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					The Scientific Basis for Hypertension Management in People with
Diabetes
Norm RC Campbell MD1, Richard E Gilbert MD PhD2, Lawrence A. Leiter MD2, Pierre
Larochelle MD3, Sheldon Tobe MD 4, Arun Chockalingam PhD5, Richard Ward MD6,
Dorothy Morris, BScN,,MA, CCN(C) 7, Ross T Tsuyuki PharmD MSc8, Stewart Harris
MD9

1 Departments of Medicine, Community Health Sciences, University of Calgary, Libin
Cardiovascular Institute of Alberta, Calgary, Alberta

2 Keenan Research Centre in the Li Ka Shing Knowledge Institute of St. Michael's
Hospital, University of Toronto, Toronto, Ontario

3 Institut de Recherches Cliniques de Montreal, University of Montreal, Montreal
Quebec

4 Division of Nephrology, University of Toronto, Toronto Ontario.

5 Faculty of Health Sciences, Simon Fraser University, Burnaby, British Columbia

6 Faculty of Medicine, University of Calgary, Calgary, Alberta

7 Canadian Council of Cardiovascular Nurses, Vancouver Island Health Authority,
Victoria, British Columbia

8. EPICORE Centre, Division of Cardiology, Department of Medicine, Faculty of
Medicine and Dentistry, University of Alberta, Edmonton Alberta

9. CDA Chair in Diabetes Management, Ian McWinney Chair For Studies in Family
Medicine, University of Western Ontario, London, Ontario


Correspondence: Dr. Norm Campbell
Libin Cardiovascular Institute of Alberta
TRW, The University of Calgary
3280 Hospital Drive NW
Calgary Alberta
T2N 4Z6
Calgary, Alberta, T2N 4N1 Canada
E-mail: hyperten@ucalgary.ca


                                                                                     1
Abstract:


Hypertension is an important risk to health that is present in over 1 in 5 adult

Canadians. In Canadians with diabetes, hypertension has a particularly high risk.

Based on Ontario data, we estimate 1 in 28 adult Canadians have both hypertension

and diabetes and in over 6 in 10 of these people, the blood pressure is uncontrolled. In

clinical trials an average of three or more drugs including a diuretic are often used and

even then, many do not reach the intended blood pressure targets. Nevertheless,

treatment of high blood pressure in people with diabetes in clinical trials has been

shown to cause large reductions in rates of death and disability and, where assessed,

was cost saving. Management strategies that include assessment and management of

cardiovascular risks including: smoking, unhealthy eating, physical inactivity, adiposity,

dyslipidemia as well as hyperglycemia result in greater health benefits. Currently, the

role of ASA in primary prevention of cardiovascular disease is uncertain in people with

hypertension and diabetes. Ongoing trials are establishing the role of ASA in people

with diabetes will result in greater health benefits. Given the current low rate of control

of hypertension in Canadians with diabetes more effective knowledge translation

strategies are required.




                                                                                              2
Current Hypertension and Diabetes Definitions


Diabetes is defined as a usual fasting plasma glucose of 7 mmol/L or higher or 2 hour

plasma glucose of 11.1 mmol/L or higher in the asymptomatic individual or a casual

plasma glucose of 11.1 mmol/L or higher with symptoms of diabetes (1). Most of the

burden of disease in people with diabetes is associated with type 2 diabetes, which is

the focus of this review. Hypertension in people with diabetes is defined by usual blood

pressure of 130/80 mmHg or higher (1).


Epidemiology of Hypertension in People with Type 2 diabetes


Increased blood pressure is the leading risk for preventable death in the world and

many countries are facing an epidemic of hypertension. Worldwide, the prevalence of

hypertension is about 25% and is expected to increase by 60% between 2000 and

2025. Over 90% of those living an average lifespan will develop hypertension (2) which

is largely a reflection of sedentary behaviour, poor dietary habits and obesity (3;4).


In Canada the prevalence of hypertension assessed by blood pressure measures has

been stable at 19-21% for the last 2 decades (5;6). The national prevalence of diabetes

as measured by blood glucose levels will be established for the first time when the

Canadian Health Measures Survey (CHMS) reports later in 2010. However, Canadians

have had very large increases in diagnoses of both hypertension and diabetes. Based

on currently unpublished data from the Canadian Chronic Disease Surveillance System

(CCDSS-Hypertension report), in 2006/7, 5,848,464 Canadians or 22.7% of the adult

population had a diagnosis of hypertension, a 52% increase in prevalence from 1997/8.

(The greater prevalence of diagnosed hypertension in CCDSS than measured


                                                                                         3
hypertension in the Canadian Health Measures Survey may in part reflect the higher

age of Canadians assessed in CCDSS.) In the year 2006/7 alone, 450,029 adult

Canadians were newly diagnosed with hypertension (CCDSS). There were just over 2

million (2,061,995) Canadians diagnosed with diabetes in 2006/7 (7) and over 1 million

(1,012,621) Canadians had a diagnosis of both hypertension and diabetes (CCDSS).

There was a 21% increase in prevalence of diagnosed diabetes in Canada between

2002/3 and 2006/7 (7) and a 69% increase in Ontario between 1995 and 2005 (8). It is

not currently known if the increase in diagnosis of diabetes reflects an increase in true

prevalence or, like hypertension, if it is largely related to increased clinical diagnosis.

Several factors including the aging population, sedentary behavior and/or, poor nutrition

(with resultant increases in adiposity and obesity) and immigration to Canada of high

risk populations would predict large increases in the prevalence of both hypertension

and diabetes. About 1 in 4 Canadians with hypertension and close to two thirds of

those with diabetes are diagnosed have both conditions (CCDSS). In a recent survey in

Ontario, 66% of people who self report a diagnosis of diabetes also had hypertension

and two thirds of those had uncontrolled blood pressure (9).




Increased Blood Pressure and Vascular Risk in People with Diabetes Mellitus


Increased blood pressure represents a major health risk to people with diabetes. Most

60-80%) people with diabetes die of cardiovascular complications and up to 75% of

specific cardiovascular complications have been attributed to high blood pressure

(Table 1) (10). Hypertension is also a major factor contributing to kidney failure and eye



                                                                                              4
disease in people with diabetes (11;12). Importantly, much of the information on the

risks of high blood pressure in people with diabetes comes from older studies using

outdated definitions of both hypertension and diabetes.




Pathophysiology of Hypertension in People with Diabetes


The pathogenesis of hypertension in diabetes is complex, multifactorial and time-

dependent, involving strong interactions between genetic predisposition and a range of

environmental factors that include unhealthy eating, sedentary behavior, sodium

retention, obesity, autonomic derangements, premature arterial stiffening and

endothelial dysfunction. Not only are patients with diabetes more likely to have co-

existent hypertension but for any level of blood pressure, subjects with diabetes are also

at substantially higher risk of cardiovascular disease. This increased risk was first

clearly shown in the Multiple Risk Factor Intervention Trial (MRFIT), demonstrating that

for any given systolic pressure, diabetes was associated with a >2-fold increase in the

age-adjusted cardiovascular death rate (13). This apparent shift of the blood pressure

versus mortality curve to the left would mean, for instance, that a diabetic patient whose

systolic blood pressure was between 120 and 139 mmHg would have a similar

cardiovascular mortality rate to a non-diabetic subject whose systolic blood pressure

was 160-179 mmHg. The exact cause of the increased morbidity and mortality

associated with hypertension in diabetic patients that persists after adjustment for other

known risk factors is unclear. However, the frequent absence of a nocturnal blood

pressure dip among diabetic subjects is likely to be contributory. Despite similar office



                                                                                             5
and even daytime home blood pressure recordings, a ‘non-dipper’ will have a higher 24

hour and nocturnal blood pressure, with the latter, in particular, a strong predictor of

cardiovascular death (14). The mortality rates for Canadians with diagnosed

hypertension and diabetes is 2.5 times higher than that or Canadians with neither

diagnosis (CCDSS).




Reducing Vascular Risk Due To Increased Blood Pressure: Self-Efficacy and

Lifestyle Change Hypertension and type 2 diabetes can be prevented. Blood pressure

and hyperglycemia can be reduced and other cardiovascular risks can be improved by

lifestyle interventions including a healthy diet, regular physical activity, low risk alcohol

consumption, reductions in dietary sodium and in some, stress reduction (Table 3).

Brief health care professional interventions can increase the probability of a person

making lifestyle changes and more comprehensive interdisciplinary care approaches

are more effective (15;16). Self management and self-efficacy is encouraged through

the use of home measurement of blood pressure (17). Home blood pressure readings

better predict cardiovascular outcomes than office readings, can detect white coat

hypertension and masked hypertension, may improve adherence to medications or

lifestyle change and result in improved blood pressures. However, a weakness of home

measurement of blood pressure is the lack of studies in diabetic populations and hence

the absence of validated target blood pressures for people with diabetes. Home blood

pressure targets likely should be less than the office target of <130/80 mmHg in people

with diabetes.



                                                                                                6
Reducing Vascular Risk Due To Increased Blood Pressure: Pharmacotherapy

Pharmacologically reducing blood pressure in people with diabetes is one of the most

effective medical interventions available to reduce death and disability. Randomized

controlled trials of blood pressure lowering treatments in people with diabetes have

demonstrated major reductions in death, cardiovascular disease, eye and kidney disease

and the benefits are accrued in a short period in time (11;12;18-22). For example, in the

Systolic Hypertension in Europe (Syst Eur) Trial of isolated systolic hypertension

(SBP>160 mmHg, DBP<90 mmHg) active treatment reduced total mortality by 55%,

cardiovascular mortality by 76% and all cardiovascular events by 67% with a reduction in

blood pressure of 9.8/3.8 mmHg (23). In the UKPDS (United Kingdom Prospective

Diabetes Study), more intensive lowering of blood pressure by 10/5 mm Hg had a major

effect in reducing cardiovascular death and disability (18). In a meta analysis of

randomized controlled trials of people with diabetes and hypertension, more vs. less

intensive lowering of blood pressure reduced blood pressure by 6/4 mmHg and reduced

total mortality by 24% and major cardiovascular events by 25% (24). In the diabetes

subgroup of the HOT trial (Hypertension Optimum Treatment trial), people with diabetes

who were assigned to have a target diastolic blood pressure below 80 mmHg were

compared to those assigned to have a target blood pressure below 90 mmHg. Although

the achieved blood pressure difference in the 2 groups at the end of the study was only 4

mmHg, this greater reduction in blood pressure still resulted in a 66% reduction in death

from heart disease and stroke (25). The use of an ACE inhibitor or angiotensin receptor

blocker (ARB) based therapeutic regime to lower blood pressure has additional

advantages in people with chronic kidney disease and micro or marco albuminuria (24).



                                                                                        7
Very recently, the ACCORD trial randomized people with diabetes to a target systolic

blood pressure of less than 140 mmHg versus less than 120 mmHg (26). The primary

outcome (a composite of myocardial infarction, stroke and cardiovascular death) was not

significantly different between the interventions. Stroke was reduced (absolute 0.21%

fewer strokes per year, relative risk reduction 41%) but serious adverse events were

higher (absolute increase of 2% per year, relative increase 253%) in the group targeted to

less than 120 mmHg systolic. The impact of the ACCORD trial on target blood pressure

in people with diabetes has yet been considered by the Canadian Hypertension

Education Program (CHEP) and the Canadian Diabetes Association (CDA)

recommendations processes.




Combining Therapies To Reduce Blood Pressure


Combinations of lifestyle modification and sometimes 4 or more drugs are required for

blood pressure control (27). An ACE inhibitor or ARB is a potential first line therapy in all

people with hypertension and diabetes (28). Alternative first line treatments include long

acting calcium channel blockers and low dose diuretics in people without

microalbuminuria (28). In the ACCOMPLISH trial, people with hypertension at high

cardiovascular risk due to prior vascular events, target organ damage, renal impairment

or diabetes were randomized to treatment with an ACE inhibitor plus either a diuretic or a

calcium channel blocker (29). The combination of the ACE inhibitor and calcium channel

blocker was superior at reducing cardiovascular events (absolute reduction in events


                                                                                           8
2.2%, relative reduction 19.6%) leading to a recommendation to consider this combination

in high risk patients (30). Diuretic therapy is underutilized in people with hypertension and

diabetes yet is generally considered necessary for blood pressure control when multiple

antihypertensive drugs are prescribed (31;32). Diuretic therapy reduces major

cardiovascular events in hypertensive people with or at risk for diabetes, to a similar

extent as other first line drugs such as long acting calcium channel blockers or ACE

inhibitors (33). Often, higher doses of diuretic are required in resistant hypertension (34).

Maintaining a normal serum potassium level is important to minimize the effect of

diuretics on blood glucose and to maximize cardiovascular event reductions (35;36).

Long acting calcium channel blockers and cardio selective beta blockers need to be

considered if blood pressure remains above target. A combination tablet of an ACE

inhibitor or ARB with a diuretic, and a long acting calcium channel blocker and

spironolactone, or a long acting beta blocker are potent once a day, three tablet (four

drug) blood pressure lowering combinations. The combination of an ACE inhibitor with an

ARB has more adverse effects than ACE inhibitor therapy alone and has no therapeutic

advantage (37;38) and hence is specifically not recommended to be used in the presence

of normal urinary albumin levels. Trials are ongoing to determine if the combination of an

ACE inhibitor and ARB has a therapeutic role in the presence of proteinuria. Regular

monitoring of serum potassium is recommended if spironolactone is prescribed,

especially if the baseline serum potassium is in the high normal range, if there is reduced

glomerular filtration rate or concurrent use of other drugs that retain potassium. Although

multiple drugs are required for control, more extensive lowering of blood pressure in

people with diabetes is one of the very few cost saving medical interventions (39) (i.e. the



                                                                                           9
cost of blood pressure lowering is actually less than the cost of the complications

prevented by blood pressure lowering). Furthermore, quality of life can improve with

more intensive blood pressure lowering (40).




Benefits of a Comprehensive Approach to Reducing Vascular Risk in People With

Diabetes

Although hypertension is a leading risk in people with diabetes, other health risks are

also very important. Dyslipidemia has a large impact in reducing cardiovascular events

and a meta-analysis of statin based lipid lowering therapy in diabetes, revealed that

every 1 mmol/l reduction in LDL cholesterol was associated with a 9% reduction in total

mortality, 13% reduction in cardiovascular mortality and 21% reduction in major

cardiovascular events (41). Smoking is a risk for the development of diabetes (42) and

a major risk for not only cardiovascular disease and cancer, but also nephropathy and

retinopathy in the person with diabetes. Interventions for smoking cessation can reduce

mortality rates by almost 20% (43). Diabetes is defined by elevated blood glucose

levels and interventions to reduce glucose have resulted in reductions in cardiovascular

events, albuminuria and reduced development and progression of retinopathy (44-46).

(47). While future trials will establish optimum glucose targets, the Canadian Diabetes

Association (CDA) currently recommends reducing blood glucose levels to achieve a

A1C target of < 7.0% and consideration of reducing A1C to < 6.5% (1). Current

evidence is unclear as to the role of ASA in people with diabetes and hypertension. In

the HOT trial, hypertensive people benefited from ASA therapy with reduced

cardiovascular events (25). However there is a lack of benefit of ASA therapy in the


                                                                                          10
primary prevention of cardiovascular disease in studies of people with diabetes (48-50).

A comprehensive program that included lifestyle and pharmacotherapy for multiple risk

factors has been associated with a 40% reduction in total mortality highlighting the

importance of integrated programs that assess and address all cardiovascular risks

(51). Focusing efforts on improving lifestyle and proven therapies to reduce blood

pressure could have a very large impact on the longevity and disability of people with

diabetes. Unfortunately practice surveys demonstrate inadequate use of proven

therapies and especially antihypertensive and statin therapies in people with diabetes

(52-54).




Managing Hypertension in People with Diabetes: A Canadian Care Gap


The recent Ontario Heart and Stroke Foundation blood pressure survey demonstrated a

marked improvement in blood pressure control in hypertensive people with and without

diabetes (9). The improved treatment of hypertension in Canada has been associated

with a marked reduction in death and hospitalization from cardiovascular disease

(55;56). However the control of blood pressure in those with diabetes is worse than

those without diabetes, with two-thirds having blood pressures of 130/80 mmHg or

above (9). In diabetic people with uncontrolled blood pressure, 27% were not treated

and only 45% of those on multiple drugs were prescribed a diuretic (31). The Ontario

survey indicates substantive improvement in blood pressure control is required in

people with diabetes, which if implemented, will result in large reductions in death and

disability rates and health care costs. Currently the Canadian data is being analyzed



                                                                                           11
from the CHMS to determine the prevalence, awareness, treatment and control rates of

hypertension in people with diabetes.




Recommended Interventions

To improve the control rate for hypertension in people with diabetes a consistent long

term knowledge translation program aimed at health care professionals and people with

diabetes is recommended. Components of the knowledge translation program could

include a short series of key recommendations for both health care professionals and

people with diabetes, short and more detailed summaries of why control of blood

pressure is important and the sequential steps of how to control blood pressure.

Standardized education sessions are recommended to be a part of forums where

clinical education of health care professionals and people with diabetes occurs.

Standardized educational resources including slide presentations, typical clinical patient

case studies, and video are likely to facilitate the important components of care being

consistently emphasized in education and training.



The impact of the knowledge translation intervention is recommended to be assessed

using current and developing surveillance resources including the Canadian Health

Measures Survey, the Canadian Community Health Survey (CHHS), the Survey of

Living with Chronic Diseases in Canada ((SLCDC) Hypertension component), the

Canadian Chronic Disease Surveillance system (CCDSS) and the evolving

Hypertension Outcomes System Team (HOST) project. Specific measures to be

assessed (for both diabetes and hypertension) include rates of overall prevalence,

                                                                                          12
awareness of the diagnosis, treatment and control. This surveillance is recommended

to be regularly and routinely conducted and the results used to revise the knowledge

translation intervention programs to address care gaps identified.



To reduce the prevalence of diabetes and hypertension, a coordinated whole

government approach is required to ensure Canadians eat a healthy diet, obtain regular

physical activity, attain and maintain a healthy body weight and follow low risk alcohol

consumption recommendations. The Canadian Heart Health Strategy (www.chhs-

scsc.ca/web/ accessed March 1, 2010) and Canadian Diabetes Strategy (www.phac-

aspc.gc.ca/cd-mc/diabetes-diabete/diabetes_strategy-diabete_strategie-eng.php

accessed March 1 2010) outline such approaches. To be successful the strategies

require substantive governmental policy changes to ensure all Canadians have easy

access to healthy foods and safe areas conducive to physical activity. Past inaction to

implement such healthy public policies is responsible at least in part for the current

epidemic of hypertension, diabetes, dyslipidemia, obesity and many cancers.



Special efforts are being made for health care professionals to have greater
accessibility to hypertension resources. In 2010, health care professionals can enrol at
www.htnupdate.ca to get automated email notices when new or updated hypertension
resources are available for them or their patients. They can also download current
resources at www.hypertension.ca/tools.      A case-based interactive lecture series on
clinically important hypertension topics will also be launched on the internet so health
care professionals can learn and interact with top national hypertension experts. The
lecture series will feature important clinical topics provided by national experts, have a
case presentation and an opportunity to ask questions and make comments. The
lectures can be watched wherever there is internet coverage. Sign up at

                                                                                             13
www.htnupdate.ca to be notified when they start. CHEP will also continue and expand a
program to train community leaders in hypertension.

Hypertension Canada will be developing a hypertension association for Canadians with
high blood pressure. Encourage your patients to sign up for 2010 membership at
www.myBPsite.ca. Members will receive notices of updated and new educational
resources, a regular newsletter, incentives to encourage a healthy lifestyle, lectures and
possibly in the future personalized health care professional advice. Members will be
provided opportunities to provide advice on the need for new hypertension resources
and revise current blood pressure resources.



Acknowledgement: The authors are grateful to Selina Omar Allu for carefully reviewing

and revising the manuscript




                                                                                       14
Table 1: The definition of diabetes and of hypertension in the presence of

diabetes (1)

                                          Definition


Diabetes                                  -Fasting plasma glucose of 7 mmol/L or


                                          -Casual plasma glucose of 11.1 mmol/L or

                                          higher with symptoms of diabetes or


                                          -2 hour plasma glucose of 11.1 mmol/L or

                                          higher


Hypertension in people with diabetes      Systolic BP > 130 mmHg or


                                          Diastolic BP > 80 mmHg




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Table 2: Proportion of diabetic complications attributable to high blood pressure

(57)*


Complication                            Proportion attributable to hypertension

Stroke                                  75%

Coronary artery disease                 35%

End stage renal disease                 50%

Eye disease**                           35%

Leg amputation                          35%




* Hypertension defined as >160/95 and >140/90 mmHg in different studies.

** defined as retinopathy




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Table 3: Lifestyle therapy to reduce the risk of blood pressure-related

cardiovascular complications in hypertension

1.       Healthy diet: high in fresh fruits and vegetables, low fat dairy products, dietary
         and soluble fibre, whole grains and protein from plant sources, low in saturated
         fat, cholesterol and salt in accordance with Canada's Guide to Healthy Eating

2.       Regular physical activity: accumulation of 30-60 minutes of moderate intensity
         dynamic exercise 4-7 days per week in addition to daily activities

3.       Low risk alcohol consumption (≤2 standard drinks/day and less than 14/week for
         men and less than 9/week for women)


4.       Attaining and maintaining ideal body weight (BMI 18.5-24.9 kg/m2)


5.       A healthy waist circumference
                Europid                     < 94 cm for men
                                            < 80 cm for women
                South Asian, Japanese,      < 90 cm for men
                Chinese                     < 80 cm for women



6.       Reduction in sodium intake to 1500 mg /day is recommended for adults if under
         age 50; 1300 mg if aged 51-70; 1200 mg if age >70*

7.       A smoke free environment

With permission from the Canadian Hypertension Education Program



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