a Randomized Evaluation of the smooth muscle cell-specific manner.57 Although extensive
AGE Breaker Alagebrium in Diastolic Heart Failure I experimental evidence showed a renoprotective effect of Nox4
(BREAK-DHF-I; NCT00662116), and Evaluating the Effi- inhibition in diabetes, a recent clinical study using
cacy and Safety of Alagebrium (ALT-711) in Patients With GKT137831, a Nox1/4 inhibitor, failed to show improve-
Chronic Heart Failure (BENEFICIAL; NCT00516646). ment in renal function in patients with diabetic nephropa-
However few data have been published from these studies. thy.58 Whether targeting Nox5 may have better clinical
Some small clinical studies demonstrated cardiovascular benefit outcomes is unclear, because to date there are no Nox5 in-
in patients with diabetes and hypertension.46 In particular, hibitors available.
alagebrium improved endothelial function, reduced aortic
stiffness, and increased vascular compliance.47 Inflammation and the immune system
Links between inflammation and the immune system with
Oxidative stress and Nox metabolic dysfunction, hypertension, and cardiovascular
Oxidative stress is a key mechanism of glucotoxicity in morbidity are supported by extensive experimental data.59
diabetes, as evidenced by increased vascular ROS generation This encompasses a number of immune metabolic aspects,
in response to hyperglycemia and accumulation of oxidation including the key role of the tricarboxylic cycle or sphingo-
by-products of lipids, proteins, and nucleic acids.27 NADPH sine-1-phosphate in the regulation of vascular inflamma-
oxidases and dysfunctional endothelial nitric oxide synthase tion.59,60 Clinical studies have shown that patients with T2D
are principal sources of increased ROS in human vasculature have increased total leukocyte counts, particularly neutrophils
in T2D.48,49 ROS interact with DNA and stimulate many and lymphocytes, that correlate with insulin sensitivity,61
redox-sensitive signalling pathways that lead to inflammation, which is in part mediated by inflammatory changes of adi-
fibrosis, and vascular damage. Increased vascular oxidative pose tissue.62 Inflammatory biomarkers are also useful in
stress in diabetes and hypertension promotes posttranslational developing targeted cardiovascular therapies in the context of
oxidative modification of proteins, causing cellular damage metabolic dysfunction.63 The link between inflammation and
and vascular dysfunction. Hyperglycemia also induces acti- T2D is further supported by genetic studies and clinical trials
vation of redox-sensitive protein kinase C and polyol and showing protective effects of immune-targeted therapies and
hexosamine pathways, further contributing to mitochondrial anti-inflammatory actions of classic antidiabetes drugs.64
dysfunction, oxidative stress, endoplasmic reticulum stress, Circulating and locally produced effector cytokines such as
and consequent cellular damage.50 Oxidative stress is also TNF-a, interferon-g, IL-1b, and IL-12 may influence insulin
associated with reduced bioavailability of the vasodilator nitric sensitivity of peripheral tissues and can modulate insulin
oxide, causing endothelial dysfunction. release in the pancreatic islets.65-68 Increased glucotoxicity and
Diabetes-induced oxidative stress is caused by numerous lipotoxicity have been associated with immune cell infiltration
processes, including glucose-stimulated mitochondrial respi- of target tissues, thereby affecting diabetes-associated target
ration, endoplasmic reticulum stress, activation of the renin- organ damage and cardiovascular complications,68,69
angiotensin system (which is pro-oxidant), decreased including the development of metabolic cardiomyopa-
vascular antioxidant capacity, reduced activity of the master thy.70,71 Inflammation is a key modulator of metabolic and
antioxidant transcription factor nuclear factor-erythroid 2- diabetic CVD.
related factor (Nrf-2), and activation of Nox isoforms.51 Of
these mechanisms activation of Nox types is particularly Genetic evidence. Although genome-wide association
important. Four Nox isoforms have been demonstrated in studies (GWAS) for insulin resistance or T2D have not shown
human vessels, including Nox1, Nox2, Nox4, and Nox5. strong associations with immune-related genes, numerous
Nox-derived ROS influence redox-sensitive signalling path- metabolic traits are linked to immune-related loci.72 Studies
ways in vascular cells such as MAPKs, protein tyrosine integrating metabochip approaches with GWAS have shown
Petrie et al. 579
Diabetes, Hypertension, and Vascular Complications

that classic immunometabolic genes including JNK signalling analogue 5-aminoimidazole-4-carboxamide ribonucleotide,
pathways (such as MAP3K1), nuclear factor kappa B (NF-kB) effects that appear stronger than those of metformin.80 Recent
regulators (MACROD1), inflammasome activators (NRF3), studies have shown that salicylates have anti-inflammatory
and interferon-g receptor genes associate with T2D.73,74 This effects that involve inhibition of NF-kB and that they also
also corresponds to results of recent large T2D GWAS that prevent diabetes and improve insulin resistance in experi-
identified genes related to macrophage function and antigen mental models and humans.81,82 Drugs such as glicazide and
presentation (MAEA, ST6GAL1), and T-cell signalling (CMIP troglitazone, as well as N-acetylcysteine, decrease inflamma-
or PTPRJ).72,75 While trying to interpret these important tory markers in patients with diabetic nephropathy and
studies, it should be appreciated that GWAS approaches have diabetic retinopathy.83
limitations, because only a small component of heritability of Epigenetics is another mechanism that may influence
complex traits is directly explainable by single-gene inflammation and immunometabolism in diabetes.59 Histone
variability.76 deacetylase (HDAC) inhibitors cause NF-kB inhibition
through acetylation of the p65 subunit. Givinostat (formerly
Clinical evidence. Increasing clinical evidence indicates an ITF2357), an orally active HDAC inhibitor, has been shown
immune component in T2D and its cardiovascular compli- to prevent the development of diabetes.84,85 Similarly, acti-
cations. Immune-targeted therapies currently available for the vation of sirtuin1, which is involved in inflammation, meta-
treatment of rheumatoid arthritis and autoimmune disorders, bolism, and aging, has been shown to have anti-inflammatory
including anti-TNF therapies, may prevent insulin resistance properties in diabetes.86
as well as cardiovascular risk.64,77 A recent meta-analysis of
studies with anti-TNF agents supports an overall protective
effect of anti-TNF therapies on lifetime risk of diabetes as well MiRNAs, Diabetes, and Vascular Complications
as insulin sensitivity and obesity.74 miRNAs are a group of noncoding RNAs that are multi-
A recent large proof of concept trial of anti-inflammatory functional. They fine tune gene expression and have been
therapy in patients after myocardial infarction (A Random- implicated in various pathologic processes, including T2D
ized, Double-blind, Placebo-controlled, Event-driven Trial of and the development of diabetic vascular complications. A
Quarterly Subcutaneous Canakinumab in the Prevention of number of pancreatic B-cellespecific miRNAs have been
Recurrent Cardiovascular Events Among Stable Post- identified, including miR-375, miR-124a, miR-96, miR-7a,
Myocardial Infarction Patients With Elevated hsCRP miR7a2, miR-30d, miR-9, miR-200, miR-184, and let-7.87
[CANTOS]; canakinumab targeting IL-1b) showed a clear These play a role in pancreatic function, insulin secretion,
reduction in the rate of cardiovascular events, albeit with an and glucose tolerance. Differential miRNA signatures have
associated increase in the rate of severe infections.78 These been identified among prediabetic individuals, patients with
results were particularly evident in high-risk patients, although diabetes, and patients with diabetes and vascular complica-
effects on metabolic profile remain unclear.78 However, evi- tions, suggesting that miRNAs may be novel biomarkers.
dence that IL-1b targeting may have significant metabolic Diabetic cardiovascular complications are associated with
benefits has been well established, as evidenced by improved increased levels of miR-223, miR-320, miR-501, miR504,
profile insulin sensitivity in response to IL1-b blockade.79 The and miR1 and decreased levels of miR-16, miR-133,
potential beneficial effects of anti-inflammatory and immune- miR-492, and miR-373.9 Whether these changes in miRNA
modulating agents in T2D and its complications may relate to are simply biomarkers of disease or whether they are directly
direct vasoprotective effects. These studies have led to the involved in the vasculopathy of diabetes remains unclear.
rapid development of the concept of immunometabolism,
clearly linking metabolic changes in the tissues to the regu- Treatment of diabetes mellitus and its cardiovascular
lation of inflammation as well as metabolic status of immune complications
cells to their activation.28,56 The latter can be characterized by Once T2D has been diagnosed, the aim of achieving
a switch between oxidative phosphorylation and anaerobic glucose control is principally to avoid microvascular compli-
glycolysis, which is observed in macrophages and T cells.30,59 cations. There are some benefits with respect to macrovascular
This also emphasizes the importance of the interplay between complications, but this is dependent on the profile of indi-
vascular oxidative stress and the development of inflammation vidual drug classes and even appears to be different for agents
in adipose tissue and the vasculature. within the same class.88 The role of BP lowering to improve
prognosis in T2D has been established since the UK Pro-
Anti-inflammatory properties of antidiabetic therapies. spective Diabetes Study (UKPDS) in 1998.89,90 However,
Classic approaches improving metabolic health, such as more recently, more widespread use of glucose-lowering
weight reduction and the use of metformin, statin drugs, agents that reduce (rather than increase) weight, lower BP,
pioglitazone, and insulin have been shown to have anti- and have beneficial “off-target” effects (as demonstrated in
inflammatory effects. Metformin reduces C-reactive protein recent large cardiovascular outcome trials) facilitates cardio-
levels by 13%. More recently, a novel anti-inflammatory vascular risk factor control and is playing a role in improving
mechanism of metformin affecting M1/M2 polarization of the cardiovascular prognosis of T2D.91,92
macrophages has been shown to reduce obesity-associated Achieving glucose control in T2D begins with weight
low-grade inflammation, possibly because of adenosine management. Particularly in the first 8 years after diagnosis,
monophosphate-activated protein kinase (AMPK) activation. normal glucose tolerance can be restored if radical weight
These effects were modulated by AMPK and the AMPK reduction can be achieved, most effectively using a very low
580 Canadian Journal of Cardiology
Volume 34 2018

calorie liquid replacement diet.93 In obese patients, this can associated reductions in BP and plasma volume, which
also occur after successful bariatric surgery, particularly the together may have been responsible for the early reduction in
Roux-en-Y procedure.94 The mechanism may involve reduc- cardiovascular event rates seen with empagliflozin in Empa-
tion in ectopic fat, and consequent relief from its proin- gliflozin, Cardiovascular Outcomes, and Mortality in Type 2
flammatory effects, in and around the pancreatic islets of Diabetes (EMPA-REG OUTCOME) trial.91 A shift in fuel
Langerhans.95 substrate metabolism from glucose to NEFAs and ketones,
All current glucose-lowering guidelines suggest the early including by the myocardium, is 1 of the mechanisms by
addition of metformin as first-line therapy. Unlike the sul- which SGLT2 inhibitors may provide cardiovascular pro-
phonylureas, which augment insulin secretion, metformin tection,107 but studies in apoE knockout mice and Zucker
lowers blood glucose levels principally by decreasing hepatic diabetic fatty rats suggest that anti-inflammatory effects may
glucose production and promoting weight reduction (with also play a role.108
little effect on BP). Among the many proposed mechanisms of
action of metformin is activation of AMPK: This is now
Diabetes, vasoprotection, and potential new therapies
thought to be a secondary effect of inhibition of the mito-
chondrial respiratory chain.96 Such effects of metformin may Data from landmark clinical trials in T2D including
act directly (ie, independent of blood glucose lowering) on UKPDS, ADVANCE, and Action to Control Cardiovascular
other tissues, including vascular endothelial cells. Metformin Risk in Diabetes (ACCORD) demonstrate that treating
treatment is associated with improvements in endothelial comorbidities including hypertension and hypercholesterole-
biomarkers and reduction in plasma high-sensitivity C-reac- mia is a more effective strategy for reducing cardiovascular
tive protein levels.97,98 It was associated with cardiovascular complications than targeting blood glucose levels with con-
benefit in the landmark UKPDS.99 ventional agents.109 Antihypertensive drugs such as
Other second-line agents used in glucose lowering include angiotensin-converting enzyme inhibitors, angiotensin-
pioglitazone, a thiazolidinedione that directly promotes the receptor blockers, mineralocorticoid-receptor blockers, and
differentiation of adipocytes within subcutaneous adipose calcium-channel blockers may have direct vasoprotective
depots (by activation of peroxisome proliferator-activated effects, and their use may contribute, at least in part, to
receptor-g), thus promoting storage of non-esterified fatty reduced vascular complications in patients with diabetes and
acids (NEFAs).100 Pioglitazone reverses many of the metabolic concomitant hypertension.110 Tight control of BP has been
features associated with insulin resistance without much effect shown to reduce cardiovascular risk in T2D: most recent US
on BP. Anti-inflammatory effects have been demonstrated in and Canadian guidelines recommend a target of < 130/80
human adipose tissue biopsy samples and also in some animal mm Hg.111,112 Statin drugs and clopidrogel are also vaso-
models.101 There was great hope in the 1990s that agents protective and may have extra benefit in patients with
from this class would have major benefits for the cardiovas- diabetes. Some of the beneficial effects of these drugs have
cular system, a hypothesis that was to some extent supported been attributed to their antioxidant and anti-inflammatory
by the results of the Prospective Pioglitazone Clinical Trial in properties.
Macrovascular Events (PROACTIVE) cardiovascular New therapeutic approaches targeting oxidative stress,
outcome trial, although beneficial effects were offset by weight inflammation, and fibrosis are currently being developed to
gain and fluid retention.102 treat diabetes-associated cardiovascular complications.113 In
More recently introduced classes of glucose-lowering particular, drugs that increase Nrf-2 activity, such as bardox-
agents have heralded an exciting era in T2D pharmaco- olone methyl, and strategies to inhibit the pyrin domain
therapy because they are associated with weight reduction, BP containing 3 (NLRP3) inflammasome, may have therapeutic
reduction, and, importantly, reduced rates of major adverse potential. A novel bardoxolone methyl derivative, dh404, has
events in long-term cardiovascular outcome trials.91,92,103 been shown to attenuate endothelial dysfunction, reduce
Glucagon-like peptide-1 agonists are injectable agents that Nox1 expression, decrease oxidative stress, and inhibit
augment glucose-dependent insulin secretion (the “incretin” inflammation in diabetic mice, suggesting that upregulation of
effect), delay gastric emptying (enhancing satiety), and have Nrf2 may have therapeutic potential to limit diabetes-
central effects on hypothalamic nuclei to reduce appetite.104 associated vascular damage.114 Another example includes
Systolic BP is lowered beyond the effect that would be inhibition of dipeptidyl peptidase-4 by linagliptin, which
expected purely from weight loss, and there is an improve- reduces obesity-related insulin resistance and inflammation by
ment in pulse-wave velocity, reflecting a reduction in arterial regulating M1/M2 macrophage status.115 Other therapies on
stiffness. However, the time course of cardiovascular event the horizon for the treatment of cardiovascular complications
reduction in the Liraglutide Effect and Action in Diabetes: of diabetes include pentoxifylline (methylxanthine derivative
Evaluation of Cardiovascular Outcome Results (LEADER) and nonspecific phosphodiesterase inhibitor with anti-
trial suggests a primary antiatherosclerotic rather than hemo- inflammatory and antifibrotic effects), ruboxistaurin (selec-
dynamic effect.91 Indeed, liraglutide has been shown to have tive protein kinase C-b inhibitor), pirfenidone (TGF-b
anti-inflammatory actions on the cardiovascular system in a inhibitor), bindarit (MCP-1/CCL2 inhibitor), sulodexide (an
number of preclinical and clinical studies.103,105 oral formulation composed of 2 glycosaminoglycans),
SGLT2 inhibitors promote lowering of the threshold for AKB-9778 (Tie2 activator), baricitinib (JAK/STAT inhibi-
urinary glucose excretion: an additional glucose equivalent to tor), and Nox inhibitors.116 The clinical benefit of these
300 kcal per day is therefore cleared by the kidneys, pro- compounds awaits further confirmation, and novel nano-
moting weight loss and a catabolic state with increased therapeutic approaches are being developed to target
circulating ketone bodies and NEFAs.106 There are inflammation.117
Petrie et al. 581
Diabetes, Hypertension, and Vascular Complications

Conclusions 12. Haffner SM, Lehto S, Ronnemaa T, Pyorala K, Laakso M. Mortality

Diabetes is associated with an increased risk of CVD, from coronary heart disease in subjects with type 2 diabetes and in
which is exaggerated with coexistent hypertension. Many of nondiabetic subjects with and without prior myocardial infarction.
N Engl J Med 1998;339:229-34.
the underlying molecular mechanisms, including oxidative
stress, inflammation, and fibrosis causing microvascular and 13. Abbott RD, Donahue RP, Kannel WB, Wilson PW. The impact of
macrovascular complications of diabetes, also cause vascular diabetes on survival following myocardial infarction in men vs women.
remodelling and dysfunction in hypertension. Controlling The Framingham Study. JAMA 1988;260:3456-60.
comorbidities, especially hypertension, and targeting strategies
14. Balkau B, Eschwège E, Papoz L, et al. Risk factors for early death in
to promote vascular health, may be especially important in
non-insulin dependent diabetes and men with known glucose tolerance
reducing the microvascular and macrovascular complications status. BMJ 1993;307:295-9.
of diabetes.
15. Miller ME, Williamson JD, Gerstein HC, et al. Effects of randomiza-
tion to intensive glucose control on adverse events, cardiovascular dis-
Funding Sources ease, and mortality in older versus younger adults in the ACCORD trial.
This work was supported by grants from the British Heart Diabetes Care 2014;37:634-43.
Foundation (RG/13/7/30099, RE/13/5/30177), the Well-
16. Gæde P, Oellgaard J, Carstensen B, et al. Years of life gained by
come Trust Senior Biomedical Fellowship (to T.J.G.), and the
multifactorial intervention in patients with type 2 diabetes mellitus and
National Science Centre of Poland (2011/03/B/NZ4/02454). microalbuminuria: 21 years follow-up on the Steno-2 randomised trial.
Diabetologia 2016;59:2298-307.
Disclosures 17. Ferrannini E, Buzzigoli G, Bonadonna R, et al. Insulin resistance in
The authors have no conflicts of interest to disclose. essential hypertension. N Engl J Med 1987;317:350-7.

18. Giordano A, Murano I, Mondini E, et al. Obese adipocytes show ul-

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