Can J Diabetes 42 (2018) 118–123

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Practical Diabetes

Angiotensin-Converting Enzyme Inhibitors vs. Angiotensin Receptor

Blockers for the Treatment of Hypertension in Adults With Type 2
Diabetes: Why We Favour Angiotensin Receptor Blockers
Thomas A. Mavrakanas MD a,b; Mark L. Lipman MD c,*
a Division of Nephrology, Department of Medicine, McGill University, Montreal, Quebec, Canada
b
Division of General Internal Medicine, Geneva University Hospitals, Geneva, Switzerland
c Division of Nephrology, Jewish General Hospital, McGill University, Montreal, Quebec, Canada

Key Messages

• Angiotensin receptor blockers (ARBs) have efficacy similar to that of angiotensin-converting enzyme inhibitors (ACEIs) with respect
to cardiovascular and renal outcomes in patients with diabetes.
• The combination of an ACEI or ARB with a mineralocorticoid receptor blocker in patients with diabetic nephropathy has shown
promising results.
• Sodium-glucose cotransporter type 2 inhibitors constitute a useful adjunct to ARBs for the prevention of cardiovascular and renal
events in patients with diabetes.

a r t i c l e i n f o a b s t r a c t

Article history: Cardiovascular disease is the principal cause of morbidity and mortality in patients with diabetes mel-
Received 20 August 2017
litus. The incidence or progression of kidney disease is also common in these patients. Several clinical
Received in revised form
trials have established the efficacy of angiotensin receptor blockers for the prevention of adverse car-
14 November 2017
Accepted 27 November 2017 diovascular and renal outcomes in this population and are summarized in this review article. Head-to-
head comparison of angiotensin receptor blockers with angiotensin-converting enzyme inhibitors has shown
similar cardioprotective and renoprotective properties of both medication classes. However, angioten-
Keywords:
adverse cardiovascular events sin receptor blockers have an improved safety profile with fewer episodes of cough and angioedema and
angiotensin receptor blockers may be the agent of choice in patients with diabetes and hypertension. Novel therapeutic strategies, such
chronic kidney disease progression as those that include a mineralocorticoid receptor blocker or a selective sodium-glucose cotransporter
diabetes mellitus type 2 inhibitor, may further protect patients with diabetes from cardiovascular and renal complications.
© 2017 Canadian Diabetes Association.

Mots clés :
événements cardiovasculaires indésirables
bloqueurs des récepteurs de l’angiotensine
progression de la maladie rénale chronique
diabète sucré
r é s u m é
Les maladies cardiovasculaires sont la principale cause de morbidité et de mortalité chez les patients atteints
de diabète sucré. L’incidence ou la progression de la maladie rénale est également fréquente chez ces
patients. Dans le présent article de revue, nous résumons de nombreux essais cliniques qui ont permis
d’établir l’efficacité des bloqueurs des récepteurs de l’angiotensine dans la prévention des événements
cardiovasculaires et rénaux indésirables dans cette population. La comparaison directe des bloqueurs des
récepteurs de l’angiotensine aux inhibiteurs de conversion de l’angiotensine a démontré des propriétés
cardioprotectrices et rénoprotectrices similaires des deux classes de médicaments. Toutefois, puisque les
bloqueurs des récepteurs de l’angiotensine ont un meilleur profil d’innocuité et entraînent moins d’épisodes
de toux et d’angioœdème, ils constituent le médicament de choix chez les patients diabétiques et
hypertendus. De nouvelles stratégies telles que celles qui utilisent un bloqueur du récepteur
minéralocorticoïde ou un inhibiteur du cotransporteur sodium-glucose de type 2 peuvent davantage protéger
les patients diabétiques des complications cardiovasculaires et rénales.
© 2017 Canadian Diabetes Association.

* Address for correspondence: Mark L. Lipman, MD, Division of Nephrology, Jewish General Hospital, McGill University, 3755 chemin de la Côte-Sainte-Catherine, Montreal,
Quebec H3T 1E2, Canada.
E-mail address: mark.lipman@mcgill.ca

1499-2671 © 2017 Canadian Diabetes Association.

The Canadian Diabetes Association is the registered owner of the name Diabetes Canada.
https://doi.org/10.1016/j.jcjd.2017.11.006
 T.A. Mavrakanas, M.L. Lipman / Can J Diabetes 42 (2018) 118–123
Introduction
Cardiovascular disease is the principal cause of morbidity and
mortality in patients with diabetes mellitus (1). Comprehensive man-
agement of these patients includes not only adequate glycemic
control but also attention to additional recognized risk factors. Hyper-
tension is a cardiovascular risk factor with very high prevalence in
people with diabetes, and several clinical trials have demon-
strated improved cardiovascular or renal outcomes with blood pres-
sure (BP) control in patients with diabetes (2).
The hallmark trial demonstrating improved clinical outcomes
with BP reduction was the United Kingdom Prospective Diabetes
Study, which enrolled 1,148 patients who had hypertension with
diabetes and randomized them to achieve a BP target of below 150/
85 mmHg (intensive arm) or below 180/105 mmHg (control arm)
by using captopril or atenolol. The primary outcome, a composite
of any diabetes-related complication, was reduced by 24% in the
intensive arm over a mean follow-up period of 8.4 years (3). Micro-
vascular and macrovascular complications were reduced by 37% and
34%, respectively.
Several trials were conducted thereafter using various antihy-
pertensive agents and various BP targets and assessing cardiovas-
cular or renal outcomes. Blockade of the renin angiotensin
aldosterone system with either angiotensin-converting enzyme
inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) was dem-
onstrated to be highly effective for cardiovascular and renal pro-
tection. This review article focuses on current evidence of ARBs in
patients with type 2 diabetes and explores novel strategies that may
enhance the cardioprotective and renoprotective properties of ARBs.
Cardiovascular Outcomes with ARBs in Patients with Diabetes
When ARBs became available, several trials evaluated their effi-
cacy in cardiovascular outcomes in the general population and in
various patient subgroups. The Candesartan in Heart failure Assess-
ment of Reduction in Mortality and morbidity (CHARM) program
was the first to assess efficacy of an ARB in patients with heart failure
and included 3 independent randomized controlled trials (4). A total
of 28% of patients in the CHARM program had diabetes. The primary
endpoint for each of the 3 CHARM trials was time to cardiovascu-
lar death or hospital admission for heart failure. It occurred in 30%
of patients in the candesartan arm and in 35% of patients in the
placebo arm; adjusted hazard ratio (HR) 0.84, 95% confidence inter-
val (CI) 0.77 to 0.91. Candesartan was also associated with reduc-
tion in all-cause mortality (adjusted HR 0.90, 95% CI 0.82 to 0.99),
driven by reduction of cardiovascular mortality, particularly in
patients with heart failure involving reduced left ventricular ejec-
tion fraction (<40%).
The Losartan Intervention For Endpoint reduction study enrolled
patients with hypertension and left ventricular hypertrophy on elec-
trocardiogram and randomized them to receive either a losartan-
based or an atenolol-based antihypertensive regimen. A prespecified
subgroup analysis included the 1,195 patients who had diabetes at
the beginning of the study (5). The primary composite endpoint of
cardiovascular mortality, stroke or myocardial infarction occurred
in 18% of patients in the losartan group vs. 23% of patients in the
atenolol group (adjusted HR, 0.76, 95% CI 0.58 to 0.98). Patients in
the losartan group also had lower incidences of all cause-mortality
and heart failure compared with patients in the atenolol group. These
results were obtained despite a similar BP decrease in both arms
throughout the follow-up period.
The Telmisartan Randomised AssessmeNt Study in ACE iNtolerant
subjects with cardiovascular Disease (TRANSCEND) Trials evalu-
ated the efficacy of telmisartan vs. placebo in patients with estab-
lished cardiovascular disease or diabetes with end-organ damage
119
who were intolerant to ACEIs (6). More than 35% of the 5,926 patients
enrolled had diabetes. The primary outcome, a composite of car-
diovascular death, myocardial infarction, stroke or hospitalization
for heart failure, occurred in 15.7% of patients in the telmisartan
group vs. 17.0% of patients in the placebo group (HR 0.92, 95% CI
0.81 to 1.05). The secondary outcome of cardiovascular death, myo-
cardial infarction or stroke occurred in 13.0% of patients in the
telmisartan group vs. 14.8% of patients in the placebo group (HR
0.87, 95% CI 0.76 to 1.00). These important outcomes trended in
favour of a benefit from telmisartan but did not reach statistical sig-
nificance due to an event rate that was too low for the power of
the study and that could be attributed to improved standard-of-
care baseline treatment (55% of patients were taking statins, 58%
were taking beta blockers and 85% were taking antiplatelet agents).
Despite these limitations, another secondary outcome, hospital-
izations for any cardiovascular cause, was statistically signifi-
cantly lower (p=0.025) in favour of the telmisartan group (30.3%)
vs. the placebo group (33.0%). Importantly, the proportion of patients
who discontinued telmisartan for the same reason they were intol-
erant to ACEIs was low and was similar to that of the placebo group.
The Irbesartan Diabetic Nephropathy Trial enrolled patients with
type 2 diabetes, proteinuria of at least 0.9 g/24 h, BP >135/85 mmHg
and moderate kidney impairment (creatinine 88 to 265 μmol/L in
women or 106 to 265 μmol/L in men). Patients were randomized
to receive irbesartan (titrated from 75 to 300 mg daily), amlodipine
(titrated from 2.5 to 10 mg daily) or placebo (7). Cardiovascular end-
points were monitored as secondary outcomes in this study and
were reported separately (8). The composite cardiovascular end-
point included death from cardiovascular causes, nonfatal myocar-
dial infarction, hospitalization for heart failure, cerebrovascular event
with permanent neurologic deficit, or above-the-ankle lower-
limb amputation. No significant difference was detected among the
3 treatment groups for this outcome. However, the study was not
adequately powered for the cardiovascular endpoint. Irbesartan was
superior to amlodipine for the heart failure component of the car-
diovascular outcome (p=0.002).
The reduction of endpoints in the Noninsulin-Dependent Dia-
betes Mellitus trial with the Angiotensin II Antagonist Losartan trial
included patients with type 2 diabetes, albuminuria (albumin to cre-
atinine ratio ≥ 300 mg/g or 24 h proteinuria of at least 0.5 g) and
moderate kidney impairment (creatinine 115 to 265 μmol/L). They
were randomized to receive losartan (titrated up to 100 mg daily)
or placebo on the top of conventional antihypertensive medica-
tion. The BP target was <140/90 mmHg (9). The secondary outcome
of the study was a composite of death from cardiovascular causes,
myocardial infarction, stroke, first hospitalization for heart failure
or unstable angina, and coronary or peripheral revascularization. It
occurred in 32.9% of patients in the losartan group vs. 35.2% in the
placebo group (p=0.26). However, the study was not adequately
powered for the cardiovascular endpoint. Furthermore, a first hos-
pitalization for heart failure was less commonly observed in the
losartan group (11.9%) compared with the placebo group (16.7%;
p<0.01).
The Candesartan Antihypertensive Survival Evaluation in Japan
trial enrolled hypertensive Japanese patients with 1 additional risk
factor and randomized them to receive either candesartan at 4 to
8 mg daily (increasing up to 12 mg per day) or amlodipine at 2.5
to 5 mg per day (up to 10 mg daily). The primary outcome of the
study was a composite of cardiovascular and renal events (sudden
cardiac death; stroke or transient ischemic attack; heart failure,
angina pectoris or acute myocardial infarction; dissecting aortic
aneurysm or occlusion of a peripheral artery; creatinine ≥4 mg/
dL; doubling creatinine; or end-stage renal disease). A posthoc analy-
sis including 2,018 patients with diabetes at baseline was published
separately (10). Although diabetes was an independent predictor
of cardiovascular events, no difference was detected between patients
120 T.A. Mavrakanas, M.L. Lipman / Can J Diabetes 42 (2018) 118–123
taking candesartan or amlodipine for the outcomes of primary
cardiovascular events, cerebrovascular events, cardiac events, all-
cause mortality or cardiovascular mortality.
The Olmesartan Reducing Incidence of Endstage renal disease
in diabetic Nephropathy Trial (ORIENT) was designed to examine
the renoprotective effect of olmesartan in patients with type 2
diabetes, urine albumin to creatinine ratio >33.9 mg/mmol, and
serum creatinine of 1.0 to 2.5 mg/dL in women or 1.2 to 2.5 mg/dL
in men (11). Patients were randomized to receive either 10 mg of
olmesartan (titrated up to 40 mg daily if the BP target of <130/85
was not achieved) or placebo. The following cardiovascular events
were combined in the secondary composite endpoint: cardiovas-
cular death; hospital admission for heart failure or unstable angina;
nonfatal myocardial infarction; nonfatal stroke; coronary, carotid
or peripheral artery revascularization; or lower-extremity ampu-
tation. The composite cardiovascular outcome occurred in 14% of
patients in the olmesartan group vs. 19% in the placebo group
(adjusted HR 0.66, 95% CI 0.43 to 1.00).
The Nagoya Heart Study enrolled patients with hypertension and
type 2 diabetes or impaired glucose tolerance (12). Patients were
randomized to valsartan- or amlodipine-based regimens with a BP
target of ≤130/80 mmHg. The primary outcome was a composite
of sudden cardiac death, myocardial infarction, stroke, heart failure
admission or coronary revascularization. It occurred in 9.4% of
patients in the valsartan group and in 9.7% in the amlodipine group
(HR 0.97, 95% CI 0.66 to 1.40). When each component of the primary
outcome was assessed separately, the incidence of heart failure
admission was lower in patients taking valsartan (p=0.01).
Renal Outcomes with ARBs in Patients with Diabetes
In 2001, 3 hallmark trials were published demonstrating the effi-
cacy of the ARBs to prevent the occurrence or delay the progres-
sion of nephropathy in patients with diabetes. The Irbesartan Diabetic
Nephropathy Trial, which was briefly presented previously, aimed
to identify whether irbesartan, as compared with amlodipine or
placebo, was associated with a lower incidence of a composite
outcome of death from any cause, doubling serum creatinine or pro-
gression to end-stage renal disease. After a mean follow up of 2.6
years, the composite primary outcome occurred in 32.6% of patients
in the irbesartan group, 39.0% in the placebo group (p=0.02 vs.
irbesartan) and 41.1% in the amlodipine group (p=0.006 vs. irbesartan)
(7). Mean BP was significantly higher in the placebo group but was
similar in the 2 active treatment groups. Median proteinuria was
2.9 g at baseline for all groups. In patients treated with irbesartan,
proteinuria decreased by 1.1±1.7 g/24 h compared with 0.1±2.9 g/
24 h in the amlodipine group and 0.3±4.3 g/24 h in the placebo group.
The Angiotensin II Antagonist Losartan trial compared losartan
to placebo in patients with diabetic nephropathy. After a mean follow
up of 3.4 years, the primary composite endpoint of death from any
cause, doubling of serum creatinine or end-stage renal disease was
reached in 43.5% of patients in the losartan group vs. 47.1% of patients
in the placebo group (p=0.02) (9). Losartan also reduced the urine
albumin-to-creatinine ratio by 35%, whereas it tended to increase in
the placebo group (p<0.001). BP declined progressively throughout
the study in both groups without any significant difference between
them at baseline or at the end of the trial.
The Irbesartan Diabetic Nephropathy Trial and Angiotensin II
Antagonist Losartan trials were conducted in patients with rela-
tively advanced diabetic nephropathy at baseline. The Irbesartan
in Patients with Type 2 Diabetes and Microalbuminuria study evalu-
ated whether irbesartan could prevent or delay progression to
advanced diabetic nephropathy in patients with type 2 diabetes,
hypertension (>135/85 mmHg), persistent microalbuminuria (20 to
200 μg/min) and serum creatinine levels of ≤97 μmol/L for women
or 133 μmol/L for men (13). Study patients were randomized to
receive irbesartan 150 mg once daily, 300 mg once daily or match-
ing placebo. The primary outcome was development of overt
nephropathy, defined as urine albumin excretion >200 μg/min with
at least a 30% increase from baseline. After a median follow up of
2 years, 14.9% of patients in the placebo group developed the primary
outcome vs. 9.7% of patients in the irbesartan 150 mg group (p=0.08)
and 5.2% in the irbesartan 300 mg group (p<0.001 vs. placebo).
Irbesartan reduced urinary albumin excretion by 24% in the 150 mg
group and by 38% in the 300 mg group, and there was a 2% decrease
in the placebo group.
ORIENT evaluated the nephroprotective effect of olmesartan in
patients with diabetic nephropathy (11). The primary outcome was
composite of death from any cause, doubling of serum creatinine,
reaching a creatinine level of 442 μmol/L, chronic dialysis or trans-
plantation. It occurred in 41% of patients in the olmesartan group
and 45% of patients in the placebo group (adjusted HR 1.02, 95% CI
0.79 to 1.32). Proteinuria decreased from baseline in the olmesartan
but not in the placebo group (p=0.005) (10).
Of the cardiovascular studies involving ARBs, 3 reported renal
outcomes. In the Losartan Intervention For Endpoint study, albu-
minuria was observed less frequently in the losartan than in the
atenolol arm (7% vs. 13%; p=0.002) (5). In the Candesartan Antihy-
pertensive Survival Evaluation in Japan trial, renal events, defined
as doubling of serum creatinine or reaching a creatinine of 354 μmol/L
or end-stage renal disease did not differ between the candesartan
and amlodipine groups (p=0.32) (9). A prespecified analysis in the
TRANSCEND study focused on a composite renal endpoint that
included doubling of serum creatinine or need for dialysis (14). This
outcome was observed in 2.0% of patients taking telmisartan vs. 1.6%
taking placebo (HR 1.29, 95% CI 0.87 to 1.89).
Direct Comparison between ACEIs and ARBs in Patients
with Diabetes
Following the emergence of renin-angiotensin blockade, using
either ACEIs or ARBs, as an effective strategy to prevent cardiovas-
cular and renal outcomes in patients with diabetes, the issue arose
as to whether there was a preference between these 2 classes of
agents.
There were 2 meta-analyses that suggested a potential benefit
from ACEIs but not from ARBs on cardiovascular and renal out-
comes. The first showed that ACEIs, but not ARBs, reduce all-
cause mortality, cardiovascular mortality and major adverse
cardiovascular events in patients with diabetes mellitus (15).
However, most ACEI studies were conducted before 2000, whereas
the ARB studies were done more recently. As a consequence, patients
in the ARB studies received overall superior cardiovascular protec-
tive treatment at baseline, making it harder to show cardiovascu-
lar benefit for these drugs. Furthermore, the number of patients
taking ARBs was almost half the number of patients taking ACEIs,
and failure to demonstrate efficacy might have been related to the
studies’ power issues. Therefore, results of this meta-analysis should
be interpreted with caution.
The second meta-analysis showed that ACEIs prevented new
onset of diabetic nephropathy, whereas ARBs did not (16). This dif-
ference was due to lower incidence of micro- or macroalbuminuria
with ACEIs compared to placebo. However, direct comparison of
ACEIs to ARBs in the same meta-analysis failed to show any differ-
ence between the 2 agents for this outcome. Furthermore, albu-
minuria is a surrogate marker for more advanced kidney disease,
not a hard clinical endpoint. When the effects of both ACEIs and ARBs
on doubling serum creatinine or progression to end-stage renal
disease were examined, results were similar for both drugs.
There were 3 trials that addressed this question in head-to-
head comparisons between ACEIs and ARBs. The first of these
 T.A. Mavrakanas, M.L. Lipman / Can J Diabetes 42 (2018) 118–123
trials enrolled patients with type 2 diabetes, mild-to-moderate
hypertension (diastolic BP <115 mmHg) and albuminuria of 20 to
350 μg/min. Patients were randomized to receive either losartan or
enalapril (17). Similar reductions in albuminuria and declines in glo-
merular filtration rate (GFR) at 1 year were observed in both groups.
The Diabetics Exposed to Telmisartan And Enalapril (DETAIL)
study examined whether telmisartan was noninferior to enalapril
for the preservation of GFR in patients with type 2 diabetes and mild
to moderate hypertension (<180/95 mmHg) after at least 3 months
of treatment with an ACEI (18). At 5 years, GFR had declined by
17.9 mL/min/1.73 m2 in patients taking telmisartan and by 14.9 mL/
min/1.73 m2 in patients taking enalapril (treatment difference of
−3 mL/min/1.73 m 2 , 95% CI −7.6 to 1.6, consistent with a pre-
defined noninferiority cutoff of −10.0 mL/min/1.73 m2). Annual
change in proteinuria was similar in both study arms.
The ONgoing Telmisartan Alone and in combination with Ramipril
Global Endpoint Trial (ONTARGET) included patients with coro-
nary artery disease, peripheral artery disease, cerebrovascular disease
or diabetes mellitus who had evidence of end-organ damage and
serum creatinine levels ≤265 μmol/L at baseline (19). Participants
were randomized to receive telmisartan, ramipril or both. The
primary outcome, a composite of cardiovascular death, myocar-
dial infarction, stroke or hospitalization for heart failure, occurred
in 16.7% of patients in the telmisartan group and in 16.5% of patients
in the ramipril group (HR 1.01, 95% CI 0.94 to 1.09; p=0.83) (19).
The renal endpoint of any dialysis, kidney transplantation, dou-
bling of serum creatinine or death from any cause was observed
in 13.4% of patients treated with telmisartan and in 13.5% of patients
treated with ramipril (HR 1.00, 95% CI 0.92 to 1.09) (20). Telmisartan
and ramipril had similar effects on both outcomes in the sub-
group of patients with diabetes. More patients taking ramipril than
telmisartan discontinued the study’s medication (4.5% vs. 1.2%),
mainly because of cough or angioedema.
Furthermore, a recently published network meta-analysis includ-
ing 30 trials in patients with hypertension and diabetes demon-
strated that ARBs have efficacy similar to that of ACEIs for all-
cause and cardiovascular mortality (HR 0.95, 95% CI 0.73 to 1.30 and
HR 1.23, 95% CI 0.64 to 2.78, respectively) (21).
The evidence presented above shows that ARBs have efficacy
similar to that of ACEIs with respect to cardiovascular and renal out-
comes in patients with diabetes. However, the breadth of clinical
trials with ARBs, their superior safety profile involving fewer epi-
sodes of cough and angioedema, and the longer half-life of most
agents make ARBs the preferred choice in patients with hyperten-
sion and diabetes.
Strategies to Improve Cardiovascular and Renal Outcomes in
Patients with Diabetes Who Are Taking ARBs
Combined renin-angiotensin blockade
Once renin-angiotensin blockade, with either ACEIs or ARBs, was
demonstrated to improve cardiovascular and renal outcomes in
patients with diabetes, 2 trials were designed to assess whether the
combination of these agents could further improve these out-
comes in high-risk patients.
ONTARGET, referred to earlier, showed that combination therapy
with telmisartan and ramipril did not improve cardiovascular out-
comes (p=0.38 vs. ramipril). In addition, combination treatment was
associated with higher incidence of the composite adverse renal
outcome (relative risk 1.33, 95% CI 1.22 to 1.44 vs. ramipril). Finally,
there were more cases of acute dialysis in the combination group,
and more patients discontinued combination treatment because of
adverse events (19,20).
The Veteran Affairs Nephropathy in Diabetes trial enrolled patients
with type 2 diabetes and nephropathy (defined as an estimated GFR
121
between 30 and 90 mL/min/1.73 m2 and a urine albumin-to-creatinine
ratio ≥300 mg/g) (22). All patients were prescribed losartan, then ran-
domized to receive either lisinopril or placebo. The primary outcome
was a composite of death from any cause, significant decline in GFR
(≥30 mL/min/1.73 m2, or ≥50% if the baseline estimated GFR was
<60 mL/min/1.73 m2) or end-stage renal disease (defined as a GFR
<15 mL/min/1.73 m2 or initiation of chronic dialysis). Although no dif-
ference was detected between the 2 groups with respect to the
primary outcome, the study was prematurely stopped because of 17
more serious adverse events per 100 patient-years (mainly acute
kidney injury and hyperkalemia) in the combined treatment group.
The ALiskiren Trial In Type 2 diabetes Using carDiorenal End-
points (ALTITUDE) trial evaluated the efficacy and safety of dual
renin-angiotensin blockade with aliskiren, a direct renin inhibitor,
vs. placebo as an adjunct to an ACEI or an ARB (23,24). The study
was discontinued prematurely because of a higher incidence of
adverse events in the aliskiren arm (hyperkalemia, renal impair-
ment and hypotension), whereas the composite cardiac and renal
outcomes occurred at a similar rate in both study arms.
After failure of these landmark trials to identify any cardiovas-
cular or renal benefit with dual renin-angiotensin blockade (ACEI
plus ARB or ACEI/ARB plus aliskiren) and premature discontinua-
tion of most of them due to higher adverse-event rates in the dual
blockade group, this initially promising strategy was abandoned.
Mineralocorticoid receptor blockers in association with ARBs in
patients with diabetes
Although most trials with dual renin-angiotensin blockade evalu-
ated the efficacy and safety of the ACEI plus the ARB or ACEI/ARB
plus aliskiren association, several small studies assessed the poten-
tial benefit of the combination of an ACEI or ARB with a mineralo-
corticoid receptor blocker (MRB), such as spironolactone or
eplerenone, in patients with diabetic nephropathy. These studies
had promising results (25). However, their sample sizes were small,
and they used such surrogate outcomes as reduction in protein-
uria from baseline rather than hard renal outcomes (doubling of
serum creatinine, dialysis initiation, etc.).
A small single-centre randomized trial studied the association
of losartan/enalapril vs. losartan/spironolactone in patients with
type 2 diabetes and albuminuria >30 mg/24 h. Although albumin-
uria reduction was higher in the spironolactone arm at 12 and 18
months, no difference was identified in creatinine increase or GFR
decline between the 2 study groups (26).
More studies are needed to identify whether MRBs could be con-
sidered as an adjunct to ACEIs or ARBs for the prevention of car-
diovascular or renal outcomes in patients with diabetes.
Sodium-Glucose Cotransporter Type 2 Inhibitors in
Association With ARBs in Patients With Diabetes
ACEIs and ARBs have demonstrated cardio- and nephroprotective
properties in patients with diabetes, and no other single drug group
has been able to show any benefit on hard outcomes in patients
with diabetes. Recently introduced selective sodium-glucose
cotransporter type 2 (SGLT-2) inhibitors constitute a major break-
through in the management of patients with diabetes, showing high
efficacy for the prevention of cardiovascular and renal outcomes in
this population (27).
The Empagliflozin Cardiovascular Outcome Event Trial in Type 2
Diabetes Mellitus Patients trial enrolled adult patients who had
type 2 diabetes, had an estimated GFR ≥30 mL/min/1.73 m2 and had
established cardiovascular disease (28). A total of 80% of patients
were already taking an ACEI or an ARB. They were randomized to
receive empagliflozin (10 mg or 25 mg) or matching placebo. The
122 T.A. Mavrakanas, M.L. Lipman / Can J Diabetes 42 (2018) 118–123
primary cardiovascular outcome, a composite of cardiovascular
death, nonfatal myocardial infarction or stroke occurred in 10.5%
of patients in the empagliflozin group and in 12.1% in the placebo
group (HR 0.86, 95% CI 0.74 to 0.99). The incidence of hospitaliza-
tion for heart failure was significantly lower in the empagliflozin
arm compared with the placebo arm. A secondary analysis assessed
the renal outcomes of the same trial (29). Empagliflozin was asso-
ciated with significant risk reduction compared with placebo for
the outcomes of incident or worsening nephropathy, progression
to macroalbuminuria, doubling of serum creatinine with an esti-
mated GFR ≤45 mL/min/1.73 m2, initiation of renal replacement
therapy, or the composite outcomes of incident or worsening
nephropathy and cardiovascular death or the doubling of serum cre-
atinine with an estimated GFR ≤45 mL/min/1.73 m2, initiation of renal
replacement therapy and death from renal disease.
The Canagliflozin Cardiovascular Assessment Study program
included 2 sister trials in individuals with diabetes and an esti-
mated GFR >30 mL/min/1.73 m2 (30). Patients 30 years of age or older
who had histories of symptomatic cardiovascular disease or patients
50 years of age or older who had 2 additional cardiovascular risk
factors were randomized to receive canagliflozin (100 or 300 mg)
or matching placebo. A total of 80% of patients were receiving a renin
angiotensin inhibitor at baseline. The primary outcome was a com-
posite of cardiovascular death, nonfatal myocardial infarction or non-
fatal stroke. A total of 26.9 participants had an event per 1000
patients-years in the canagliflozin group vs. 31.5 in the placebo group
(HR 0.86, 95% CI 0.75 to 0.97). Regression of albuminuria occurred
more commonly in patients assigned to canagliflozin. A compos-
ite renal outcome of sustained 40% decline in GFR, need for renal
replacement therapy or death from renal cause was observed less
commonly in the canagliflozin group (HR 0.60, 95% 0.47 to 0.77)
(30). The renoprotective effects of canagliflozin seem to be inde-
pendent of its glycemic effects (31).
Although studies with dapagliflozin for the same outcomes are
still ongoing, a class effect appears to be emerging from trials involv-
ing empagliflozin and canagliflozin. Therefore, SGLT-2 inhibitors con-
stitute a useful adjunct to renin-angiotensin blockade for the
prevention of cardiovascular and renal complications in patients with
type 2 diabetes.
Conclusions
Cardiovascular disease is the principal cause of morbidity and
mortality in patients with diabetes mellitus. Several clinical trials
have established the efficacy of ARBs for the prevention of cardio-
vascular and renal outcomes in patients with diabetes. Head-to-
head comparison of ARBs with ACEIs has demonstrated similar
cardioprotective and renoprotective properties of both medica-
tion classes. However, ARBs have an improved safety profile that
involves fewer episodes of cough and angioedema and may be the
agent of choice for patients with diabetes and hypertension. Novel
therapeutic strategies, such as the association of an MRB or an SGLT-2
inhibitor with an ARB, may further protect patients with diabetes
from cardiovascular and renal complications.
Author Disclosures
The authors declare no conflicts of interest.
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