Hypertension Research

https://doi.org/10.1038/s41440-017-0008-y

REVIEW ARTICLE

Hypertension with diabetes mellitus complications

Daisuke Yamazaki1 Hirofumi Hitomi1 Akira Nishiyama1
● ●

Received: 23 July 2017 / Revised: 2 September 2017 / Accepted: 6 September 2017

© The Japanese Society of Hypertension 2018

Abstract
Chronic diabetic complications are classified as microvascular or macrovascular and contribute to mortality and loss of
quality of life. Hyperglycemia plays a critical role in the pathogenesis of microvascular complications, such as diabetic
retinopathy, incipient nephropathy, and neuropathy, while atherosclerosis contributes to the pathogenesis of macrovascular
complications. Diabetes mellitus and hypertension are frequently present together. Among many microvascular diabetic
complications, hypertension plays a predominant role in the progression of diabetic nephropathy by glomerular
hyperfiltration. Hypertension also induces atherosclerosis in diabetes. Thus, hypertension is a high-risk factor for both
microvascular and macrovascular chronic diabetic complications. In this review, we summarize the current knowledge on
the pathophysiological mechanisms of microvascular and macrovascular chronic diabetic complications with particular
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emphasis on the contribution of hypertension. We also briefly discuss various options available for the treatment of each
diabetic complication.

Introduction The pathophysiology of microvascular complications has

Diabetic complications are classified as acute and chronic
complications. Acute complications include diabetic
ketoacidosis, nonketotic hyperosmolar coma, and hypo-
glycemia. Chronic complications include injuries to the
small (microvascular complications) and large blood vessels
(macrovascular complications).
Microvascular complications are involved in diabetic
neuropathy, retinopathy, and nephropathy. In contrast,
macrovascular complications contribute to the pathogenesis
of cardiovascular disease (CVD), such as coronary, cere-
brovascular and peripheral arterial diseases. The presence of
either microvascular or macrovascular complications redu-
ces quality of life, because these lead to blindness, end-
stage renal disease, heart failure, and lower leg amputation
[1]. It has been shown that macrovascular complications are
the leading cause of death and account for 44 and 52% of
deaths in patients with type 1 and type 2 diabetes, respec-
tively, from 10 centers throughout the world [2].
* Akira Nishiyama
akira@kms.ac.jp
1
Department of Pharmacology, Faculty of Medicine, Kagawa
University, Kagawa, Japan
still not been completely elucidated, but several clinical
studies have suggested that long-lasting hyperglycemia may
play a central role. For example, epidemiological studies
have shown that the duration of diabetes is strongly asso-
ciated with the onset of microvascular complications [3].
Furthermore, microvascular complications can be prevented
or minimized by optimal blood glucose control [4, 5].
Several molecular mechanisms, including the polyol path-
way, the sorbitol pathway, advanced glycation end pro-
ducts, activation of protein kinase C, the hexosamine
pathway and oxidative stress may play an important role in
the pathophysiological mechanisms of microvascular dia-
betic complications [6].
Hypertension also contributes to the pathogenesis of
microvascular complications in diabetes, because blood
pressure control can decrease the onset and development of
microvascular complications [7]. However, the precise
pathophysiological mechanisms responsible for
hypertension-induced microvascular complications are
unclear.
Atherosclerosis leads to stenosis or obstruction of arter-
ies, which plays a predominant role in the progression of
macrovascular diabetic complications. Atherosclerosis
develops in combination with the other cardiovascular risk
factors, such as hypertension. Indeed, hypertension is more
frequent in patients with type 2 diabetes, and the risk of

CVD in patients with both hypertension and diabetes is
greater than that in patients with either disease alone [8].
The association between diabetes and hypertension can
be partially explained by insulin resistance. Clinical studies
have demonstrated that approximately half of patients with
hypertension display hyperinsulinemia [9]. Hyper-
insulinemia leads to hypertension by enhancing sodium
reabsorption in the kidney and stimulating the sympathetic
nervous system [10]. Thus, insulin resistance may be an
important therapeutic target for preventing CVD in hyper-
tensive patients with diabetes.
In this review, we summarize the current knowledge on
the pathophysiological mechanisms and management of
microvascular diabetic complications (diabetic retinopathy,
nephropathy, and neuropathy) with particular emphasis on
the contribution of hypertension. Macrovascular diabetic
complications are also briefly discussed.
Diabetic microvascular complications
Diabetic retinopathy
Pathophysiology of diabetic retinopathy
Diabetic retinopathy is a disorder of the retinal vasculature
in the light-sensitive tissue that eventually leads to blind-
ness. Duration of diabetes and the severity of hyperglyce-
mia are major risk factors for the development and
progression of diabetic retinopathy. Hypertension is also
included as a risk factor for diabetic retinopathy [11].
Several molecular pathways have been investigated for
the pathogenesis of diabetic retinopathy. Vascular endo-
thelial growth factor (VEGF) is considered to be an
important mediator of diabetic retinopathy [12]. VEGF is
highly expressed in the retina of patients with proliferative
diabetic retinopathy [13], where it induces angiogenesis
[14]. Clinical trials have shown that intraocular injection
of antibodies against VEGF is more effective than tradi-
tional laser therapy for patients with diabetic macular edema
[15]. Currently, two drugs (ranibizumab or aflibercept)
have been clinically approved for diabetic macular edema
in Japan.
Hypertension exacerbates diabetic retinopathy by
hemodynamic changes and VEGF-dependent pathways
[16]. The blood flow in the retinal artery is regulated stably
by autoregulation in healthy subjects. However, retinal flow
is increased in hypertensive patients with diabetes [17].
These results suggest that there are associations between
diabetes, hypertension, and retinal blood flow. Reduced
contraction of retina pericytes or thickening of retinal
capillary basement membrane may impair retinal blood
flow regulation [18]. Hypertension also contributes to the
D. Yamazaki et al.
upregulation of retinal expression of the VEGF receptor
VEGF-R2 by increasing cyclic stretch of the retinal
artery [19].
Treatment of diabetic retinopathy
Screening by an ophthalmologist is necessary for early
detection of diabetic retinopathy. Therapeutic approaches
include ophthalmologic treatment, such as laser surgery,
vitrectomy, and VEGF antibody injection. In addition,
glycemic control and blood pressure management are
important to reduce the incidence and slow the progression
[20]. The Diabetes Control and Complications Trial
(DCCT) demonstrated that intensive glycemic control
reduced the risk of incidence and slowed the progression of
diabetic retinopathy in patients with type 1 diabetes [4]. The
DCCT/Epidemiology of Diabetes Interventions and Com-
plications (EDIC) study was conducted to determine the
lasting effect of previously assigned therapies after the
DCCT was terminated. Data revealed that the efficacy of
risk reduction persisted despite worsening of glycosylated
hemoglobin levels at least 4 years after study completion
[21]. These results suggest that tight glycemic control has a
lasting effect on diabetic retinopathy. The United Kingdom
Prospective Diabetes Study (UKPDS) also demonstrated a
similar effect of glycemic control on diabetic retinopathy in
patients with type 2 diabetes [5]. The Kumamoto study [22]
demonstrated that a glycemic goal of glycosylated hemo-
globin less than 6.5% was desirable for preventing the
incidence and development of diabetic retinopathy. Of note,
this study is the only study to indicate a proper glycemic
goal for preventing and slowing diabetic microvascular
complications.
Intensive quick glycemic control may cause not only
hypoglycemia but also early worsening of diabetic retino-
pathy. In the DCCT, worsening diabetic retinopathy was
observed in 13.1% of the intensive glycemic control group
vs. 7.6% of the control group. However, this deterioration
was reversible, and there was no serious vision loss asso-
ciated with worsening diabetic retinopathy [23].
Blood pressure control may be important for diabetic
retinopathy, but the efficacy remains controversial. The
UKPDS showed that intensive blood pressure control
(<150/85 mmHg) significantly inhibited the progression of
diabetic retinopathy and visual deterioration in patients with
type 2 diabetes [7]. However, the Appropriate Blood Pres-
sure Control in Diabetes (ABCD) trial demonstrated that
there was no difference in progression of diabetic retino-
pathy between the intensive (132/78 mmHg) and moderate
blood pressure control (138/86 mmHg) groups [24]. The
lack of efficacy of blood pressure control may be associated
with the short time period of the trial and/or poor glycemic
control. Recent systematic reviews of 15 randomized trials
Diabetic complications and hypertension
have shown that blood pressure control reduces the inci-
dence but not progression of diabetic retinopathy [25].
Several studies have suggested that renin angiotensin
system (RAS) inhibitors elicit a significant reduction in the
risk of diabetic retinopathy. The EURODIAB Controlled
Trial of Lisinopril in Insulin-Dependent Diabetes Mellitus
(EUCLID) revealed that the angiotensin converting enzyme
(ACE) inhibitor lisinopril reduced the progression of dia-
betic retinopathy in normotensive patients with type 1 dia-
betes without albuminuria [26]. However, the UKPDS
69 study showed that the effects of ACE inhibitors were not
superior to β blockers [27]. The Diabetic Retinopathy
Candesartan Trials Prevent and Project (DIRECT) 1 study
indicated that the angiotensin receptor blocker (ARB) can-
desartan tends to reduce the incidence of diabetic retino-
pathy in patients with type 1 diabetes. However, these
changes were not statistically significant [28]. In the Dia-
betic Retinopathy Candesartan Trials Prevent and Project
(DIRECT) 2 study, candesartan also tends to reduce the
progression of diabetic retinopathy [29]. It was also
demonstrated that control of hyperlipidemia with fenofi-
brate decreased the number of patients with type 2 diabetes
and diabetic retinopathy that required laser treatment in the
Fenofibrate Intervention and Event Lowering in Diabetes
(FIELD) study [30].
Diabetic kidney disease
Pathophysiology of diabetic nephropathy
Diabetic kidney disease (DKD) is characterized by albu-
minuria and a decline in the glomerular filtration rate
(GFR). DKD is the primary cause of end stage renal disease
requiring renal replacement therapy and is associated with
increased CVD. Microalbuminuria (30–299 mg/day, mod-
erately increased albuminuria) is a predictive factor for later
progression of DKD and is the earliest clinical manifesta-
tion [31]. Without medical treatment, albuminuria increases
at a rate of 10 to 20% per year. Thereafter, the GFR falls by
2–20 ml/min/1.73 m2/year [31]. In contrast to incipient
nephropathy, nephropathy with urine protein of more than
300 mg/day is termed overt nephropathy. Microalbuminuria
is also an independent risk factor of CVD [32]. Hypergly-
cemia, hypertension, dyslipidemia, glomerular hyperfiltra-
tion (defined by GFR between 125 and 140 mL/min/1.73 m2
or greater than 2 standard deviations above the average
GFR in healthy individuals) and smoking, in addition to
protein intake, are modifiable risk factors of DKD [33–35].
In addition to hyperglycemia, glomerular hypertension,
and hyperfiltration are characteristic mechanisms of DKD
that lead to proteinuria and glomerular injury [36]. GFR is
controlled by renal autoregulation, which is regulated by
glomerular afferent arteriolar tone. Both the myogenic
response and tubuloglomerular feedback (TGF) play an
important role in the regulation of glomerular afferent
arterial tone. Glomerular hyperfiltration is assumed to
develop because of impaired regulation of glomerular
afferent arterial tone [37]. The following two hypotheses
explain this proposed mechanism. The vascular hypothesis
suggests that glomerular hyperfiltration is caused by an
abnormality in the afferent arteriolar myogenic response
[38]. Inappropriate afferent arteriolar vasodilation is
induced by an impaired myogenic response in diabetes, thus
leading to glomerular hyperfiltration. Glomerular hyperfil-
tration causes mechanical stretch on the glomerular struc-
ture and then produces an extracellular matrix, which is
responsible for glomerular sclerosis [39]. RAS blockade
causes glomerular efferent arteriole dilation, which prevents
glomerular hyperfiltration [40].
TGF regulates GFR by altering afferent arteriole tone in
response to altered sodium, chlorine and solute delivery to
the macular densa. In patients with diabetes, sodium reab-
sorption in the proximal tubule is increased and sodium
chloride delivery to the macula densa is decreased [41].
This reduction in sodium chloride delivery causes glo-
merular hyperfiltration by vasodilating afferent arteriole
tone through a reduction in TGF activity [42]. The reno-
protective effect of sodium glucose transporter 2 (SGLT2)
inhibitors can be partially explained by restored TGF [43].
SGLT2 inhibition blocks sodium and glucose reabsorption
in the proximal tubule, leading to increased solute delivery
to the macular densa and TGF activity.
DKD and hypertension are bidirectional. Diabetes mel-
litus amplifies the effects of blood pressure by impairing
autoregulation as mentioned above. In addition, the sup-
pression of RAS and NO by sodium loading is weak in
diabetes, leading to hypertension [44]. Increased sympa-
thetic nerve activity also contributes to the pathogenesis of
hypertension with diabetic nephropathy [45]. Furthermore,
oxidative stress is associated with hypertension, because
oxidative stress influences vasoactive agents, such as RAS,
and causes endothelial dysfunction [46].
Treatment of diabetic nephropathy
Several studies have indicated that glycemic control is
effective for incipient diabetic nephropathy. The DCCT
study and UKPDS showed that intensive glycemic control
reduced the incidence of microalbuminuria in both type 1
and type 2 diabetes with normoalbuminuria [4, 5]. The
DCCT/EDIC study demonstrated that the legacy effects of
intensive glycemic control were sustained at least 4 years
after the DCCT was concluded [23]. Furthermore, the
Action in Diabetes and Vascular Disease: PreterAx and
DiamicroN‐MR Controlled Evaluation (ADVANCE) trial
revealed that intensive glycemic control significantly

decreased the incidence and progression of diabetic
nephropathy in high-risk patients with type 2 diabetes [47].
However, the efficacy of intensive glycemic control for
overt diabetic nephropathy is controversial. In the DCCT
study, intensive glycemic control did not slow the pro-
gression from microalbuminuria to overt diabetic nephro-
pathy. However, the DCCT/EDIC, the trial that investigated
the glycemic legacy effect after the DCCT was concluded,
demonstrated that the progression to proteinuria was pre-
vented in patients who were treated with intensive glycemic
control within the DCCT. This occurred, despite no dif-
ferences of in the current condition of glycemic control
conditions with in comparison with control patients [48].
The UKPDS did not collect any data regarding the efficacy
on preventing the progression to overt diabetic nephropathy
[5]. Interestingly, histological analysis, which was per-
formed 10 years after pancreas transplantation in patients
with type 1 diabetes, revealed that thickening of the base-
ment membrane, mesangial matrix expansion, and
Kimmelstiel–Wilson nodular lesions were significantly
reduced [49]. This result suggests that diabetic glomerular
injury is reversible by long-term glycemic control.
Blood pressure management plays an important role in
both the incidence of microalbuminuria and the progression
of DKD. The UKPDS BP trial demonstrated that a reduc-
tion in blood pressure from 154/87 to 144/82 mmHg
decreased the incidence of microalbuminuria in patients
with type 2 diabetes [7]. However, the ABCD study
revealed that there was no significant difference in the
incidence of microalbuminuria and the transition of creati-
nine clearance between the intensive (aimed for diastolic
blood pressure 75 mmHg) and mild (aimed for diastolic
blood pressure 80–89 mmHg) blood pressure control
groups. In the Microalbuminuria, Cardiovascular and Renal
Outcomes-Heart Outcomes Prevention Evaluation
(MICRO-HOPE) study, the ACE inhibitor ramipril
decreased the progression from normoalbuminuria to overt
diabetic nephropathy [50]. The ARB valsartan showed
greater inhibition of the progression from incipient to overt
diabetic nephropathy as compared with the calcium channel
blocker amlodipine in patients with type 2 diabetes and
microalbuminuria [51]. This study also indicated that the
efficacy for treatment of microalbuminuria is independent
of blood pressure reduction. The Investigation On Type 2
Diabetic Nephropathy (INNOVATION) trial showed that
the ARB telmisartan slowed the transition from incipient
diabetic nephropathy to overt diabetic nephropathy in
Japanese patients with type 2 diabetes and micro-
albuminuria [52]. In patients with overt diabetic nephro-
pathy, blood pressure control is emphasized, because the
effect of glycemic control is less evident. The National
Kidney Foundation Hypertension and Diabetes Executive
Committees Working Group recommends that the goal of
D. Yamazaki et al.
blood pressure control should be less than 130/80 mmHg in
patients with diabetes regardless of the severity of DKD
[53]. Consistent with this recommendation, the Japanese
Society of Hypertension also recommends that the target
blood pressure should be less than 130/80 mmHg [54].
However, the Action to Control Cardiovascular Risk in
Diabetes (ACCORD) trial demonstrated that intensive
blood pressure control (systolic blood pressure less than
120 mmHg) did not reduce CVD and rather increased
adverse events, such as hypotension and elevated serum
creatinine [55].
RAS inhibitors have renoprotective effects by reducing
glomerular hypertension. There are two important studies
that established the efficacy of RAS inhibitors on overt
diabetic nephropathy [56, 57]. In both studies, the compo-
site primary endpoint was doubling of serum creatinine,
progression to end stage renal disease and death. The
Reduction in Endpoints in NIDDM with the Angiotensin
Antagonist Losartan (RENAAL) trial revealed that the ARB
losartan reduced the occurrence of primary endpoints
compared with the placebo group in patients with type 2
diabetes and overt diabetic nephropathy, but there was no
significant difference in CVD incidence [56]. The Irbesartan
in Diabetic Nephropathy Trial (IDNT) found that the ARB
irbesartan decreased the occurrence of primary endpoints
compared with the calcium channel blocker amlodipine in
patients with type 2 diabetes and overt diabetic nephropathy
[57]. Importantly, adjustment for blood pressure did not
change the outcome in either study. These results suggest
that ARB has a renoprotective effect independent of blood
pressure changes. However, the Olmesartan Reducing
Incidence of Endstage Renal Disease in Diabetic Nephro-
pathy Trial (ORIENT) demonstrated that the ARB olme-
sartan did not reduce the primary renal composite outcome
(doubling serum creatinine, progression to end stage renal
disease and death) in Asian patients with type 2 diabetes
and overt diabetic nephropathy [58]. In this study, 77% of
assigned patients were treated with an ACE inhibitor. Fur-
thermore, hyperkalemia was more frequently observed in
the olmesartan group. Sub-analysis showed that primary
composite outcomes were more frequently observed in
patients with rapid decline of renal function than those with
slow decline. These data suggest that RAS inhibitors do not
elicit renoprotective effects in patients with DKD who
display a rapid reduction in GFR [59]. The systematic
review of 49 trials with RAS inhibitors demonstrated that
ARBs reduced the risk of end stage renal disease and
doubling of creatinine but did not change all-cause mortality
in patients with DKD [60]. The Aliskiren Trial in Type 2
Diabetes Using Cardio-Renal Endpoints (ALTITUDE)
study demonstrated that the direct renin inhibitor aliskiren
in combination with an ACE inhibitor or ARB did not
decrease the incidence of cardiovascular events but
Diabetic complications and hypertension
increased adverse events, including hyperkalemia, in
patients with type 2 diabetes at high risk for cardiovascular
and renal events [61]. This study suggests that laboratory
examinations should be performed carefully to check
plasma potassium concentrations while dual RAS inhibition
therapy is performed.
Recently, the Empagliflozin Cardiovascular Outcome
Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-
REG) OUTCOME study demonstrated that the SGLT2
inhibitor empagliflozin combined with standard therapy
reduced the cardiovascular composite outcome [62]. In this
study, empagliflozin also slowed the progression of DKD
and reduced the incidence of renal outcomes [63]. These
effects of empagliflozin may be partially explained by
reductions in blood glucose levels, body weight and blood
pressure. However, renoprotective effects of empagliflozin
are associated with an initial reduction in GFR. These data
suggest that improvement of hyperfiltration by a mechanism
involving activation of TGF is a promising mechanism to
explain the renoprotective effect of SGLT2 inhibitors.
However, another clinical study revealed that the GFR-
lowering effect of SGLT2 inhibitors contributes to a
reduction in proteinuria by only 1% [64]. These data indi-
cate that the anti-proteinuric effect of SGLT2 inhibitors is
not associated with a reduction in GFR, i.e., improved
glomerular hyperfiltration [40]. Further studies are needed
to clarify the mechanism underlying the SGLT2 inhibitor-
induced renoprotective effects in patients with DKD.
Diabetic neuropathy
Pathophysiology of diabetic neuropathy
Diabetic neuropathy is the most common chronic compli-
cation of diabetes [65]. Chronic, symmetrical, peripheral
polyneuropathy is the most common variety. Duration of
diabetes and glycated hemoglobin levels are associated with
a high incidence of diabetic neuropathy [66]. Hypertension
is also one of the risk factors for diabetic neuropathy [67].
The molecular pathways, such as the polyol pathway and
enhanced advanced glycation end product formation
because of lasting hyperglycemia, are associated with the
pathogenesis of diabetic neuropathy [68]. Moreover,
reduced nerve oxygenation is suggested to be an important
factor [69]. In patients with diabetic neuropathy, neuro-
vascular structural changes, such as thickening of the
basement membrane, degeneration of pericytes, endothelial
cell hyperplasia and arterio-venous shunt, occur [70]. These
structural changes lead to ischemia in peripheral neurons,
which induces peripheral neuronal injury through increased
reactive oxygen species [71]. Since peripheral vascular
disease is associated with hypertension [72], hypertension
also contributes to diabetic neuropathy.
Treatment of diabetic neuropathy
Both the DCCT and Kumamoto studies demonstrated that
intensive glycemic control reduced the incidence and pro-
gression of diabetic neuropathy [4, 22]. The DCCT/EDIC
study found that the legacy effect of glycemic control was
sustained for diabetic neuropathy, similar to other micro-
vascular complications [21]. A recent systematic review of
17 randomized control studies demonstrated that intensive
glycemic control prevented the development of diabetic
neuropathy in patients with type 1 diabetes [73]. Con-
versely, in patients with type 2 diabetes, intensive glycemic
control did not significantly reduce the incidence of neu-
ropathy, although nerve conduction was significantly
improved [73].
There is no direct evidence regarding the efficacy
of blood pressure control on the incidence and develop-
ment of diabetic neuropathy. In animal studies, blood
pressure reduction with an ACE inhibitor improved
oxygenation and nerve conduction [74]. Similarly,
ACE inhibitor treatment improved motor and sensory
nerve conduction velocity in patients with diabetes [75].
Thus, it is possible that blood pressure reduction with an
ACE inhibitor improves nerve conduction, while the
progression of diabetic neuropathy is not substantially
prevented.
Pharmacological symptomatic therapies are important for
the treatment of painful polyneuropathy [76]. Tricyclic
antidepressants, anticonvulsants (pregabalin) and nor-
epinephrine reuptake inhibitors (duloxetine) are recom-
mended for symptom control [77, 78]. Epalrestat, an aldose
reductase inhibitor, is approved in Japan for diabetic neu-
ropathy. A randomized control trial showed that epalrestat
tended to attenuate neural symptoms of diabetic neuropathy
and improve neural conduction velocity [79]. However, the
efficacy was limited to the early stage of neuropathy.
Clinical trials have also shown that the antioxidant α-lipoic
acid attenuates neural symptoms in patients with diabetes
and neuropathy but does not improve neural conduction
[80, 81].
Diabetic autonomic neuropathy is a diabetic neuro-
pathy pattern and causes the dysfunction of several
organs, such as gastrointestinal dysfunction and ortho-
static hypotension [82]. To prevent orthostatic hypoten-
sion, treatment with antihypertensive drugs should be
stopped to avoid sudden postural changes [83]. Patients
with diabetes and autonomic neuropathy also display an
absence of the normal nighttime reduction in blood
pressure, because sympathetic nerve activity is increased
at nighttime [84]. Thus, during the development of dia-
betes, a non-dipper pattern of blood pressure is often
associated with the incidence of diabetic autonomic
neuropathy.

Cardiovascular disease (CVD) as a
macrovascular complication
Macrovascular complications are strongly associated with
mortality in patients with diabetes. The Framingham study
determined that patients with diabetes have a 2–3-fold
higher incidence of coronary artery disease than non-
diabetic subjects [85]. However, the risk of myocardial
infarction in patients with diabetes without prior myocardial
infarction is similar [86]. The Diabetes Epidemiology:
Collaborative Analysis of Diagnostic Criteria in Europe
(DECODE) study found a significant contribution of post-
prandial glucose to CVD mortality in patients with diabetes
[87]. Subsequent studies demonstrated that the cardiovas-
cular risks of diabetes are determined by both diabetic
factors, such as postprandial glucose level, and classic
cardiovascular factors, such as hypertension, dyslipidemia
and obesity [88].
The efficacy of glycemic control for CVD remains con-
troversial. The DCCT study revealed that intensive gly-
cemic control tended to reduce the CVD. However, these
effects were not statistically significant [4]. The UKPDS
also showed that intensive glycemic control reduced the risk
of myocardial infarction with borderline statistical sig-
nificance [5]. However, the DCCT/EDIC trial demonstrated
that the previous strict glycemic control significantly
reduced nonfatal myocardial infarction, stroke and cardio-
vascular death [21]. In contrast, ADVANCE and ACCORD
trials showed that intensive glycemic control did not
improve CVD outcomes [47, 55]. In the ACCORD study,
intensive glycemic control instead increased mortality due
to the incidence of hypoglycemia [55].
The UKPDS 34 found that intensive glycemic control
with metformin elicited a better CVD outcome than insulin
or sulphonylurea treatment in overweight patients with type
2 diabetes [89]. It has also been shown that thiazolidine-
dione treatment does not significantly improve the primary
composite outcome, including cardiovascular death, myo-
cardial infarction and acute coronary syndrome, leg ampu-
tation and leg revascularization [90]. Dipeptidyl peptidase 4
inhibitors also do not improve cardiovascular outcomes. In
the Saxagliptin Assessment of Vascular Outcomes Recor-
ded in Patients with Diabetes Mellitus study (SAVOR),
saxagliptin increased the incidence of hospitalization due to
heart failure [91]. However, the Trial Evaluating Cardio-
vascular Outcomes with Sitagliptin (TECOS) study
demonstrated that sitagliptin was not inferior to the placebo
for cardiovascular outcomes and did not increase the inci-
dence of hospitalization due to heart failure [92]. In con-
trast, the Liraglutide Effect and Action in Diabetes:
Evaluation of Cardiovascular Outcome Results (LEADER)
trial indicated that an analogue of human glucagon-like
peptide 1, liraglutide, decreased CVD death and the first
D. Yamazaki et al.
occurrence of nonfatal myocardial infarction or stroke in
patients with type 2 diabetes [93].
The EMPA-REG OUTCOME trial demonstrated that
SGLT2 inhibitor treatment conclusively decreased the pri-
mary cardiovascular composite outcome, including cardio-
vascular death, nonfatal myocardial infarction and nonfatal
stroke [62]. This underlying mechanisms are unknown, but
SGLT2 inhibitor possibly decreases the primary cardio-
vascular outcomes by improving arterial pressure lability
and circadian rhythm of blood pressure [94, 95].
Blood pressure control is particularly important for pre-
vention of CVD in diabetes. The Japanese Society of
Hypertension recommends that the goal for blood pressure
should be less than 130/80 mmHg in patients with hyper-
tension and diabetes [54], based on the UKPDS and
Hypertension Optimal Treatment (HOT) trial [96]. The
Home blood pressure measurement with Olmesartan Naive
patients to Establish Standard Target blood pressure
(HONEST) study revealed that both white coat hyperten-
sion and masked hypertension are associated with increased
CVD risk, and control of blood pressure is important to
reduce CVD risk in DM patients [97]. These trials
demonstrated that lower blood pressure control improved
CVD outcomes, especially stroke. In contrast, the
ACCORD trial revealed that there were no significant dif-
ferences in primary cardiovascular composite outcomes,
including nonfatal myocardial infarction, nonfatal stroke
and cardiovascular mortality, between two different systolic
blood pressure target (120 and 140 mmHg) groups. How-
ever, strict blood pressure control significantly decreased
the incidence of stroke [55].
In systematic reviews, cholesterol lowering by statin
therapy reduced cardiovascular outcomes [98]. Further-
more, recent systematic review indicated that temporal
intensive cholesterol lowering exerts long-term cardiopro-
tective effect [99]. Fenofibrate did not decrease the inci-
dence of coronary artery disease [100]. Eicosapentaenoic
acid in combination with statin treatment reduced the inci-
dence of CVD in Japanese patients with dyslipidemia and
impaired glucose metabolism [101]. However, n-3 fatty
acids containing eicosapentaenoic acid and docosahex-
aenoic acid did not reduce the incidence of CVD in patients
at high CVD risk with diabetes or impaired glucose toler-
ance [102]. Ezetimibe in combination with statin treatment
improved cardiovascular outcomes [103], but the efficacy of
ezetimibe monotherapy is unclear. When added to statin
therapy, ezetimibe resulted in incremental lowering of LDL
cholesterol levels and improved cardiovascular outcomes.
Pharmacologic inhibitors of proprotein convertase
subtilisin-kexin type 9, novel drugs lowering low-density
lipoprotein cholesterol, effectively reduce the incidence of
CVD similarly to statins [104]. Thus, intensified multi-
factorial intervention to treat every factor associated with
Diabetic complications and hypertension
cardiovascular events is important to reduce the cardiovas-
cular events associated with diabetes [105].
Conclusions
This review focused on chronic complications associated
with diabetes. Microvascular and macrovascular complica-
tions are strongly associated with mortality and loss of
quality of life in patients with diabetes. Microvascular
complications are induced predominantly by lasting
hyperglycemia, which activates many molecular pathways.
However, the pathogenesis of diabetic macrovascular
complications is based on the process of arteriosclerosis.
Both glycemic and blood pressure controls are particularly
important for inhibiting these chronic diabetic complica-
tions. However, therapeutic strategies for diabetic retino-
pathy, nephropathy, neuropathy, and macrovascular
complications should be determined based on their patho-
physiological mechanisms.
Acknowledgements This work was supported by the Japan Society for
the Promotion of Science (JSPS) Grants-in-Aid for Scientific Research
(KAKENHI) (26460343 to Akira Nishiyama) and the Hoansha
Foundation (to Akira Nishiyama).
Compliance with ethical standards
Conflict of interest AN has received honoraria from Boehringer
Ingelheim, Daiichi Sankyo, Mochida and Taisho-Toyama, as well as
research grant from Boehringer Ingelheim, Daiichi Sankyo, Mochida
and Taisho-Toyama. The remaining authors declare that they have no
conflict of interest.
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