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Can J Diabetes 36 (2012) 345e353

Contents lists available at SciVerse ScienceDirect

Canadian Journal of Diabetes


journal homepage:
www.canadianjournalofdiabetes.com

Review

Management of Hypertension in People with Diabetes Mellitus: Translating the


2012 Canadian Hypertension Education Program Recommendations into Practice
Mark Makowsky BSP, PharmD a, Ally P.H. Prebtani BScPhm, MD, FRCPC b, *,
Mark Gelfer MD, CCFP(C), FCFP(C) c, Advaita Manohar PhD, MD d, Charlotte Jones MD, PhD, FRCPC e
a

Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada
Division of Endocrinology and Metabolism, Department of Medicine, McMaster University, Hamilton, Ontario, Canada
c
Department of Family Medicine, University of British Columbia, Vancouver, British Columbia, Canada
d
Pine Valley Medical, Toronto, Ontario, Canada
e
Department of Medicine, University of British Columbia, Okanagan Campus, Kelowna, British Columbia, Canada
b

a r t i c l e i n f o

a b s t r a c t

Article history:
Received 29 June 2012
Received in revised form
8 September 2012
Accepted 17 September 2012

Hypertension is a common problem in people with diabetes and several changes have occurred to the joint
Canadian Hypertension Education Program and Canadian Diabetes Association hypertension recommendations over the past 5 years. This article uses a case-based approach to review contemporary issues in
hypertension management in the context of diabetes, including: treatment targets, optimal combination
therapy, choice of diuretic therapy, the role of aldosterone antagonists, role of aliskiren, bedtime dosing of
antihypertensive agents, benets of sodium reduction, impact of lifestyle interventions, vascular risk
reduction with antiplatelet therapy, adherence strategies, the role of home blood pressure monitoring, and
treatment considerations based on ethnocultural background. Particular emphasis is given to linking the
recommendations to practice. Up to 80% of people with diabetes and hypertension will die of cardiovascular
disease, especially stroke. The 2012 Canadian Hypertension Education Program hypertension in diabetes key
messages for knowledge translation are that clinicians should: 1) ensure people with diabetes are screened
for hypertension, 2) assess blood pressure at all appropriate healthcare visits, 3) encourage home monitoring
with approved devices, 4) initiate pharmacotherapy and lifestyle modication concurrently, 5) assess and
manage all other vascular risk factors, and 6) enable sustained lifestyle and medication adherence.
2012 Canadian Diabetes Association

Keywords:
diabetes
hypertension

r s u m
Mots cls:
diabte
hypertension

Lhypertension est un problme frquent chez les personnes ayant le diabte, et de nombreuses modications sont apparues aux recommandations conjointes sur lhypertension du Programme ducatif canadien
sur lhypertension et de lAssociation canadienne du diabte au cours des 5 dernires annes. Cet article
utilise une approche par cas pour passer en revue les problmes contemporains de la prise en charge de
lhypertension dans le contexte du diabte, incluant les objectifs de traitement, le traitement combin
optimal, le choix dun traitement diurtique, le rle des antagonistes de laldostrone, le rle de laliskirne, la
posologie des agents antihypertenseurs au coucher, les bnces de la rduction du sodium, les effets des
interventions sur le mode de vie, la rduction du risque vasculaire par un traitement antiplaquettaire, les
stratgies dobservance, le rle de la surveillance de la pression artrielle domicile et les plans de traitement
fonds sur le milieu ethnoculturel. Une importance particulire est accorde au fait de lier les recommandations la pratique. Jusqu 80 % des personnes ayant le diabte et de lhypertension mourront dune
maladie cardiovasculaire, particulirement dun accident vasculaire crbral. Les messages cls sur lapplication des connaissances du Programme ducatif canadien sur lhypertension au sujet de lhypertension au
cours du diabte sont que les cliniciens doivent : 1) faire en sorte que les personnes ayant le diabte soient
soumises un dpistage de lhypertension; 2) valuer la pression artrielle lors de toutes visites appropries
en soins de sant; 3) encourager la surveillance domicile laide dappareils approuvs; 4) amorcer
simultanment la pharmacothrapie et la modication du mode de vie; 5) valuer et prendre en charge tous
les autres facteurs de risque vasculaires; 6) permettre un mode de vie viable et lobservance mdicamenteuse.
2012 Canadian Diabetes Association

* Address for correspondence: Ally P.H. Prebtani, HHSC, Hamilton General Hospital
Site, McMaster Wing, Room 411, 237 Barton St. E. Hamilton, Ontario L8L 2X2, Canada.
E-mail address: prebtani@hhsc.ca (A.P.H. Prebtani).
1499-2671/$ e see front matter 2012 Canadian Diabetes Association
http://dx.doi.org/10.1016/j.jcjd.2012.09.002

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M. Makowsky et al. / Can J Diabetes 36 (2012) 345e353

Introduction
Diabetes is a major health issue in Canada with w8.7% of the
adult Canadian population having been diagnosed with diabetes in
2008 to 2009 (1). High blood pressure is a very common problem in
people with diabetes with the most recent national data, from the
2007 to 2009 Canadian Health Measures Survey (CHMS), indicating
that 75% of Canadians reporting diabetes also have hypertension.
This rate is 4 times higher among hypertensive individuals with
diabetes than among those without diabetes (74% vs. 17%) (2). This
is consistent with other reports, particularly the 2009 National
Diabetes Surveillance System (NDSS), which reported that 63% of
Canadians with diabetes have hypertension (3). Although the
CHMS and NDSS do not differentiate hypertensive individuals
based on type of diabetes, an estimated 90% to 95% of Canadians
living with diabetes have type 2 diabetes mellitus and therefore the
most commonly encountered scenario in clinical practice is that of
individuals with both type 2 diabetes and hypertension (1).
Between 60% to 80% of people with diabetes die of cardiovascular complications and up to 75% of specic cardiovascular
complications are attributable to hypertension (4,5). Epidemiologic
data has shown that hypertension accounts for up to 75% of stroke
(6), 41% of cardiovascular events (7) and 44% of all deaths among
individuals with diabetes (7). Additionally, hypertension is also
a major causal factor of end stage kidney failure, blindness and
nontraumatic amputation in people with diabetes, where attributable risks are 50%, 35% and 35%, respectively (6). Observational
data from the United Kingdom Prospective Diabetes Study (UKPDS)
has shown that the risks of macrovascular and microvascular
complications in type 2 diabetes are strongly associated with mean
systolic blood pressure, with each 10 mm Hg reduction in blood
pressure reducing the risk of a fatal or nonfatal stroke by 19%, fatal
and nonfatal myocardial infarction by 12% and microvascular
disease by 13% (8).
Randomized controlled trials of blood pressure lowering treatments in people with diabetes have demonstrated major reductions in death, stroke, cardiovascular disease and eye and kidney
disease (9e18). For example, the blood pressure lowering arm of
the Action in Diabetes and Vascular Disease: Preterax and
Diamicron-MR Controlled Evaluation (ADVANCE) trial is one of the
largest individual studies to date that illustrates the benets of
blood pressure lowering in patients with diabetes (12). It showed
that in comparison to a placebo, xed dose combination therapy
with perindopril/indapamide, in addition to usual therapy, reduced
the relative risk of a major macrovascular or microvascular event, at
a median of 5 years, by 9%, the relative risks of cardiovascular death
by 18% and total mortality by 14%. The reduction in blood pressure
in this trial was 5.6/2.2 mm Hg vs. placebo. Lowering blood pressure
is likely the single most effective way to prevent death and
disability in those with diabetes (19).
Most recent data from the CHMS indicates that 89% of adults
with diabetes were aware of having hypertension and 88% were
treated with antihypertensive medication, but only 56% were
treated and controlled to the current Canadian Hypertension
Education Program (CHEP)- and Canadian Diabetes Association
(CDA)-endorsed blood pressure target of <130/80 mm Hg (2). This
rate is much improved compared to historical data from <10%
below 140/90 mm Hg from 1986 to 1992 (2). This number is also
higher than previously available data from the province of Ontario
that indicated that only one-third of patients with diabetes and
hypertension were receiving treatment and had controlled hypertension, and that over 25% with diabetes and hypertension were not
being treated for hypertension at all (20).
Several changes have occurred to the CHEP and CDA hypertension recommendations since the publication of the CDA 2008
Clinical Practice Guidelines for the Prevention and Management of

Diabetes in Canada (21). With revised CDA guidelines expected in


2013, our aim was to illustrate several key points and controversies
about the treatment of hypertension in people with diabetes from
the 2012 CHEP using an illustrative case to link the recommendations to practice (22). Recognizing that clinicians need up to date
information for practice, this article will also discuss evidence not
specically addressed in the CHEP 2012 guidelines.
Case
Mr. J is a 65-year-old retired structural engineer with hypertension and type 2 diabetes mellitus who you are seeing in your
clinic today. His blood pressure, measured in the ofce, is 144/93
mm Hg and his home measures over the past week have averaged
out to 138/87 mm Hg. He likes to chart his blood pressure at home
every day, multiple times per day. He was rst diagnosed with
diabetes 4 years ago and his blood glucose has been well controlled
(glycated hemoglobin 6.5%) on metformin 500 mg twice a day
(BID). He has not had a myocardial infarction or stroke in the past
and has no family history of cardiovascular disease. He has no
history of retinopathy but has a slightly elevated albumin-tocreatinine ratio (ACR) of 3.8 mg/mmol and an estimated glomerular ltration rate >60 mL/min/1.73 m2. Otherwise he has mild
osteoarthritis in his right knee that is adequately managed with
occasional ibuprofen. He eats supper in restaurants almost every
night, deli meat sandwiches for lunch and enjoys a cigar and brandy
every evening. He is modestly active, playing golf 3 times a week
during the summer. His total cholesterol is 4.1 mmol/L; low-density
lipoprotein: 1.9 mmol/L; high-density lipoprotein: 1.1 mmol/L and
his body mass index (BMI) is 30 kg/m2. His electrolytes are all
within normal limits including potassium, which is 4.8 mmol/L. He
has no evidence of left ventricular hypertrophy on electrocardiogram (ECG). He is currently taking ramipril 10 mg daily, hydrochlorothiazide 12.5 mg daily, rosuvastatin 10 mg daily and
metformin 500 mg BID. He is not taking low dose acetylsalicylic
acid (ASA).
Translating the CHEP 2012 Recommendations into Practice
The key messages for the management of hypertension in
people with diabetes and CHEP 2012 pharmacotherapy recommendations are shown in Tables 1 and 2. The case of Mr. J. illustrates
several controversies in managing hypertension in patients with
diabetes.
What is the target blood pressure for people with diabetes?
CHEP and the CDA recommend that people with diabetes achieve and maintain a blood pressure of <130/80 mm Hg (22,23).
These targets are based on the best available evidence, which
historically has included the Hypertension Optimal Treatment
(HOT) and UKPDS-38 randomized controlled trials for the diastolic
target of <80 mm Hg (10,17) and less rigorous evidence, most
notably the normotensive Appropriate Blood Pressure Control in
Diabetes (ABCD) trial for the systolic target of <130 mm Hg (8,11,24).
More recently, the blood pressure arm of the Action to Control
Cardiovascular Risk in Diabetes (ACCORD) trial directly studied
whether a systolic blood pressure target of <120 mm Hg (intensive
therapy) might be preferable to a target of <140 mm Hg (standard
therapy) in patients with diabetes (25). There were no signicant
benets of the intensive target on the primary composite outcome
of nonfatal myocardial infarction, nonfatal stroke or cardiovascular
death, or secondary outcomes of all cause mortality or cardiovascular death. However, there was a 41% relative reduction in total
stroke and a 37% relative decrease in nonfatal stroke, which were
both prespecied secondary outcomes. Signicant adverse events

M. Makowsky et al. / Can J Diabetes 36 (2012) 345e353

347

Table 1
Hypertension in diabetes: key messages
Up to 80% of people with diabetes and hypertension will die of CV disease, especially stroke.
1. Ensure people with diabetes are screened for hypertension.
Diagnosis of hypertension in diabetes: BP 130/80 mm Hg, conrmed within 1 month.
2. Assess BP at all appropriate healthcare visits.
Regular monitoring of BP forms the basis for making decisions about treatment and reinforces the importance of maintaining a target BP level.
3. Encourage home monitoring with approved devices.
 Home BP readings are more strongly associated with improved CV outcomes than readings taken in a healthcare professionals ofce.
 Home readings can be used to: conrm the diagnosis of hypertension, improve BP control, reduce the need for medications in those with white coat effect, identify
those with white coat and masked hypertension, and improve medication adherence.
 Home BP readings should be obtained twice in the morning and twice in the evening, for a 7-day period. Discard the readings of the rst day and calculate the
average of the last 6 days.
 The target home reading is <130/80 mm Hg.
4. Pharmacotherapy and lifestyle modication should be initiated concurrently.
 Aggressive treatment using multiple (3 or more) BP lowering medications is often required to achieve target levels of <130/80 mm Hg for people with diabetes.
 First line therapies include in alphabetic order ACE inhibitors, ARB, dihydropyridine CCBs and thiazide or thiazide-like diuretics.
5. Assess and manage all other vascular risk factors.
 A comprehensive approach is needed to address the following risk factors: smoking, dyslipidemia, glycemic control, obesity, unhealthy eating and physical
inactivity.
 A reduction in these risk factors can cut an individuals vascular risk by more than half.
6. Enable sustained lifestyle modication and medication adherence.
 At every visit, people should be asked how they are managing their BP.
 Recommended lifestyle changes, especially limiting sodium intake and medication adherence, should be reviewed at each visit.
ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blockers; BP, blood pressure; CCB, calcium channel blocker; CV, cardiovascular.

due to antihypertensive therapy were more common in the


intensive therapy arm as compared to standard therapy (3.3% vs.
1.3%; p<0.001). These events included hypotension, syncope,
bradycardia, hyperkalemia, angioedema and renal failure.
Subsequently, 2 systematic reviews have further explored the
benet of a systolic blood pressure target <140 mm Hg (26,27).
Bangalore et al. (26) reviewed 13 trials that achieved systolic blood
pressure <140 mm Hg on the outcomes of mortality, cardiovascular
mortality, heart attack, heart failure and stroke. They found that
compared to a systolic blood pressure target <140 mm Hg, reducing
systolic blood pressure to 135 mm Hg reduced the odds of
mortality (8.2% vs. 7.3%; odds ratio [OR] 0.87; 95% condence
interval [CI] 0.79e0.95). Reducing systolic blood pressure 130 mm Hg
reduced the odds of stroke (1.6% vs. 0.82% OR 0.53; 95% CI
0.38e0.75). Overall, serious adverse events were increased with
intensive therapy (OR 1.20; 95% CI 1.08e1.32) and were more likely
in patients with systolic blood pressure <130 mm Hg (OR 1.40;
95% CI 1.19e1.64).
Reboldi et al. (27) included 31 antihypertensive trials in their
review and looked at the impact of more tight vs. less tight blood

Table 2
Treatment of hypertension in association with diabetes mellitus: CHEP 2012 (22)
1. Persons with diabetes should be treated to attain SBPs of <130 mm Hg
(Grade C) and DBPs of <80 mm Hg (Grade A). These target BP levels
are the same as the BP treatment thresholds.
Combination therapy using 2 rst-line agents may also be considered as
initial treatment of hypertension (Grade B) if SBP is 20 mm Hg above target
or if DBP is 10 mm Hg above target. However, caution should be exercised
in patients in whom a substantial fall in BP is more likely or poorly
tolerated (e.g. elderly patients and patients with autonomic neuropathy).
2. For persons with CV or kidney disease, including microalbuminuria or
with CV risk factors in addition to diabetes and hypertension, an
ACE inhibitor or an ARB is recommended as initial therapy (Grade A).
3. For persons with diabetes and hypertension not included in the above
recommendation, appropriate choices include (in alphabetical order):
ACE inhibitors (Grade A), ARB (Grade B), dihydropyridine CCBs (Grade A)
and thiazide/thiazide-like diuretics (Grade A).
4. If target BPs are not achieved with standard-dose monotherapy,
additional antihypertensive therapy should be used. For persons in
whom combination therapy with an ACE inhibitor is being considered,
a dihydropyridine CCB is preferable to hydrochlorothiazide (Grade A).
ACE, angiotensin-converting enzyme; ARB, angiotensin receptor blockers; BP, blood
pressure; CCB, calcium channel blocker; CV, cardiovascular; DBP, diastolic blood
pressure; SBP, systolic blood pressure.

pressure control on myocardial infarction and stroke. They also


found that more tight control reduced the risk of stroke (relative
risk [RR] 0.61; 95% CI 0.48e0.79) but had no inuence on the risk of
myocardial infarction (OR 0.87; 95% CI 0.74e1.02). The risk of stroke
decreased by 13% (95% CI 5e20) for every 5 mm Hg reduction in
systolic blood pressure and by 11.5% for every 2 mm Hg reduction in
diastolic blood pressure.
On the basis of these ndings, CHEP recommends that the blood
pressure goal of <130/80 mm Hg remain unchanged. This recommendation balances the association between systolic blood pressure levels <130 mm Hg and reduction in stroke with the small but
clinically important increases in absolute number of serious
adverse events that occur primarily when systolic blood pressure is
<120 mm Hg (22). Notably this recommendation is consistent with
those from the American Diabetes Association (ADA) 2012 standards for diabetes care (28).

What is the optimal combination therapy for hypertension


treatment in the context of diabetes?
Many people with hypertension and diabetes will require the
use of 3 or 4 medications to achieve target blood pressure levels.
For example, in the Antihypertensive and Lipid Lowering Treatment
to Prevent Heart Attack (ALLHAT) study, up to one-third of subjects
required more than 3 medications (29). For persons who have highrisk diabetes (i.e. diabetes with albuminuria, renal disease,
cardiovascular disease, or additional cardiovascular risk factors) in
whom combination therapy with an angiotensin converting
enzyme (ACE) inhibitor is being considered, CHEP recommends
that addition of a dihydropyridine calcium channel blocker (CCB) is
preferable to a thiazide diuretic (30). This is based on the ndings of
the Avoiding Cardiovascular Events through Combination Therapy
in Patients Living with Systolic Hypertension (ACCOMPLISH) study,
which showed that benazepril plus amlodipine compared to
benazepril plus hydrochlorothiazide reduced the primary
composite endpoint of death from cardiovascular causes, nonfatal
myocardial infarction, nonfatal stroke, hospitalization for angina,
resuscitation after sudden cardiac arrest and coronary revascularization by 21% (absolute risk reduction 3%) in patients with highrisk diabetes (31). Those who are not included in this high-risk
category may receive combinations of rst-line drugs or similarly

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M. Makowsky et al. / Can J Diabetes 36 (2012) 345e353

to high-risk patients, combination therapy with an ACE inhibitor


and dihydropyridine CCB (22).
Although small studies such as Candesartan and Lisinopril
Microalbuminuria (CALM) suggest that combination ACE inhibitor
and angiotensin receptor blocker (ARB) therapy may have benets
on surrogate outcomes (e.g. urinary albumin-to-creatinine ratio) in
patients with diabetes and nephropathy, combination therapy with
ACE inhibitor and ARB is not recommended in this population as no
studies have demonstrated benets in long-term renal function or
reductions in major cardiovascular events (32e34). Additionally,
the ndings of the Ongoing Telmisartan Alone and in Combination
with Ramipril Global Endpoint Trial (ONTARGET), which showed
increased risk of hypotensive symptoms, syncope and renal
dysfunction when combinations of an ACE inhibitor and ARB were
used to prevent vascular events in high-risk patients who had
cardiovascular disease or diabetes but did not have heart failure, led
to this combination being specically not recommended in patients
with hypertension without other compelling indications (35). An
exception is advanced heart failure, where combination therapy
may be considered in selected and closely monitored patients
based on the ndings of the Candesartan in Heart Failure: Assessment of Reduction in Mortality and Morbidity (CHARM) study,
which showed positive clinical outcomes in this population (36).
Is diuretic therapy suitable in patients with hypertension and
diabetes?
Although many clinicians are uncomfortable prescribing
diuretics to people with diabetes, possibly because diuretics cause
a small increase in blood glucose, diuretics have been shown to be
equally effective as ACE inhibitors in preventing cardiovascular
complications (29,37). CHEP considers thiazide (e.g. hydrochlorothiazide) or thiazide-like diuretics (e.g. chlorthalidone and indapamide) suitable treatment alternatives in patients with
hypertension and diabetes (22). Although there are no trials
specically comparing hydrochlorothiazide to other thiazide or
thiazide-like diuretics on clinical outcomes, some clinicians have
questioned the choice of hydrochlorothiazide as the diuretic
therapy of choice (38). More robust evidence exists for chlorthalidone, which has been shown to reduce cardiovascular outcomes in
major clinical trials including patients with diabetes (37). Chlorthalidone is w1.5 to 2 times as potent as hydrochlorothiazide, offers
a longer half-life (45e60 hours vs. 8e15 hours, respectively) and
a prolonged duration of action with long-term dosing (48e72 hours
vs. 16e24 hours, respectively) (39). The starting dose of chlorthalidone is 12.5 to 25 mg daily. This can be difcult to achieve given
that it is currently only available in Canada in 50 mg and 100 mg
tablets, although the tablets are scored and can be cut. An alternate
dosing regimen given its long half-life is 25 mg of chlorthalidone
dosed every other day but historical data suggests this regimen
may not be maximally effective (40). Comparatively, hydrochlorothiazide offers more exibility in dosing due to a wider availability
of dosages and is available in many single pill combinations.
Patients with diabetes have a higher incidence of chronic kidney
disease and increased monitoring of potassium is warranted.
Maintaining a normal serum potassium level is important to
minimize the effect of diuretics on blood glucose and maximize
cardiovascular event reductions. Although evidence regarding the
importance of kidney function in the hypotensive effects of thiazides is contradictory, CHEP recommends substitution of a loop
diuretic if creatinine clearance is <30 mL/min, especially if volume
control is required (22,41). The mechanism underlying how thiazides reduce blood pressure is not well understood, and some
studies report a reduction in antihypertensive effect with thiazides
in renal failure, whereas others have demonstrated no loss of
antihypertensive efcacy (42,43). Emerging data suggests that

vasodilatory effects in reducing total peripheral resistance account


for the blood pressure lowering effect of thiazide when used
chronically. However, how they cause vasodilation is unclear and
several hypotheses exist including both via direct action on blood
vessels and indirect actions through a chronic vascular response to
acute reduction in plasma volume (36).
What is the role of aldosterone antagonists in hypertension and
diabetes
Although CHEP has addressed the role of aldosterone antagonists in patients with systolic dysfunction, recent cardiovascular
hospitalization, acute myocardial infarction, elevated brain natriuretic peptide (BNP) or N-terminal pro-BNP (NT proBNP), or New
York Heart Association (NYHA) class II to IV symptoms, they have
not yet addressed the role of aldosterone antagonists in patients
with hypertension in diabetes (22). Although there are several
short-term (40 weeks) studies in diabetic nephropathy that
associate aldosterone antagonists with a reduction in albuminuria,
there are no long-term studies assessing cardiovascular disease
outcomes from which to make rm recommendations (44).
Aldosterone antagonists however, may be considered in patients
with resistant hypertension that may be particularly problematic in
patients with diabetes (45). Resistant hypertension is dened as
blood pressure that remains above goal in spite of the concurrent
use of 3 antihypertensive agents of different classes. Ideally, one of
the 3 agents should be a diuretic and all agents should be prescribed
at optimal doses (46). When secondary causes of hypertension (e.g.
primary aldosteronism) are suspected or identied, effective
management may require referral to an appropriate specialist.
Careful monitoring of potassium and renal function is recommended when aldosterone antagonist therapy is implemented.
What is the role of aliskiren in patients with hypertension and
diabetes?
In December 2011, Novartis stopped the Aliskiren Trial in Type 2
Diabetes Using Cardiorenal Disease Endpoints (ALTITUDE) study
that was designed to compare aliskiren 300 mg daily added to
conventional therapy including an ACE inhibitor or ARB vs. placebo
in patients with type 2 diabetes and renal impairment (47).
Unexpectedly, a higher incidence of nonfatal stroke, renal complications (end stage renal disease and renal death), hyperkalemia and
hypotension occurred in aliskiren-treated patients. This led Health
Canada to issue updated safety information in January 2012 stating
that aliskiren is contraindicated in patients with diabetes taking an
ACE inhibitor or ARB (48).
Is bedtime dosing of antihypertensive agents benecial in patients
with diabetes?
Although CHEP has not yet made a recommendation regarding
the role of bedtime dosing of antihypertensive agents, in 2012 the
ADA has implemented a recommendation to administer one or
more antihypertensive agents at bedtime (level of evidence: A)
(28). Previous research has shown sleep time blood pressure to be
a better predictor of cardiovascular risk than a single daytime or
24-hour blood pressure measurement however, the Ambulatory
Blood Pressure Monitoring for Prediction of Cardiovascular Events
(MAPEC) study, a prospective, randomized open-label, blinded
endpoint evaluation trial was the rst to put this hypothesis to the
test (49). A total of 2156 patients were randomized to take one or
more antihypertensive medications at bedtime vs. usual care (all
antihypertensives taken on wakening). The primary outcome (a
composite of total cardiovascular events) was signicantly reduced
(17.3% vs. 6.3%, absolute risk reduction [ARR] 11%: number needed

M. Makowsky et al. / Can J Diabetes 36 (2012) 345e353

to treat [NNT] 9) and all cause mortality modestly reduced (1.1% vs.
2.6% ARR: 1.5% NNT: 67) in the bedtime dosing group. These overall
results were consistent in the diabetes subgroup as well as those
with chronic kidney disease (50,51). In addition to the ADAs strong
recommendation, Portaluppi and Smolensky (52) have called for
urgent reconsideration of a number of commonly accepted
concepts currently applied in practice such as the normotensive
nondipper, aiming for constant blood pressure lowering over the
24-hour dosing interval, and reliance on occasional blood pressure
assessments without regard for blood pressure levels at other times
of the day and night. On the ip side, others have expressed a desire
for more conrmatory research before full-scale implementation of
this studys ndings into practice. This desire is driven by the studys
limitations including poorly described randomization, single center,
open label design, lack of a robust validated algorithm for antihypertensive medication titration, and the large relative risk reduction
for major cardiovascular events (71%) that seems out of line with, for
example, the Heart Outcome Prevention Evaluation (HOPE) trial
that also found a reduction in bedtime blood pressure but showed
a 22% relative risk reduction in cardiovascular events (53).

What are the benets of sodium reduction on blood pressure control


in diabetes?
According to CHEP, a dietary sodium intake of <1500 mg, <1300
mg, or <1200 mg is recommended for adults <50 years of age,
adults between the ages of 51e70 and adults over the age of 70
respectively (22). This represents the adequate intake of sodium,
which is an amount sufcient to sustain health even under conditions in which signicant losses of sodium occur. Importantly, the
terms sodium and salt are often used synonymously but the reader
should recognize the distinction between the two (i.e. that sodium
chloride [NaCl] is the chemical name for table salt and that 1 level
teaspoon contains 5.8 grams of salt, 2300 mg of sodium, or 100
mmol of sodium) (54). Additionally, it is important to recognize
that a higher recommendation for sodium intake is implied on
nutrition labels present on all packaged foods in Canada. These
nutrition facts tables include the sodium content of a food serving
as a percentage of the recommended daily value, with a value of
100% corresponding to 2400 mg sodium per day (55). This value is
similar to the 2300 mg of sodium per day that CHEP recommends to
be the tolerable upper intake level of daily sodium intake for all
adults regardless of age (54).
It is estimated the average Canadian currently consumes about
3000 mg/day of sodium (56). Most sodium intake comes from
processed foods and eating out. Reducing sodium in patients with
hypertension by 1800 mg/day has been demonstrated to reduce
blood pressure by 5.1/2.7 mm Hg (57). This data suggests that
development and implementation of a population health strategy
to reduce sodium intake among Canadians should be a major
focus (58).
The food categories providing the greatest contribution to
Canadian sodium intakes are bread products (w14%), prepared
meats (w9%), prepared vegetables and vegetable juice (w8%),
soups (w7%), pasta dishes (w 6%) and cheese (5%) (59). The large
contribution of some products (e.g. bread) is largely driven by the
amount and/or widespread nature of their consumption, whereas
other food groups (e.g. prepared meats) may be eaten to a lesser
extent but provide a signicant contribution because of their high
sodium content (54). Ways to reduce sodium intake include eating
fewer processed, canned and instant foods, choosing fresh foods
more often, limiting salted snack foods, such as nuts, chips or
popcorn, not adding salt to home cooking, using spices instead,
taking the salt shaker off the table, reading labels and selecting
lower sodium options of similar foods.

349

What are the benets of other lifestyle interventions on blood


pressure and glucose control?
Several lifestyle interventions are effective in preventing and
treating hypertension (22). These interventions can also reduce the
risk of developing type 2 diabetes, reduce blood glucose, improve
other markers of vascular risk and improve overall quality of life.
They include healthy eating, maintaining a healthy body weight,
physical activity, smoking cessation, limiting alcohol consumption
and stress management (Table 3). Lifestyle modications can
reduce blood pressure by 2 to 11 mm Hg (60). Although this range is
derived from the general population with hypertension and not
those specically with hypertension and diabetes, several studies in
patients with diabetes have established benets of lifestyle modication on markers of vascular risk (61,62).
Healthy eating
A healthy diet is considered the cornerstone of diabetes
management. Most people with diabetes are advised to follow
a meal plan based on Eating Well with Canadas Food Guide. Additionally, the Dietary Approach to Stop Hypertension (DASH) diet
has been shown to reduce blood pressure by 11.4/5.5 mm Hg in
people with hypertension (63). The DASH diet principles, which
emphasize fruits, vegetables, low-fat dairy products, dietary and
soluble bre, whole grains and protein from plant sources that is
low in saturated fats and cholesterol are consistent with recommended nutrition therapy for diabetes (62).
Body weight and abdominal obesity
Attaining and maintaining a healthy weight improves blood
pressure, diabetes management and reduces cholesterol. The Trials
of Hypertension Prevention (TOHP) study showed that a decrease
of 4.4 kg can lead to a blood pressure reduction of 4/3 mm Hg (64).
Physical activity
CHEP recommends a moderate intensity activity such as, brisk
walking, jogging, cycling or swimming be undertaken for 30 to 60
minutes 4 to 7 days a week. The CDA recommendations differ
slightly in that they encourage the performance of resistance
exercise 3 times per week in addition to aerobic exercise (61).
Regular physical activity has been shown to lower blood pressure
by 4.9/3.7 mm Hg in people who were previously inactive (65).
Starting an activity program can be difcult and individuals should
be encouraged to start slowly and gradually build up in intensity
and duration. An exercise ECG stress test should be considered in
those who are sedentary and at high risk for cardiovascular disease
and who wish to undertake more vigorous exercise than brisk
walking (61).
Low risk alcohol consumption
Alcohol intake should not exceed the recommended amount of
2 standard drinks a day, <4 drinks a week for men and <9 drinks
Table 3
Lifestyle recommendations and impact on blood pressure (60)
Intervention

Targeted change

Expected blood pressure


change (mm Hg)

Sodium reduction
Weight loss
Alcohol reduction
Exercise
Dietary patterns

<1800 mg/day hypertensive


per kg lost
<2 drinks/day
120e150 min/week
DASH diet Hypertensive

5.1/2.7
1.1/0.9
3.9/2.4
4.9/3.7
11.4/5.5

350

M. Makowsky et al. / Can J Diabetes 36 (2012) 345e353

a week for women (62). Alcohol restriction from 3 to 6 drinks per


day to 1 to 2 drinks per day is associated with expected blood
pressure reductions in the magnitude of 3.9/2.4 mm Hg in hypertensive patients (60).
Stress management
CHEP recommends that for hypertensive people in whom stress
may be a contributing factor to blood pressure elevation, stress
management should be considered as an intervention (22).
Smoking cessation
Living and working in a tobacco free environment is recommended by CHEP and the CDA. It has been shown that the excess
risk of coronary heart disease caused by smoking is reduced by
w50% after 1 year of quitting smoking and then declines gradually
(66). It is never too late to stop smoking.
Vascular risk reduction with antiplatelet therapy?
Although hypertension is a leading risk in people with diabetes,
a comprehensive approach to vascular risk reduction is required.
Addressing dyslipidemia, smoking, hyperglycemia and use of
antiplatelet agents may reduce vascular risk. The current evidence
for the use of ASA in patients with hypertension and diabetes in
primary prevention is unclear. In the 2008 guidelines, the CDA
recommended consideration of low dose ASA therapy in people
with established coronary artery disease and recommended that
the decision to prescribe antiplatelet therapy for primary prevention of cardiovascular events should be based on individual clinical
judgment (67). Two recent studies and a systematic review by the
Antithrombotic Trialists collaborators have shown no benet from
ASA in the primary prevention of cardiovascular events in patients
with diabetes (68e71). Additionally, the 2011 Canadian Cardiovascular Society (CCS) antiplatelet guidelines state that there is no
evidence to recommend routine use of ASA at any dose for the
primary prevention of ischemic vascular events in patients with
diabetes (Class III, Level A) (72). For patients over 40 years of age
with diabetes who are at low risk of major bleeding, low dose ASA
may be considered for primary prevention and in patients with
other cardiovascular risk factors for which its benets are established (Class IIb, Level B). Even if antiplatelet therapy is helpful, it
appears that the benets in reduction of cardiovascular outcomes
in patients at low risk of events are modest (71,73).
How can adherence to medications and lifestyle therapies be
optimized?
There are several strategies to improve adherence to medication
and lifestyle interventions in patients with diabetes and
hypertension:
 Fixed dose single pill combination therapies: the use of xed
dose single pill combination therapies is a strategy to improve
adherence to drug therapy in patients requiring multiple
medications (22).
 Vascular age: CHEP recommends considering informing
patients of their global risk to improve the effectiveness of risk
factor modication (22). Clinicians may consider using analogies that describe comparative risk such as vascular age.
Vascular age may be calculated online for free at http://www.
myhealthcheckup.com.
 Self-management education: self-management education is
one strategy to increase adherence to lifestyle interventions
and medications. Ways to promote self-management

education in patients with hypertension and diabetes include


self-monitoring blood pressure, interdisciplinary team care
and behavioural interventions.
 Multidisciplinary team-based healthcare: advocated for the
management of chronic diseases and has been advocated as
routine clinical care of hypertension in Canada (22). For
example, care from a community pharmacist and nurse team
was associated with clinically important improvements in
blood pressure in patients with hypertension and diabetes (74).
CHEP recommends that healthcare teams incorporate a pharmacist to improve monitoring of adherence with pharmacologic and lifestyle modication (22).

What is the optimal regimen for home blood pressure monitoring?


People with hypertension and diabetes should be encouraged to
be involved in all aspects of their care plan including home blood
pressure monitoring (22). Patients should be advised to purchase
and use approved blood pressure monitoring devices and healthcare professionals should ensure that patients have adequate
training to take measurements appropriately. Blood pressure
targets should be discussed with the patient and a follow-up plan
should be in place so that the patient knows how to respond if
blood pressure levels are outside the target range.
In most instances, a manual ofce blood pressure reading of
140/90 mm Hg is equated to a mean home blood pressure of 135/85
mm Hg (75). This would suggest that for patients who are monitoring their blood pressure at home, a home target below the
currently recommended <130/80 mm Hg should be pursued.
Despite this, lower targets have not been set for home monitoring
of blood pressure in patients with diabetes. Discrepancies between
ofce and home blood pressure measures may be reduced by the
use of automated ofce blood pressure measurement devices such
as the BpTRU automatic blood pressure monitor, BPM-100 electronic oscillometric ofce blood pressure monitor (VSM Med Tech,
Vancouver, BC) or the Omron HEM-907 (Omron Healthcare, Lake
Forest, IL) as they virtually eliminate the white coat effect exhibited
by many patients (75).
The following points are recommended for home blood pressure
monitoring (22):
 Check blood pressure twice daily for 1 week before a visit to the
healthcare professional. Healthcare professionals should
discard the readings of the rst day and calculate the average of
the last 6 days.
 Record blood pressure levels in a logbook, spreadsheet or
Smartphone or tablet computer application. Healthcare
providers should provide the log book and show the person
how to record their numbers.
 Patients should bring their log to all appointments with the
healthcare professional.
Excellent resources to support home blood pressure measurement, including patient handouts and an instructional video, are
available online at www.hypertension.ca/education or Hypertension Canadas YouTube channel.
Are there differences in treatment for special populations as dened
by ethnocultural background (e.g. Canadian Aboriginal Peoples and
South Asian Peoples)?
The CHEP guidelines regarding treatment of hypertension in
people with diabetes do not differ for special populations as
dened by ethnocultural background. Despite this, a few points are
worthy of consideration as it is well known that in certain cases

M. Makowsky et al. / Can J Diabetes 36 (2012) 345e353

ethnocultural background can inuence medication effectiveness.


The only instance of ethnocultural adaptation of therapy in the
current CHEP guidelines is in the area of uncomplicated hypertension, where CHEP recommends that ACE inhibitors are not
recommended for monotherapy in blacks (22). Type 2 diabetes has
reached epidemic proportions among Aboriginal peoples in
Canada, where national age adjusted prevalence is 3 to 5 times
higher than that of the general population (76). In Ontario, the
prevalence of hypertension was found to be 3-fold higher in South
Asians compared with the general population (20). Individuals
from high-risk ethnic populations also develop diabetes complications, particularly cardiovascular disease and renal failure, much
earlier than other populations (77). Given the high cardiovascular
mortality in South Asians, aggressive management of risk factors,
including hypertension and dyslipidemia, has been recommended
by the CDA to reduce morbidity and mortality. Ethnocultural
minority groups frequently have poorly controlled hypertension
and diabetes and ethnocultural-specic disease management
programs may play a role in better management (76e78).
Case Resolution
This is a case of hypertension in diabetes that is complicated by
microalbuminuria and additional cardiovascular risk factors (i.e.
smoking, sedentary lifestyle). Mr. Js ofce based blood pressure of
144/93 mm Hg is above the guideline recommended target of
<130/80 mm Hg for clinic values and the CHEP and CDA guidelines
would support further lifestyle intervention and antihypertensive
treatment concurrently to achieve this target.
Pharmacotherapy interventions
Given the patients blood pressure readings and current therapy,
consideration should be given to:
 Increasing the dose of ramipril. However, considering the
relatively at dose response curve, increasing the dose beyond
10 mg daily may have limited benet on blood pressure
reduction (79,80).
 Increasing the dose of hydrochlorothiazide to 25 mg daily given
Mr. Js normal renal function.
 Adding a dihydropyridine CCB (e.g. amlodipine) as a third
antihypertensive agent.
 Minimizing use of the as-needed nonsteroidal anti-inammatory
drugs he is on for knee osteoarthritis.
Pharmacotherapy issues not addressed by the current CHEP/CDA
guidelines:
 Thiazide-like vs. thiazide diuretic: based on current evidence,
chlorthalidone is a reasonable choice in this patient. However,
given that it is likely that Mr. J will start a third antihypertensive agent, use of a single pill combination with ramipril and
hydrochlorothiazide, or perindopril and indapamide may be
preferential to using chlorthalidone in this case.
 Aldosterone antagonists: because Mr. J does not have resistant
hypertension; spironolactone would not be a suitable agent at
this time.
 Aliskiren: is not a suitable third line antihypertensive agent in
this case.
 Nighttime dosing of at least 1 antihypertensive agent: Mr. J
does not t the inclusion criteria of the MAPEC study as he is
neither untreated nor dened as having resistant hypertension.
Therefore, in our view there is no compelling reason to dose an
antihypertensive agent at bedtime in this case.

351

Lifestyle interventions
There are several opportunities for lifestyle intervention and the
patients values should be taken into consideration when prioritize
the treatment plan:
 Healthy eating and sodium reduction: the target for sodium
intake in this patient of <1300 mg daily should be pursued via
improved awareness and strategies to minimize the most
common sources of sodium in the diet (e.g. restaurant meals,
processed foods, bread products).
 Smoking cessation: Mr. J should receive brief advice recommending smoking cessation as even a few cigars contribute to
his risk.
 Alcohol consumption: his alcohol consumption should be
further investigated and he should receive advice about low
risk alcohol consumption if he is exceeding 2 drinks per day.
 Physical activity and reducing body weight: an increase in
physical activity tailored toward his interests, lifestyle and
concomitant knee osteoarthritis should be discussed. He
should participate in creation of a personalized activity plan
and be aware that his target is a BMI of <25 kg/m2.

Vascular risk reduction with antiplatelet therapy


Given that this is a case of primary prevention, the current
guidelines would argue against offering this therapy to Mr. J.
However, a discussion of risks and benets of ASA for primary
prevention of cardiovascular events should take place with the
patient to uncover the patients values regarding this commonly
available over the counter medication and allow for individualization of therapy and shared-decision making.
Strategies to optimize adherence
 Single pill combinations: use of a single pill combination may
be considered to encourage adherence and reduce pill burden.
 Cardiovascular age: with respect to portraying cardiovascular
risk, this patients cardiovascular age is 73 years as compared to
his actual age of 65 years. Mr. J should be counselled on this
age/risk differential and the benets of adopting a healthy
lifestyle and controlling his blood pressure.
 Home blood pressure monitoring: although home blood pressure monitoring may be used to improve adherence to lifestyle
and medication therapy, measuring blood pressure at home,
every day of the year, more than twice daily is not recommended. Given that Mr. Js blood pressure is not at target, he
should be advised to check his blood pressure at home twice in
the morning and twice in the evening using a validated device
for 7 days before clinic visits.
 Multidisciplinary team-based healthcare: Mr. J may benet
from referral to a pharmacist or nurse to provide selfmanagement education and support for adherence to lifestyle
and medication therapies.
Conclusions
There are many unique aspects to the management of hypertension in patients with diabetes. Hypertension remains undertreated for the majority of people with diabetes despite evidence
that treating hypertension reduces the risk of cardiovascular
disease and microvascular complications. Although treatment
targets are controversial, both CHEP and the CDA still recommend
a blood pressure target of <130/80 mm Hg. Pharmacotherapy and
lifestyle interventions should be initiated concurrently and

352

M. Makowsky et al. / Can J Diabetes 36 (2012) 345e353

a comprehensive approach is required to address other vascular


risk factors. Home monitoring of blood pressure with approved
devices should be encouraged to promote adherence. Although
sustained adherence to medication and lifestyle interventions
represents a challenge, the collaboration of an integrated multidisciplinary team with consistent education and support may
promote the best health outcome for the patient.
Author Disclosures
APHP is a consultant for Eli Lilly and Novo Nordisk and receives
speakers honorarium from AstraZeneca, Bristol-Myers Squibb,
Sano and Eli Lilly. Preparation of this material was supported by
a grant from the Public Health Agency of Canada.
Author Contributions
All authors contributed to conception of the study. MM prepared
the rst draft of the manuscript. APHP, CJ, MG and AM critically
reviewed the manuscript for intellectual content. All authors gave
nal approval of the version to be published.
References
1. Public Health Agency of Canada. Diabetes in Canada: facts and gures from
a public health perspective. Ottawa 2011.
2. Gee ME, Janssen I, Pickett W, et al. Prevalence, awareness, treatment, and
control of hypertension among Canadian adults with diabetes, 2007 to 2009.
Can J Cardiol 2012;28:367e74.
3. National Diabetes Surveillance System. Report from the National Diabetes
Surveillance System: diabetes in Canada, 2009. (available online at http://
www.ndss.gc.ca). Accessed February 9, 2011.
4. Sowers JR, Epstein M, Frohlich ED. Diabetes, hypertension, and cardiovascular
disease: an update. Hypertension 2001;37:1053e9.
5. Campbell NR, Leiter LA, Larochelle P, et al. Hypertension in diabetes: a call to
action. Can J Cardiol 2009;25:299e302.
6. Bild D, Teutsch SM. The control of hypertension in persons with diabetes:
a public health approach. Public Health Rep 1987;102:522e9.
7. Chen G, McAlister FA, Walker RL, et al. Cardiovascular outcomes in Framingham participants with diabetes: the importance of blood pressure. Hypertension 2011;57:891e7.
8. Adler AI, Stratton IM, Neil HA, et al. Association of systolic blood pressure with
macrovascular and microvascular complications of type 2 diabetes (UKPDS 36):
prospective observational study. BMJ 2000;321:412e9.
9. Tuomilehto J, Rastenyte D, Birkenhager WH, et al. Effects of calcium-channel
blockade in older patients with diabetes and systolic hypertension. Systolic
Hypertension in Europe Trial Investigators. N Engl J Med 1999;340:677e84.
10. UK Prospective Diabetes Study Group. Tight blood pressure control and risk of
macrovascular and microvascular complications in type 2 diabetes: UKPDS 38.
BMJ 1998;317:703e13.
11. Schrier RW, Estacio RO, Esler A, Mehler P. Effects of aggressive blood pressure
control in normotensive type 2 diabetic patients on albuminuria, retinopathy
and strokes. Kidney Int 2002;61:1086e97.
12. Patel A, MacMahon S, Chalmers J, et al. Effects of a xed combination of perindopril and indapamide on macrovascular and microvascular outcomes in
patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised
controlled trial. Lancet 2007;370:829e40.
13. Heart Outcomes Prevention Evaluation Study Investigators. Effects of ramipril
on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Lancet 2000;355:
253e9.
14. Brenner BM, Cooper ME, de Zeeuw D, et al. Effects of losartan on renal and
cardiovascular outcomes in patients with type 2 diabetes and nephropathy.
N Engl J Med 2001;345:861e9.
15. Lewis EJ, Hunsicker LG, Clarke WR, et al. Renoprotective effect of the
angiotensin-receptor antagonist irbesartan in patients with nephropathy due
to type 2 diabetes. N Engl J Med 2001;345:851e60.
16. Turnbull F, Neal B, Algert C, et al. Effects of different blood pressure-lowering
regimens on major cardiovascular events in individuals with and without
diabetes mellitus: results of prospectively designed overviews of randomized
trials. Arch Intern Med 2005;165:1410e9.
17. Hansson L, Zanchetti A, Carruthers SG, et al. Effects of intensive blood-pressure
lowering and low-dose aspirin in patients with hypertension: principal results
of the Hypertension Optimal Treatment (HOT) randomised trial. HOT Study
Group. Lancet 1998;351:1755e62.
18. Abaterusso C, Lupo A, Ortalda V, et al. Treating elderly people with diabetes
and stages 3 and 4 chronic kidney disease. Clin J Am Soc Nephrol 2008;3:
1185e94.

19. Cost-effectiveness of intensive glycemic control, intensied hypertension


control, and serum cholesterol level reduction for type 2 diabetes. JAMA 2002;
287:2542e51.
20. Leenen FH, Dumais J, McInnis NH, et al. Results of the Ontario survey on the
prevalence and control of hypertension. CMAJ 2008;178:1441e9.
21. Canadian Diabetes Association Clinical Practice Guideline Expert Committee.
Canadian Diabetes Association 2008 clinical practice guidelines for the prevention and management of diabetes in Canada. Can J Diabetes 2008;32(Suppl 1):
S1e201.
22. Daskalopoulou SS, Khan NA, Quinn RR, et al. The 2012 Canadian Hypertension
Education Program recommendations for the management of hypertension:
blood pressure measurement, diagnosis, assessment of risk, and therapy. Can J
Cardiol 2012;28:270e87.
23. Canadian Diabetes Association Clinical Practice Guideline Expert Committee.
Treatment of Hypertension. In: Canadian Diabetes Association Clinical Practice
Guideline Expert Committee, ed. Canadian Diabetes Association 2008 clinical
practice guidelines for the prevention and management of diabetes in Canada.
2008;32(Suppl 1):S115eS118.
24. Orchard TJ, Forrest KY, Kuller LH, Becker DJ. Lipid and blood pressure treatment
goals for type 1 diabetes: 10-year incidence data from the Pittsburgh Epidemiology of Diabetes Complications Study. Diabetes Care 2001;24:1053e9.
25. Cushman WC, Evans GW, Byington RP, et al. Effects of intensive blood-pressure
control in type 2 diabetes mellitus. N Engl J Med 2010;362:1575e85.
26. Bangalore S, Kumar S, Lobach I, Messerli FH. Blood pressure targets in subjects
with type 2 diabetes mellitus/impaired fasting glucose: observations from
traditional and bayesian random-effects meta-analyses of randomized trials.
Circulation 2011;123:2799e810.
27. Reboldi G, Gentile G, Angeli F, et al. Effects of intensive blood pressure
reduction on myocardial infarction and stroke in diabetes: a meta-analysis in
73,913 patients. J Hypertens 2011;29:1253e69.
28. American Diabetes Association. Standards of medical care in diabetesd2012.
Diabetes Care 2012;35(Suppl 1):S11e63.
29. Whelton PK, Barzilay J, Cushman WC, et al. Clinical outcomes in antihypertensive treatment of type 2 diabetes, impaired fasting glucose concentration,
and normoglycemia: Antihypertensive and Lipid-Lowering Treatment to
Prevent Heart Attack Trial (ALLHAT). Arch Intern Med 2005;165:1401e9.
30. Jamerson K, Weber MA, Bakris GL, et al. Benazepril plus amlodipine or
hydrochlorothiazide for hypertension in high-risk patients. N Engl J Med 2008;
359:2417e28.
31. Weber MA, Bakris GL, Jamerson K, et al. Cardiovascular events during differing
hypertension therapies in patients with diabetes. J Am Coll Cardiol 2010;56:
77e85.
32. Mogensen CE, Neldam S, Tikkanen I, et al. Randomised controlled trial of dual
blockade of renin-angiotensin system in patients with hypertension, microalbuminuria, and non-insulin dependent diabetes: the candesartan and lisinopril microalbuminuria (CALM) study. BMJ 2000;321:1440e4.
33. Jacobsen P, Andersen S, Rossing K, et al. Dual blockade of the renin-angiotensin
system versus maximal recommended dose of ACE inhibition in diabetic
nephropathy. Kidney Int 2003;63:1874e80.
34. Song JH, Cha SH, Lee HJ, et al. Effect of low-dose dual blockade of reninangiotensin system on urinary TGF-beta in type 2 diabetic patients with
advanced kidney disease. Nephrol Dial Transplant 2006;21:683e9.
35. Yusuf S, Teo KK, Pogue J, et al. Telmisartan, ramipril, or both in patients at high
risk for vascular events. N Engl J Med 2008;358:1547e59.
36. McMurray JJ, Ostergren J, Swedberg K, et al. Effects of candesartan in patients
with chronic heart failure and reduced left-ventricular systolic function taking
angiotensin-converting-enzyme inhibitors: the CHARM-Added trial. Lancet
2003;362:767e71.
37. Major outcomes in high-risk hypertensive patients randomized to angiotensinconverting enzyme inhibitor or calcium channel blocker vs diuretic: the
Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial
(ALLHAT). JAMA 2002;288:2981e97.
38. Messerli FH, Bangalore S. Half a century of hydrochlorothiazide: facts, fads,
ction, and follies. Am J Med 2011;124:896e9.
39. Carter BL, Ernst ME, Cohen JD. Hydrochlorothiazide versus chlorthalidone:
evidence supporting their interchangeability. Hypertension 2004;43:4e9.
40. Bengtsson C, Johnsson G, Sannerstedt R, Werko L. Effect of different doses of
chlorthalidone on blood pressure, serum potassium, and serum urate. BMJ
1975;1:197e9.
41. Hughes AD. How do thiazide and thiazide-like diuretics lower blood pressure?
JRAAS 2004;5:155e60.
42. Bennett WM, McDonald WJ, Kuehnel E, et al. Do diuretics have antihypertensive properties independent of natriuresis? Clin Pharmacol Ther 1977;22:
499e504.
43. Jones B, Nanra RS. Double-blind trial of antihypertensive effect of chlorothiazide in severe renal failure. Lancet 1979;2:1258e60.
44. Epstein M, Williams GH, Weinberger M, et al. Selective aldosterone blockade
with eplerenone reduces albuminuria in patients with type 2 diabetes. Clin J
Am Soc Nephrol 2006;1:940e51.
45. Epstein M, Calhoun DA. Aldosterone blockers (mineralocorticoid receptor
antagonism) and potassium-sparing diuretics. J Clin Hypertens 2011;13:
644e8.
46. Calhoun DA, Jones D, Textor S, et al. Resistant hypertension: diagnosis, evaluation, and treatment: a scientic statement from the American Heart Association Professional Education Committee of the Council for High Blood
Pressure Research. Circulation 2008;117:e510e26.

M. Makowsky et al. / Can J Diabetes 36 (2012) 345e353


47. theHeart.org. Altitude halted: adverse events when aliskiren added to ACE, ARB
therapy. (available online at http://www.theheart.org/article/1331173.do).
Accessed April 10, 2012.
48. Health Canada. Rasilez (aliskiren) and Rasilez HCT (aliskiren/hydrochlorothiazide)dpotential risks of cardiovascular and renal adverse events in
patients with type 2 diabetesdfor health professionals. (available online at
http://hc-sc.gc.ca/dhp-mps/medeff/advisories-avis/prof/_2012/rasilez_hpc-cpseng.php). Accessed April 10, 2012.
49. Hermida RC, Ayala DE, Mojon A, Fernandez JR. Inuence of circadian time of
hypertension treatment on cardiovascular risk: results of the MAPEC study.
Chronobiol Int 2010;27:1629e51.
50. Hermida RC, Ayala DE, Mojon A, Fernandez JR. Inuence of time of day of blood
pressure-lowering treatment on cardiovascular risk in hypertensive patients
with type 2 diabetes. Diabetes Care 2011;34:1270e6.
51. Hermida RC, Ayala DE, Mojon A, Fernandez JR. Bedtime dosing of antihypertensive medications reduces cardiovascular risk in CKD. JASN 2011;22:2313e21.
52. Portaluppi F, Smolensky MH. Perspectives on the chronotherapy of hypertension
based on the results of the MAPEC study. Chronobiol Int 2010;27:1652e67.
53. Sinha AD, Agarwal R. ACP Journal Club. Use of 1 antihypertensive drug at
bedtime reduced CV events more than use of all drugs in the morning in CKD.
Ann Intern Med 2012;156:JC6e8.
54. Van Vliet BN, Campbell NR. Efforts to reduce sodium intake in Canada: why,
what, and when? Can J Cardiol 2011;27:437e45.
55. Health Canada. Food and nutrition. Sodium. (available online at http://www.
hc-sc.gc.ca/fn-an/label-etiquet/nutrition/cons/sodium-eng.php).
Accessed
April 10, 2012.
56. Garriguet D. Sodium consumption at all ages. Health Rep 2007;18:47e52.
57. He FJ, MacGregor GA. Effect of longer-term modest salt reduction on blood
pressure. Cochrane Database Syst Rev 2004;3:CD004937.
58. Health Canada. Sodium reduction strategy for Canada. Recommendations of
the sodium working group. (available online at http://www.healthcanada.gc.
ca/sodium. Accessed April 10, 2012.
59. Fischer PW, Vigneault M, Huang R, et al. Sodium food sources in the Canadian
diet. Applied physiology, nutrition, and metabolism Physiologie appliquee,
nutrition et metabolisme 2009;34:884e92.
60. Padwal R, Campbell N, Touyz RM. Applying the 2005 Canadian Hypertension
Education Program recommendations: 3. Lifestyle modications to prevent
and treat hypertension. CMAJ 2005;173:749e51.
61. Canadian Diabetes Association. Physical activity and diabetes. In: Canadian
Diabetes Association Clinical Practice Guideline Expert Committee, editors.
Canadian Diabetes Association 2008 Clinical Practice Guidelines for the
Prevention and Management of Diabetes in Canada. 2008;32(Suppl 1):S37eS39.
62. Canadian Diabetes Association. Nutrition THERAPY. In: Canadian Diabetes
Association Clinical Practice Guideline Expert Committee, editors. Canadian
Diabetes Association 2008 Clinical Practice Guidelines for the Prevention and
Management of Diabetes in Canada. 2008;32(Suppl 1):S40eS45.
63. Appel LJ, Moore TJ, Obarzanek E, et al. A clinical trial of the effects of dietary
patterns on blood pressure. DASH Collaborative Research Group. N Engl J Med
1997;336:1117e24.
64. Effects of weight loss and sodium reduction intervention on blood pressure and
hypertension incidence in overweight people with high-normal blood pressure.
The Trials of Hypertension Prevention, phase II. The Trials of Hypertension
Prevention Collaborative Research Group. Arch Intern Med 1997;157:657e67.
65. Whelton SP, Chin A, Xin X, He J. Effect of aerobic exercise on blood pressure:
a meta-analysis of randomized, controlled trials. Ann Intern Med 2002;136:
493e503.

353

66. U.S. Department of Health and Human Services. The Health Benets of
Smoking Cessation. Surgeon Generals Report on Smoking and Health, Vol.
2011. Atlanta: U.S. Department of Health and Human Services, Public Health
Service, Centers for Disease Control, Center for Chronic Disease Prevention and
Health Promotion, Ofce on Smoking and Health; 1990. DHHS Publication No.
(CDC) 90-8416.
67. Canadian Diabetes Association. Vascular protection in people with diabetes. In:
Canadian Diabetes Association Clinical Practice Guideline Expert Committee,
editors. Canadian Diabetes Association 2008 Clinical Practice Guidelines for the
Prevention and Management of Diabetes in Canada. 2008;32(Suppl 1):
S102eS106.
68. Antithrombotic Trialists Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial
infarction, and stroke in high risk patients. BMJ 2002;324:71e86. Erratum in:
BMJ 2002;324:141.
69. Ogawa H, Nakayama M, Morimoto T, et al. Low-dose aspirin for primary
prevention of atherosclerotic events in patients with type 2 diabetes:
a randomized controlled trial. JAMA 2008;300:2134e41.
70. Belch J, MacCuish A, Campbell I, et al. The prevention of progression of arterial
disease and diabetes (POPADAD) trial: factorial randomised placebo controlled
trial of aspirin and antioxidants in patients with diabetes and asymptomatic
peripheral arterial disease. BMJ 2008;337:a1840.
71. Baigent C, Blackwell L, Collins R, et al. Aspirin in the primary and secondary
prevention of vascular disease: collaborative meta-analysis of individual
participant data from randomised trials. Lancet 2009;373:1849e60.
72. Bell AD, Roussin A, Cartier R, et al. The use of antiplatelet therapy in the
outpatient setting: Canadian Cardiovascular Society guidelines. Can J Cardiol
2011;27(Suppl A):S1e59.
73. Seshasai SR, Wijesuriya S, Sivakumaran R, et al. Effect of aspirin on vascular and
nonvascular outcomes: meta-analysis of randomized controlled trials. Arch
Intern Med 2012;172:209e16.
74. McLean DL, McAlister FA, Johnson JA, et al. A randomized trial of the effect of
community pharmacist and nurse care on improving blood pressure
management in patients with diabetes mellitus: study of cardiovascular risk
intervention by pharmacists-hypertension (SCRIP-HTN). Arch Intern Med
2008;168:2355e61.
75. Myers MG, Godwin M, Dawes M, et al. Measurement of blood pressure in the
ofce: recognizing the problem and proposing the solution. Hypertension
2010;55:195e200.
76. Canadian Diabetes Association. Type 2 diabetes in Aboriginal peoples. In: Canadian Diabetes Association Clinical Practice Guideline Expert Committee, editors.
Canadian Diabetes Association 2008 Clinical Practice Guidelines for the Prevention and Management of Diabetes in Canada. 2008;32(Suppl 1):S187eS190.
77. Canadian Diabetes Association. Type 2 diabetes in high risk ethnic populations.
In: Canadian Diabetes Association Clinical Practice Guideline Expert
Committee, editors. Canadian Diabetes Association 2008 Clinical Practice
Guidelines for the Prevention and Management of Diabetes in Canada.
2008;32(Suppl 1):S191eS193.
78. Soha PS. Prevention and management of diabetes in South Asians. Can J Diabetes 2008;32:206e10.
79. Heran BS, Wong MMY, Heran IK, Wright JM. Blood pressure lowering efcacy
of angiotensin converting enzyme (ACE) inhibitors for primary hypertension.
Cochrane Database Syst Rev 2009;(4).
80. Song JC, White CM. Clinical pharmacokinetics and selective pharmacodynamics
of new angiotensin converting enzyme inhibitors: an update. Clin Pharmacokinet 2002;41:207e24.