Grossman and Grossman Cardiovasc Diabetol (2017) 16:3

DOI 10.1186/s12933-016-0485-3 Cardiovascular Diabetology

REVIEW Open Access

Blood pressure control in type 2 diabetic

patients
Alon Grossman1,3 and Ehud Grossman2,3*

Abstract 
Diabetes mellitus (DM) and essential hypertension are common conditions that are frequently present together. Both
are considered risk factors for cardiovascular disease and microvascular complications and therefore treatment of
both conditions is essential. Many papers were published on blood pressure (BP) targets in diabetic patients, includ-
ing several works published in the last 2 years. As a result, guidelines differ in their recommendations on BP targets in
diabetic patients. The method by which to control hypertension, whether pharmacological or non-pharmacological,
is also a matter of debate and has been extensively studied in the literature. In recent years, new medications were
introduced for the treatment of DM, some of which also affect BP and the clinician treating hypertensive and diabetic
patients should be familiar with these medications and their effect on BP. In this manuscript, we discuss the evidence
supporting different BP targets in diabetics and review the various guidelines on this topic. In addition, we discuss the
various options available for the treatment of hypertension in diabetics and the recommendations for a specific treat-
ment over the other. Finally we briefly discuss the new diabetic drug classes and their influence on BP.
Keywords:  Hypertension, Blood pressure, Diabetes, Review

Background of hypertension in diabetic patients. Recently introduced

Essential hypertension and diabetes mellitus (DM) are drug classes for the treatment of DM have also been
both extremely common conditions and therefore it is found to lower BP, thus making the interaction between
not surprising that their co-existence is extremely preva- BP and DM even more complex. In this review, we dis-
lent. Since both are considered risk factors for coronary cuss the epidemiology of diabetes and hypertension, the
artery disease, cerebrovascular disease, renal failure and benefit of lowering BP in diabetic patients, the target BP
congestive heart failure, treatment of both conditions is and the recommended treatment to achieve the target in
essential. Whether blood pressure (BP) should be low- these patients. This review deals mainly with BP control
ered to a different target in diabetic patients has been a in type 2 DM, but some of the data derived from studies
debate for many years. Current guidelines are inconsist- that included also non diabetic patients.
ent regarding BP target in diabetic patients. Whereas sev-
eral guidelines recommend a BP goal of <140/90 mmHg Epidemiology
[1, 2], some recommend a lower target for diastolic BP Hypertension is twice more common in diabetics than
[3, 4] and some recommend lower systolic BP thresholds in non-diabetics [8], but the definition of hypertension
in certain diabetic population [5–7]. The class of drug in diabetics is generally similar to the general popula-
treatment most appropriate for the treatment of hyper- tions and the threshold for treatment is persistent BP
tensive diabetics is also unclear and different guidelines values  ≥140/90  mmHg. As both hypertension and DM
emphasize use of different drug classes for the treatment are highly associated with obesity, it is not surprising
that their co-existence is particularly common in obese
individuals [9]. Both hypertension and DM increase sig-
*Correspondence: [email protected] nificantly with increasing age and their co-existence is
2
Department of Internal Medicine D and Hypertension Unit, The Chaim highest in older individuals [10]. Patients with DM more
Sheba Medical Center, 52621 Tel‑Hashomer, Israel commonly present with isolated systolic hypertension
Full list of author information is available at the end of the article

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Grossman and Grossman Cardiovasc Diabetol (2017) 16:3 Page 2 of 15

and are more resistant to treatment. In the EUROASPIRE PROGRESS trial included only 762 diabetic patients and
IV survey only 54% of the diabetic patients achieved BP they were recruited much longer following the initial
levels of less than 140/90  mmHg [11]. In addition, the stroke than in the PROFESS trial. The Telmisartan Ran-
presence of autonomic neuropathy in diabetic patients domised Assessment Study in ACE Intolerant Subjects
is associated with a less nocturnal BP decrease, a higher with CV Disease (TRANSCEND) study [37] was another
baseline heart rate and a higher BP variability than in study which 35.7% of the patients were diabetics and in
non-diabetics [12–18]. which more significant BP reduction with telmisartan
The co-existence of DM and hypertension significantly was not associated with CV benefit.
increase the risk for coronary heart disease [19], left ven- In the International Verapamil SR/Trandolapril
tricular hypertrophy [20], congestive heart failure [21] (INVEST DM) study there was no difference in short
and stroke [22] compared with either condition alone. term outcome in diabetic patients with coronary artery
In addition, both hypertension and DM are present in disease despite achievement of significantly lower BP
all prediction models for the occurrence of stroke in (<130  mmHg vs.  <140  mmHg) and in fact, there was
patients with atrial fibrillation [23–25]. Microvascular an increased in the long term all-cause mortality in the
complications are also more common in patients with co- more tightly controlled group [38]. In the Action to
existent hypertension and DM and both retinopathy and Control Cardiovascular Risk in Diabetes Blood Pressure
nephropathy are more prevalent in patients with DM and (ACCORD-BP) trial, BP reduction to  <120  mmHg did
hypertension [26, 27]. Lowering BP is particularly benefi- not reduce mortality or overall CV outcomes, but did
cial in diabetic patients [28, 29], however how low should reduce significantly only the occurrence of stroke a pre
BP be is controversial. specified secondary outcome [39]. Moreover, intensive
BP lowering was associated with an increased rate of
What should be the blood pressure target in diabetes syncope and hyperkalemia, both directly related to the
mellitus? intensive treatment. The results of this large prospective
The BP targets in diabetic hypertensive individuals are study, in addition to data from other studies, led most of
controversial. For many years it was common practice the societies to recommend less stringent BP target in
to aim for BP targets lower than 130/80  mmHg in non- diabetic patients.
proteinuric diabetic patients. This was based on evidence However, the results of the recent systolic blood pres-
from several large studies, including The Hypertension sure intervention trial (SPRINT) raised again the discus-
Optimal Treatment (HOT) study, the United Kingdom sion what should be the target BP in diabetic patients.
Prospective Diabetes Study (UKPDS) 38 and the Action The SPRINT randomized 9361 persons with systolic
in Diabetes and Vascular disease Controlled Evalua- BP  >  130  mmHg and increased CV risk, but without
tion (ADVANCE) trial [29–31]. However, in most stud- type 2 DM, to a systolic BP target <120 mmHg (intensive
ies the achieved BP was higher than 135/85  mmHg and treatment) or a target of  <140  mmHg (standard treat-
therefore the recommendation to lower BP to less than ment). At 1 year, the mean systolic BP was 121.4 mmHg
130/80  mmHg was not solid [32, 33]. Moreover, several in the intensive treatment group and 136.2 mmHg in the
studies reported no benefit and even harm when lower standard-treatment group. The study was stopped early
BP targets were achieved. In the Ongoing Telmisar- after a median follow-up of 3.26 years owing to 25% lower
tan Alone and in Combination with Ramipril Global rate of the primary composite outcome in the intensive-
End point Trial (ONTARGET) study, which included treatment group than in the standard-treatment group
9612 diabetic patients, the composite primary outcome (P  <  0.001). All-cause mortality was also lower by 27%
of death from cardiovascular (CV) causes, myocardial in the intensive treatment group (P  =  0.003) [40]. The
infarction, stroke, or hospitalization for heart failure did main benefit was observed in elderly subjects (>75 years)
not differ between groups despite achievement of lower who constituted 28% of the study population [41]. Rates
BP values in the telmisartan-ramipril arm [34]. In the of serious adverse events of hypotension, syncope, elec-
Prevention Regimen for Effectively Avoiding Second trolyte abnormalities, and acute kidney injury or failure,
Strokes (PROFESS) trial, which included 5743 diabetics, but not of injurious falls, were higher in the intensive-
recurrence of stroke was not less in patients receiving treatment group than in the standard-treatment group
telmisartan despite a significant decrease in BP [35]. The [40]. This recent study supports intensive BP lowering in
PROFESS results were different from those of the Perin- non-diabetic patients with increased CV risk. The most
dopril Protection Against Recurrent Stroke Study Collab- important question came from the SPRINT is related to
orative Group (PROGRESS) trial [36], in which treatment diabetic patients who were excluded from this study. In
with the ACE inhibitor perindopril was associated with light of the discrepancy between the ACCORD and the
a 38% risk reduction in the occurrence of stroke, but the SPRINT can we assume that the better results in SPRINT
Grossman and Grossman Cardiovasc Diabetol (2017) 16:3 Page 3 of 15

with intensive BP lowering does not apply to diabetic ACCORD than in SPRINT. The mean age for ACCORD
patients? was 62 years and for SPRINT was 68 years.
One approach is to explain why the results of the Participants in the BP arm of the ACCORD were also
SPRINT should not be applied to diabetic patients and, at lower risk because patients with dyslipidemia were
unlike our previous thoughts BP targets in diabetic assigned to the lipid arm and were excluded from the BP
patients should be higher than in non-diabetics. DM has arm.
a negative influence on arteriolar function and blood flow Another significant difference in the design of the
autoregulation that shifts the pressure/flow relationship. SPRINT and ACCORD studies was the use of diuretics.
Therefore diabetic patients are more vulnerable to com- The treatment regimen for hypertension in the ACCORD
promised blood flow to vital organs when BP reaches a study often used hydrochlorthiazide, and the SPRINT
critical low point. study primarily used chlorthalidone.
The opposite approach is that the results of the SPRINT In addition, the complexity of the factorial study design
should be applied to diabetic patients, since in most in ACCORD may have made it less likely that a statisti-
previous trials the benefits of BP reduction in diabetic cally significant difference could be demonstrated. This
patients were at least as good if not better than in non- may suggest that if diabetic patients were included in
diabetic individuals [29, 42]. To justify this approach one the SPRINT they would also benefit from intensive BP
should look at the effect of intensive BP lowering in dia- lowering.
betic patients on stroke, the long-term follow up results When we try to explain the reason for the difference
of the ACCORD study and the differences between the between the SPRINT and the ACCORD it should be
ACCORD and the SPRINT. emphasized that the results of the SPRINT are provoca-
In the ACCORD study, despite the failure to show a tive. In the recent Heart Outcomes Prevention Evalua-
decrease in primary endpoints in the intensive treat- tion (HOPE)–3 trial 12,705 participants at intermediate
ment arm the rate of stroke was significantly lower in risk who did not have CV disease were randomized to
the intensive than in the usual treatment arm [39]. It is receive either candesartan at a dose of 16  mg per day
possible that the ACCORD trial was underpowered, with plus hydrochlorothiazide at a dose of 12.5  mg per day
a much lower event rate than anticipated and therefore or placebo and were followed for 5.6  years. The first
the benefit of intensive BP lowering was not observed. co-primary outcome was the composite of death from
Recently, new results from a long-term follow-up of the CV causes, nonfatal myocardial infarction, or nonfa-
ACCORD patients, dubbed the ACCORDION trial, tal stroke; the second co-primary outcome addition-
were presented at the 2015 AHA meeting [43]. In this ally included resuscitated cardiac arrest, heart failure,
extended study 3957 patients were followed for an addi- and revascularization. Therapy with candesartan plus
tional 54–60 months. During this time, patients who had hydrochlorothiazide was not associated with a lower
been in the intensive BP arm in the main trial were no rate of major CV events than placebo despite a BP
longer aiming for the lower BP goals, so the difference in decrease of 6.0/3.0 mmHg in the active treatment group.
BP between the two groups narrowed from 14.5 mmHg The only subgroup who benefited from BP lowering
at the end of the main trial to 4.2  mmHg at the end of was the subgroup of participants with initial systolic
the follow-up period. Results from the follow-up period BP  >  143.5  mmHg [44]. A recent study that used the
showed a 9% non-significant reduction in the primary extended follow-up data from the US cohort of the Inter-
end point of major CV events over a median follow-up national Verapamil [SR]/Trandolapril Study (INVEST)
of 8.8  years from randomization. During the long-term showed that in hypertensive patients with coronary
follow-up, an interaction between BP and glycemia inter- artery disease, achieving a systolic BP of 130–140 mmHg
ventions became significant (P for interaction 0.037), seems to be associated with lower all-cause mortal-
with evidence of benefit for intensive BP lowering in ity after approximately 11.6  years of follow-up [45].
participants randomized to standard glycemia therapy Similarly, the Secondary Prevention of Small Subcorti-
(HR = 0.79, 95% CI 0.65–0.96). These long-term results cal Strokes (SPS3) trial) evaluated BP goals in patients
of the ACCORD trial do take on enhanced importance with a previous lacunar stroke testing a systolic goal of
when viewed alongside the SPRINT results. 130–149 mmHg versus <130 mmHg [46]. This trial also
Several differences in the design of the studies may did not demonstrate significant reductions in ischemic
also explain the different results. ACCORD had lower stroke or intracranial hemorrhage in the more intensive
event rates than initially predicted because of a lower treated group. Why the results of the SPRINT showed
CV risk profile in participants. The exclusion of partici- a clear benefit of lowering systolic BP to  <120  mmHg
pants aged >80 years led to a younger group of patients in whereas other studies failed to show it?
Grossman and Grossman Cardiovasc Diabetol (2017) 16:3 Page 4 of 15

One explanation is the technique of BP measurements. of  <140–150/90  mmHg is reasonable. Lower BP levels
In the SPRINT, BP was measures with an automated may be adequate if tolerated by the patients. BP levels
oscillometric office BP method that eliminated the need should be monitored closely in the sitting and the stand-
for a human to participate in the actual measurement and ing position and the treatment should be tailored to pre-
therefore reduces the white coat effect. Compared with a vent excessive fall in BP [52].
reasonably well-done standard office-based BP, the use of
an automated oscillometric office BP method will yield a Treatment goals according to current guidelines
systolic BP that is 7–10 mmHg lower in the same patient, Although previous guidelines recommended strict BP
measured on the same day. If this is true the systolic BP control in diabetic patients [53, 54], this has been chal-
of 120  mmHg in the SPRINT is equivalent to almost lenged in recent guidelines (Table 2). The British National
130  mmHg in clinical practice. Thus, it is reasonable to Institute for Health and Clinical Excellence (NICE)
suggest in high risk patients a target systolic BP of <130 guidelines published in 2011 [55] recommended com-
rather than <120 mmHg. mencing treatment in diabetic patients with stage 1
To solve the discrepancy between the various studies hypertension (Clinic BP  >  140/90  mmHg and ambula-
and to find out what should be the target systolic BP sev- tory BP monitoring (ABPM) daytime average or home
eral meta- analysis were recently published (Table 1). BP monitoring (HBPM) average BP of  >135/85  mmHg).
A meta-analysis of 49 trials including 73,738 patients The recently published 2016 American Diabetes Asso-
(most of them diabetic) showed that at BP values greater ciation (ADA) guidelines recommended that hyperten-
than 140  mmHg, BP reduction was associated with a sive diabetic patients be treated if they have a diastolic BP
decrease in mortality and CV morbidity. On the other of  >80  mmHg or a systolic BP  >  140  mmHg, with a tar-
hand, BP reduction in patients with initial BP val- get BP value of <140/90 mmHg [6]. These guidelines state
ues  <140  mmHg resulted in increased CV mortality and that individuals in whom stroke risk is a concern may, as
a tendency towards increased overall mortality [47]. part of shared decision making, have lower systolic tar-
Another meta-analysis evaluated randomized controlled gets such as 130 mmHg. This is especially true if lower BP
trails performed only in diabetic individuals and concluded can be achieved with few drugs and without side effects of
that the present evidence does not support BP targets therapy. The American Heart association (AHA)/Ameri-
lower than the standard targets in people with elevated BP can College of Cardiology (ACC) guidelines from 2014
and diabetes [48]. A recently published meta-analysis eval- recommend a target BP of <140/90 mmHg, but point out
uated BP lowering for prevention of CV disease and death that lower targets may be considered [56]. The American
and reported that the proportional reduction in major CV Society of Hypertension (ASH)/International Society of
disease events by BP reduction seemed to be larger in tri- Hypertension (ISH) guidelines from 2014 suggest a BP goal
als done in people without diabetes or chronic kidney dis- of  <140/90  mmHg in diabetic patients [2]. These values
ease [49]. This was attributed to different methodological are lower than those recommended by the majority of the
characteristics in studies in diabetic patients. Another JNC 8 panel for non-diabetic patients aged 60–79, which
meta-analysis of 13 randomized control studies includ- was  <150/90  mmHg, yet similar to those recommended
ing over 37,000 diabetic hypertensive patients has shown for non-diabetics aged 18–60  years, and similar to the
that intensive systolic BP control to less than 130 mmHg values of all non-diabetic patients by the minority view of
was associated with a 10% reduction in all-cause mortality, the JNC8 [1]. The 2013 European Society of Hypertension
yet no effects on microvascular or macrovascular events (ESH) and European Society of Cardiology (ESC) guide-
were noted. Regarding stroke, such an intensive BP reduc- lines recommend lowering systolic BP below 140 mmHg,
tion has led to a 17% risk reduction, accompanied by an and diastolic BP below 85  mmHg [3]. The Canadian
additional risk reduction with further lowering systolic Hypertension Education Program (CHEP) suggests a tar-
BP to <120 mmHg, without an increased risk for adverse get BP of <130/80 mmHg [7]. The International Diabetes
effects [50]. Another meta-analysis included 31 rand- Federation (IDF) suggests age-adjusted BP targets (BP tar-
omized control studies with over 73,000 diabetic hyper- get values of <130/80 mmHg for diabetic patients younger
tensive patients reported a 31% reduction in relative risk of than 70 years, target values of <140/90 mmHg for patients
stroke, with a 13% reduction for every 5 mmHg systolic BP 70–80  years old, and target values of  <150/90  mmHg for
or 2 mmHg diastolic BP reductions. The risk of myocardial patients over 80 years old) [5].
infarction was not significantly reduced with a more inten-
sive BP control [51]. How to reach goal blood pressure in diabetics
Thus it seems that a target of systolic BP < 130 mmHg Non‑pharmacological treatment
is reasonable in most diabetic patients. In elderly diabetic Non-pharmacological anti-hypertensive therapy
patients (>80  years) but otherwise healthy, a BP target includes weight loss, increased potassium-based diet
Table 1  Meta-analyses of anti-hypertensive treatment in diabetic patients
Topic Year Journal Number of studies Number of patients Number Mean follow-up Main conclusions
included included of diabetics (years)

Effect of antihypertensive 2016 British Medical 49 73,738 Only diabetic, most 3.7 If BP was greater than
treatment at different Journal type 2 150 mmHg, treatment
BP levels in patients with reduced all-cause mortal-
diabetes mellitus [47] ity, CV mortality, myocar-
dial infarction, stroke and
end stage renal disease.
If baseline systolic BP was
less than 140 mmHg, fur-
ther treatment increased
the risk of CV mortality
with a tendency towards
an increased risk of all-
cause mortality
BP lowering for prevention 2016 The Lancet 123 613,815 NA NA Every 10 mmHg reduction
of CV disease and in systolic BP significantly
Grossman and Grossman Cardiovasc Diabetol (2017) 16:3

death [49] reduced the risk of

major CV disease events,
coronary heart disease,
stroke and heart failure
which, in the popula-
tions studied, led to a
significant 13% reduction
in all-cause mortality.
The effect on renal failure
was not significant. Pro-
portional risk reductions
(per 10 mmHg lower
systolic BP) were noted in
trials with higher mean
baseline systolic BP and
trials with lower mean
baseline systolic BP. There
was no clear evidence
that proportional risk
reductions in major
CV disease differed by
baseline disease history,
except for diabetes and
chronic kidney disease,
for which smaller, but
significant, risk reductions
were detected
Page 5 of 15
Table 1  continued
Topic Year Journal Number of studies Number of patients Number Mean follow-up Main conclusions
included included of diabetics (years)

BP targets for hypertension 2013 Cochrane Data- 5 7314 7134 4.5 Reduction in incidence
in people with diabetes base systematic of stroke in intensive BP
mellitus [48] reviews reduction compared with
standard reduction, no
effect on mortality, sig-
Grossman and Grossman Cardiovasc Diabetol (2017) 16:3

nificant increase in other

serious adverse events
BP Targets in Subjects With 2011 Circulation 13 37,736 All 4.8 ± 1.3 A systolic BP treatment
Type 2 Diabetes Mellitus/ goal of 130 to 135 mmHg
Impaired Fasting Glucose [50] is acceptable. However,
with more aggressive
goals (<130 mmHg), the
risk of stroke continues
to fall, but there is no
benefit regarding the risk
of other macrovascular or
microvascular events, and
the risk of serious adverse
events even increased
Effects of intensive BP reduc- 2011 Journal of Hyper- 31 73,913 159 NA Tighter BP control reduced
tion on myocardial infarction tension the risk of stroke by 31%
and stroke in diabetes [51] compared with less tight
control, whereas the
reduction in the risk of MI
was not significant

CV, cardiovascular; BP, blood pressure, NA, not available; MI, myocardial infarction
Page 6 of 15
Table 2  BP goals in diabetics according to major guidelines
Guidelines NICE [54] ESH/ESC [3, 4] ASH/ISH [2] JNC 8 [1] ADA [6] CHEP [7] IDF [5]

Year published 2011 2013 2014 2014 2016 2016 2012

Blood pressure Not addressed <140/85 <140/90 <140/90 <140/90 <130/80 <130/80
(mmHg)
Special considerations Begin treatment if Systolic <140/90 mmHg in
BP > 140/90 mmHg BP < 130 mmHg and patients 70-80 years
diastolic BP < 80 may old <150/90 mmHg in
be appropriate for patients over 80 years
Grossman and Grossman Cardiovasc Diabetol (2017) 16:3

certain individuals old

with diabetes, such
as younger patients,
those with albumi-
nuria, and/or those
with hypertension
and one or more
additional athero-
sclerotic CV disease
risk factors, if they
can be achieved
without undue treat-
ment burden.
Recommended initial ACE inhibitor plus All classes of antihyper- ARB or ACE inhibitor. Thiazide-type diuretic, ACE inhibitor, ARB ACE inhibitor, ARB in In patients without
treatment either a diuretic or tensive agents are In black patients, CCB, ACE inhibitor patients with CV albuminuria, Thiazide-
a CCB recommended. RAAS it is acceptable to or ARB or kidney disease, type diuretic, CCB, ACE
blockers may be start with a CCB or a including microalbu- inhibitor or ARB
preferred, especially thiazide. minuria, or with CV
in the presence of risk factors
proteinuria or micro-
albuminua
NICE, National Institute for Health and Clinical Excellence; ESH/ESC, European Society of Hypertension/European Society of Cardiology; JNC, Joint National Committee; ASH+, American Society of Hypertension; ISH,
International Society of Hypertension; ADA, American Diabetes Association; CHEP, Canadian Hypertension Education Program; BP, blood pressure; ACE, angiotensin converting enzyme; CCB, calcium channel blocker; RAS,
renin angiotensin system; ARB, angiotensin receptor blocker; BB, beta blocker
Page 7 of 15
Grossman and Grossman Cardiovasc Diabetol (2017) 16:3 Page 8 of 15

(DASH- dietary Approach to Stop Hypertension- style of the Aliskiren Trial in Type 2 Diabetes Using Cardio-
diet), low sodium consumption (below 2400  mg/day), renal Endpoints (ALTITUDE) and the ONTARGET trials
moderation of alcohol intake and regular physical activity [34, 66]. In summary, it seems that use of ACEIs or ARBs
and exercise. Although the CV benefits of lifestyle inter- is not superior to use of other anti-hypertensive agents
ventions were not evaluated in diabetic patients, their in diabetics without evidence of nephropathy, but these
implementation seems reasonable in diabetics since they classes are legitimate first-line treatment options in the
may positively affect glycemia and lipid profile. There- absence of contraindications.
fore their adoption for all diabetic patients with BP val-
ues  >120/80  mmHg was recommended by recent ADA Beta blockers
standards of care [6]. The use of beta blockers has been discouraged in diabetic
patients due to its potential adverse metabolic effects,
Pharmacological treatment including an increase in triglyceride levels, a decrease in
Renin‑angiotensin‑aldosterone blockers HDL cholesterol levels, weight gain, masking hypoglyce-
Angiotensin converting enzyme inhibitors (ACEI), and mia and impairing insulin sensitivity [67]. In addition, it
angiotensin receptor blockers (ARBs) have long been has been suggested that use of beta blockers in non-dia-
considered the cornerstone of anti-hypertensive treat- betic individuals, particularly those who are overweight
ment in diabetic patients. Previous studies have demon- or obese, might increase the risk for development of dia-
strated that both renin-angiotensin-aldosterone system betes compared with an alternative agent [68]. As beta
(RAAS) blockers, ACEI and ARB, are associated with blockers are being used infrequently as first-line agents
prevention of new onset DM in hypertensive patients for the treatment of hypertension, their use in diabetes
[57] and are particularly favorable among patients with is also infrequent, but beta blockers may still be used as
albuminuria [57]. Although ACEIs were reported to add-on treatment in those who require multiple agents
reduce overall CV risk, overt nephropathy, renal fail- and in patients in whom another indication for the use of
ure and retinopathy among non-hypertensive diabetics, beta blockers is present, such as those with tachycardia,
other studies failed to show the superiority of ACEI over heart failure or ischemic heart disease [1, 3].
beta blockers in lowering BP and preventing nephropa-
thy or retinopathy in diabetic patients [58, 59]. Despite Calcium channel blockers (CCBs)
the fact that ACEIs were found to be superior to ARBS CCBs are considered a potential first-line treatment for
in preventing all-cause mortality and CV morbidity and hypertensive diabetics, particularly in the elderly with
mortality in two meta-analysis [60, 61], in the ONTAR- isolated systolic hypertension [69]. CCBs have been
GET study, outcome was similar between the two drug shown to be particularly effective in the prevention of
classes [34] and in a recent real-world study ARBS were stroke, but are less effective than RAAS blockers in pre-
found to be more effective than ACEI in the prevention vention of heart failure [70]. Although non-dihydropyri-
of stroke [62]. Therefore it seems that ACEIs and ARBs dines decrease urinary protein excretion and serve as an
are probably equally efficacious for the prevention of CV alternative in RAAS inhibitor-intolerant patients [71],
outcomes in hypertensive diabetics. ARBs and ACEIs most research in recent years has focused on the efficacy
are equally effective in preventing progression of kidney and safety of dihydropyridines. The Anglo-Scandinavian
disease in diabetic patients with early nephropathy with Cardiac Outcomes Trial (ASCOT BPLA) compared use
ARBS having comparable BP lowering capacity with of atenolol with amlodipine and found that amlodipine
fewer side effects compared with ACEIs [63]. In a recent was more effective than atenolol in reducing stroke, CV
study that compared the BP lowering effect of ARBs in events and all-cause mortality [67]. This advantage of
diabetic patients, azilsartan medoxomil was more effec- amlodipine was evident in the large group of 5137 dia-
tive than olmesartan and valsartan [64]. A recent meta- betics included in the study [72]. Notably, an ACEI was
analysis of 19 randomized controlled trials with over added to the amlodipine arm when BP was not con-
25,000 participants found that ACEIs or ARBs were asso- trolled, whereas in the atenolol arm, a thiazide was added.
ciated with a similar risk of death (relative risk 0.99, 95% A systematic review from 2015 evaluated the efficacy of
CI 0.93–1.05), CV death (1.02, 0.83–1.24), myocardial amlodipine in the treatment of patients with  hyperten-
infarction (0.87, 0.64–1.18), angina pectoris (0.80, 0.58– sion with concomitant  DM  and/or renal dysfunction
1.11), stroke (1.04, 0.92–1.17), heart failure (0.90, 0.76– compared with other classes of antihypertensive medi-
1.07), revascularization (0.97, 0.77–1.22) and end stage cation and found that amlodipine was at least as effec-
renal disease (0.99, 0.78–1.28) as compared with other tive as other anti-hypertensive agents in the treatment
anti-hypertensive agents [65]. Combining two RAAS of hypertension, was associated with a decrease in stroke
blockers is discouraged based on the discouraging results risk and an increase in heart failure risk [73]. CCBs are
Grossman and Grossman Cardiovasc Diabetol (2017) 16:3 Page 9 of 15

ineffective for the prevention of diabetes in non-diabetic and therefore has less adverse effects like gynaecomastia,
individuals [74]. In summary, CCBs may be used as first- impotence, low sex drive and hyperkalemia. A recent
line agents for the treatment of hypertension in diabetic study showed that in patients with diabetic nephropathy
individuals, particularly in the elderly with isolated sys- the addition of finerenone to an angiotensin-converting
tolic hypertension. enzyme inhibitor or an angiotensin receptor blocker
improved urinary albumin-creatinine ratio better than
Diuretics placebo [87]. It seems that aldosterone antagonists have
Although there has been concern that diuretics might a renoprotective effect that is independent of systemic
increase the risk for the development of diabetes mel- hemodynamic alterations [88]. Diabetic individuals tend
litus [75] due to their potential to negatively influence to develop type 4 renal tubular acidosis and therefore
insulin resistance [76], diuretics are important agents hyperkalemia may be a concern in those treated with
used for the treatment of hypertension in diabetics. In a aldosterone antagonists, particularly when combined
sub-analysis of the Antihypertensive and Lipid-Lowering with ACEIs or ARBs, although the long-term risk is low
Treatment to Prevent Heart Attack Trial (ALLHAT), [89].
chlortalidone was found to be as good as amlodipine
or lisinopril in preventing fatal and non-fatal coronary Combination therapy
artery disease and was more effective in the prevention More than two-thirds of hypertensive individuals are
of heart failure in diabetic patients [77]. The benefits of inadequately controlled on mono therapy [90]. Most
diuretics were also observed in the SHEP trial [78, 79]. In diabetic individuals are treated with RAAS inhibi-
all studies in which diuretics were found to be effective tors and most guidelines recommend adding a calcium
in hypertensive diabetics, chlorthalidone or indapamide antagonist or diuretic as add-on therapy [1, 5, 6]. In a
were used. To summarize, diuretics may be used for the sub-analysis of 6946 diabetic patients, in the Avoiding
treatment of hypertension in diabetics either as first line cardiovascular Events through combination Therapy in
agents or as add-on treatment, but glucose and electro- Patients Living with Systolic Hypertension (ACCOM-
lytes should be monitored when initiating therapy. PLISH) trial, a combination of benazepril plus amlodi-
pine was significantly more effective in reducing the
Alpha blockers composite of CV death, nonfatal myocardial infarction,
There are no specific studies which evaluated the efficacy nonfatal stroke, hospitalization for angina, resuscita-
of alpha blockers in diabetic patients. Alpha blockers do tion after sudden cardiac arrest, and coronary revas-
not adversely affect glucose metabolism or lipid profile, cularization, compared to therapy with benazepril plus
but they have been reported to be less effective than chlo- hydrochlorothiazide [42]. The superiority of amlodipine
rthalidone for prevention of stroke and heart failure [80, over hydrochlorothiazide as an addition to benazepril
81] and therefore are used almost exclusively in patients disappeared in obese individuals [91]. Combining a
with hypertension and prostate hyperplasia or as third or RAAS blocker with a CCB provides better renopro-
fourth-line agents. tection and leads to less ankle edema compared with a
CCB alone [92]. In addition, combining an ARB with
Aldosterone antagonists a CCB was associated with improved insulin sensitiv-
Low dose spironolactone was found to be effective in ity compared with an ARB and a diuretic [93]. Based
controlling BP in patients with hypertension and diabetes on these studies, it seems that CCBs are appropriate as
[82]. The addition of spironolactone is particularly effec- second-line agents in diabetic patients already treated
tive in those with serum potassium of <4.5 mmol/L [83]. with RAAS blockers. In obese individuals or when vol-
To prevent hyperkalemia thiazide or thiazide like diuret- ume overload is present, diuretics may be used as well.
ics should be continued when aldosterone antagonists In a large group of patients with stage I hypertension a
are added [84]. The addition of spironolactone to con- combination of chlorthalidone and amiloride yielded a
ventional antihypertensive treatment in diabetic patients greater reduction in BP than the ARB losartan [94]. In
was shown to reduce albuminuria [85] and in diabetic patients requiring triple therapy, RAAS blockers should
patients with albuminuria, addition of an aldosterone be combined with diuretics and CCBs, unless there is
antagonist to an ACEI has been shown to have renopro- compelling indication for the use for a different anti-
tective effects superior to those shown with the addition hypertensive class (heart failure or ischemic heart dis-
of an ARB, even when BP reduction rates were similar ease for beta blockers or benign prostate hyperplasia for
[86]. Finerenone is a new non-steroidal anti mineralo- alpha blockers). Patients with resistant hypertension,
corticoid which has less relative affinity than spironolac- particularly in the presence of low potassium levels,
tone and eplerenone to other steroid hormone receptors, may benefit from aldosterone antagonists. These should
Grossman and Grossman Cardiovasc Diabetol (2017) 16:3 Page 10 of 15

be used cautiously, particularly in patients already on Sodium‑glucose‑ transporter 2 (SGLT2) inhibitors

RAAS blockers. Once BP goal has been achieved anti- Three representatives of this new class of anti-diabetics
hypertensive treatment should be continued. In the are currently in the market-canagliflozin, dapagliflozin
ADVANCE trial discontinuation of antihypertensive and empagliflozin. Some others are under development.
medications was associated with increased risk of com- Although agents differ in their affinity for the sodium-
bined macro and microvascular events [95]. glucose transporter, their clinical efficacy is quite simi-
lar. All three have similar efficacy in terms of glucose
Diabetic treatment effective for the control control and all are associated with significant weight
of hypertension loss [106]. All three have been reported to significantly
In the last decade there is a surge of new anti-diabetic decrease systolic and diastolic BP by 3–5/2–3  mmHg
medications working on different pathways in insulin [107]. A meta-analysis published in 2014 reported that
production and glucose disposal. Some of these agents SGLT2 inhibitors decrease systolic and diastolic BP
have beneficial effects on BP and may prove as important by 4 and 1.6  mmHg compared with placebo [108]. A
agents for the control of hypertension in diabetic indi- pooled analysis of studies of canagliflozin and dapagli-
viduals. In this paragraph we will discuss these classes of flozin concluded that orthostatic hypotension was not
agents and the evidence for their effect on elevated BP in increased during treatment with these SGLT2 inhibitors
both normotensive and hypertensive individuals. compared with placebo. Three independent studies pub-
lished after this meta-analysis specifically evaluated the
Glucagon‑like‑polypeptide 1 analogues effect of SGLT2 inhibitors on BP in diabetic individuals.
Glucagon-like-polypeptide 1 analogues (GLP1a) lead to The dapagliflozin BP study [109] reported a 4.28 mmHg
a clinically significant weight loss in both diabetics and statistically significant decrease in seated systolic BP
non-diabetics [96, 97] and thus may aid in a better BP during a 12-week period compared with placebo and a
control. On the other hand, they have been reported to non-statistically significant decrease in diastolic BP com-
increase heart rate through sympathetic nervous system pared with placebo. Orthostatic hypotension was not
activation [98] and this may result in BP elevation. In the increased in the treatment arm compared with placebo.
recently published Liraglutide Effect and Action in Dia- In another study Weber MA et  al. showed a 3.1  mmHg
betes: Evaluation of Cardiovascular Outcome Results fall in seated systolic BP and 2.9 mmHg fall in systolic BP
(LEADER) trial [99], patients treated with liraglutide had recorded by 24H ambulatory blood pressure monitor-
a mild decrease in systolic BP (1.5  mmHg) and a mild ing after 12  weeks of treatment with dapagliflozin[110].
increase in diastolic BP (0.6 mmHg). In the trial to evalu- The Empagliflozin Cardiovascular Outcome Event Trial
ate CV and other long-term outcomes with Semaglutide in Type 2 Diabetes Mellitus Patients (EMPA-REG) BP
in Subjects with Type 2 Diabetes (SUSTAIN-6) in which study [111] reported that mean systolic BP as evaluated
the CV safety of semaglutide was evaluated [100], the by ambulatory BP monitoring was significantly lower in
mean systolic BP in the semaglutide group, as compared patients treated with both 10  and 25  mg empagliflozin
with the placebo group, was 1.3  mmHg lower in the compared with placebo. Patients who entered the study
group receiving 0.5 mg (P = 0.10) and 2.6 mmHg lower with uncontrolled hypertension had a more significant
in the group receiving 1.0  mg (P  <  0.05). Thus it seems response to empagliflozin compared with those in which
the GLP1a have a neutral effect on BP and may even BP was well controlled prior to study initiation. Orthos-
result in a mild decrease in BP, but probably cannot serve tatic hypotension was more prevalent in the empagliflo-
as an alternative to anti-hypertensive treatment in hyper- zin group, but none of the patients who had orthostatic
tensive diabetics. hypotension experienced clinical events related to this
finding, making its clinical significance questionable. The
Dipeptidyl peptidase‑4 (DPP4) inhibitors canagliflozin BP study was the smallest of the three stud-
DPP4 inhibitors elevate endogenous GLP1 through ies [112] and reported findings consistent with the previ-
inhibition of the endogenous substance responsible ously mentioned studies with a decrease in systolic BP as
for its degradation. Several studies reported that these assessed by ambulatory BP monitoring of approximately
agents produce a modest decrease in BP [101–103], oth- 2 mmHg for both 100 and 300 mg. Orthostatic hyperten-
ers reported that they increase BP [104] and yet others sion as assessed by ambulatory BP monitoring or through
reported that they negate the hypotensive effects of ACEI clinical symptoms occurred only in the canagliflozin
[105]. Overall it seems that DPP4 inhibitors are neutral in group. It is important to note that patients enrolled to all
term of BP control and their initiation probably does not three studies of SGLT2 inhibitors in hypertensive diabet-
significantly affect BP control. ics were Caucasian and data evaluating the influence of
Grossman and Grossman Cardiovasc Diabetol (2017) 16:3 Page 11 of 15

SGLT inhibitors on BP in diabetics of non-Caucasian ori- Canagliflozin Cardiovascular Assessment Study (CAN-
gin is much less extensive. VAS) [116] and DECLARE-TIMI 55 (for dapagliflozin)
In addition, these drugs were reported to have a posi- [117] studies which are expected to be complete on 2017
tive effect on the circadian rhythm in rats who devel- and 2019 respectively will clarify whether the CV bene-
oped hypertension [113]. The mechanism underlying the fits reported for empagliflozin are a class-effect.
BP decrease by SGLT2 inhibitors is unclear and poten-
tial mechanisms include diuresis, nephron remodeling, Conclusions
decrease in arterial stiffness, and  weight loss [114]. This Current evidence does not support a more stringent BP
class of agents is certainly promising as it can be used to control strategy for all diabetic patients and the evidence
control glucose, weight and BP. In fact, the EMPA-REG to support stringent control in certain diabetic patients is
trial indeed showed that empagliflozin is associated with also inconclusive. In elderly diabetic patients (>80  years)
decreased CV morbidity, CV mortality and overall mor- BP levels should be less than 140–150/90  mmHg and
tality [115]. Several potential non-glycemic mechanisms should be monitored closely in the sitting and the standing
such as BP decrease and weight reduction have been position and the treatment should be tailored to prevent
suggested to explain the CV benefit of SGLT2 (Fig.   1). excessive fall/decrease in BP. This is reflected in recom-
Whether SGLT2 inhibitors can be used for BP control mendations in most current BP treatment guidelines. The
in non-diabetic individuals is unclear. The results of the choice of anti-hypertensive agent is supported by minimal

Decreased
glycated Beneficial effect
hemoglobin on lipid profile
Decreased
LDL-c
uric acid
Triglyceride
HDL-c

Decrease in
Decreased Decreased
blood pressure
cardiovascular oxidative stress

outcomes

Decreased
SNS activation,
Decreased decreased
weight Decreased
ventricular
Inflammation,
arrhythmia
arterial stiffness
and myocardial
fibrosis

Fig. 1  Beneficial effects of SGLT2 inhibitors, SNS, sympathetic nervous system; LDL-c, low density lipoprotein cholesterol; HDL, high density lipopro-
tein cholesterol
Grossman and Grossman Cardiovasc Diabetol (2017) 16:3 Page 12 of 15

evidence although RAAS blockers are usually used as first- diseases of the European Society of Cardiology (ESC) and developed in
collaboration with the European Association for the Study of Diabetes
line agents. When requiring more than one agent for the (EASD). Eur Heart J. 2013;34(39):3035–87.
control of hypertension in diabetics, calcium antagonists 5. International Diabetes Federation Clinical Guidelines Task Force. Global
or diuretics are probably appropriate as second line agents. Guideline for Type 2 Diabetes. info@idforg. 2012.
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tension Canada’s 2016 Canadian Hypertension Education Program
choice to use a certain anti-diabetic treatment. Guidelines for blood pressure measurement, diagnosis, assessment
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erogeneous treatment model, relates directly to general litus and the metabolic syndrome. Am J Hypertens. 2003;16(11 Pt
trends in modern medicine, reflecting an aspiration for 2):41S–5S.
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S, Nigam SC, Schuette R. Prevalence of obesity, type II diabetes mellitus,
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Abbreviations blood pressure control and treatment among type 2 diabetes with
DM: diabetes mellitus; BP: blood pressure; CV: cardiovascular. comorbid hypertension in the United States: 1988–2004. J Hypertens.
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Authors’ contributions 11. Gyberg V, De Bacquer D, De Backer G, Jennings C, Kotseva K, Mellbin L,
AG reviewed the literature and wrote the first draft. EG reviewed the literature Schnell O, Tuomilehto J, Wood D, Ryden L, et al. Patients with coronary
and finalized the manuscript. Both authors read and approved the final artery disease and diabetes need improved management: a report
manuscript. from the EUROASPIRE IV survey: a registry from the EuroObservational
Research Programme of the European Society of Cardiology. Cardiovasc
Author details Diabetol. 2015;14:133.
1
 Department of Internal Medicine E, Rabin Medical Center, Petach Tikva, Israel. 12. Brown MJ, Castaigne A, de Leeuw PW, Mancia G, Palmer CR,
2
 Department of Internal Medicine D and Hypertension Unit, The Chaim Sheba Rosenthal T, Ruilope LM. Influence of diabetes and type of hyper-
Medical Center, 52621 Tel‑Hashomer, Israel. 3 Sackler Faculty of Medicine, Tel- tension on response to antihypertensive treatment. Hypertension.
Aviv University, Tel‑Aviv, Israel. 2000;35(5):1038–42.
13. Fogari R, Zoppi A, Malamani GD, Lazzari P, Destro M, Corradi L. Ambula-
Acknowledgements tory blood pressure monitoring in normotensive and hypertensive type
Not applicable. 2 diabetes. Prevalence of impaired diurnal blood pressure patterns. Am
J Hypertens. 1993;6(1):1–7.
Competing interests 14. Grossman E, Shemesh J, Motro M. Hypertensive patients with diabetes
The authors declare that they have no competing interests. mellitus have higher heart rate and pulse pressure. J Hypertens.
2002;20(Suppl 4):S60.
Consent for publication 15. Ozawa M, Tamura K, Iwatsubo K, Matsushita K, Sakai M, Tsurumi-Ikeya
The authors give their consent for publication. Y, Azuma K, Shigenaga A, Okano Y, Masuda S, et al. Ambulatory blood
pressure variability is increased in diabetic hypertensives. Clin Exp
Received: 17 November 2016 Accepted: 20 December 2016 Hypertens. 2008;30(3):213–24.
16. Pop-Busui R. Cardiac autonomic neuropathy in diabetes: a clinical
perspective. Diabetes Care. 2010;33(2):434–41.
17. Stevens SL, Wood S, Koshiaris C, Law K, Glasziou P, Stevens RJ, McManus
RJ. Blood pressure variability and cardiovascular disease: systematic
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