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Can J Diabetes 36 (2012) 345e353Canadian Journal of Diabetesjournal homepage:

www.canadianjournalofdiabetes.comReview

Management of Hypertension in People with Diabetes Mellitus: Translating the2012 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, MDd, Charlotte Jones MD, PhD, FRCPC e

a Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, CanadabDivision of Endocrinology and Metabolism, Department of Medicine, McMaster University, Hamilton, Ontario, CanadacDepartment of Family Medicine, University of British Columbia, Vancouver, British Columbia, Canadad Pine Valley Medical, Toronto, Ontario, CanadaeDepartment of Medicine, University of British Columbia, Okanagan Campus, Kelowna, British Columbia, Canadaa r t i c l e i n f o

Article history:Received 29 June 2012Received in revised form8 September 2012Accepted 17 September 2012

Keywords:diabeteshypertensionMots cls:diabtehypertension* Address for correspondence: Ally P.H. Prebtani, HHSite, McMasterWing, Room 411, 237 Barton St. E. Hami

E-mail address: prebtani@hhsc.ca (A.P.H. Prebtani

1499-2671/$ e see front matter 2012 Canadian Diahttp://dx.doi.org/10.1016/j.jcjd.2012.09.002a b s t r a c t

Hypertension is a common problem in peoplewith diabetes and several changes have occurred to the jointCanadian Hypertension Education Program and Canadian Diabetes Association hypertension recommen-dations over the past 5 years. This article uses a case-based approach to review contemporary issues inhypertension management in the context of diabetes, including: treatment targets, optimal combinationtherapy, choice of diuretic therapy, the role of aldosterone antagonists, role of aliskiren, bedtime dosing ofantihypertensive agents, benefits of sodium reduction, impact of lifestyle interventions, vascular riskreductionwith antiplatelet therapy, adherence strategies, the role of home blood pressure monitoring, andtreatment considerations based on ethnocultural background. Particular emphasis is given to linking therecommendations to practice. Up to 80% of peoplewith diabetes and hypertensionwill die of cardiovasculardisease, especially stroke. The2012CanadianHypertensionEducationProgramhypertension indiabeteskeymessages for knowledge translation are that clinicians should: 1) ensure people with diabetes are screenedforhypertension,2) assessbloodpressureat all appropriatehealthcarevisits, 3) encouragehomemonitoringwith approved devices, 4) initiate pharmacotherapy and lifestyle modification concurrently, 5) assess andmanage all other vascular risk factors, and 6) enable sustained lifestyle and medication adherence.

2012 Canadian Diabetes Association

r s u m

Lhypertension est un problme frquent chez les personnes ayant le diabte, et de nombreuses modifica-tions sont apparues aux recommandations conjointes sur lhypertension du Programme ducatif canadiensur lhypertension et de lAssociation canadienne du diabte au cours des 5 dernires annes. Cet articleutilise une approche par cas pour passer en revue les problmes contemporains de la prise en charge delhypertension dans le contexte du diabte, incluant les objectifs de traitement, le traitement combinoptimal, le choixdun traitementdiurtique, le rle desantagonistes de laldostrone, le rlede laliskirne, laposologie des agents antihypertenseurs au coucher, les bnfices de la rduction du sodium, les effets desinterventions sur le mode de vie, la rduction du risque vasculaire par un traitement antiplaquettaire, lesstratgies dobservance, le rlede la surveillancede la pressionartrielle domicile et les plansde traitementfonds sur le milieu ethnoculturel. Une importance particulire est accorde au fait de lier les recomman-dations la pratique. Jusqu 80 % des personnes ayant le diabte et de lhypertension mourront dunemaladie cardiovasculaire, particulirement dun accident vasculaire crbral. Les messages cls sur lappli-cation des connaissances du Programme ducatif canadien sur lhypertension au sujet de lhypertension aucours du diabte sont que les cliniciens doivent : 1) faire en sorte que les personnes ayant le diabte soientsoumises un dpistage de lhypertension; 2) valuer la pression artrielle lors de toutes visites appropriesen soins de sant; 3) encourager la surveillance domicile laide dappareils approuvs; 4) amorcersimultanment la pharmacothrapie et lamodification dumode de vie; 5) valuer et prendre en charge touslesautres facteursde risquevasculaires; 6)permettreunmodedevieviableet lobservancemdicamenteuse.

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M. Makowsky et al. / Can J Diabetes 36 (2012) 345e353346Introduction

Diabetes is a major health issue in Canada with w8.7% of theadult Canadian population having been diagnosed with diabetes in2008 to 2009 (1). High blood pressure is a very common problem inpeople with diabetes with the most recent national data, from the2007 to 2009 Canadian Health Measures Survey (CHMS), indicatingthat 75% of Canadians reporting diabetes also have hypertension.This rate is 4 times higher among hypertensive individuals withdiabetes than among those without diabetes (74% vs. 17%) (2). Thisis consistent with other reports, particularly the 2009 NationalDiabetes Surveillance System (NDSS), which reported that 63% ofCanadians with diabetes have hypertension (3). Although theCHMS and NDSS do not differentiate hypertensive individualsbased on type of diabetes, an estimated 90% to 95% of Canadiansliving with diabetes have type 2 diabetes mellitus and therefore themost commonly encountered scenario in clinical practice is that ofindividuals with both type 2 diabetes and hypertension (1).

Between 60% to 80% of people with diabetes die of cardiovas-cular complications and up to 75% of specific cardiovascularcomplications are attributable to hypertension (4,5). Epidemiologicdata has shown that hypertension accounts for up to 75% of stroke(6), 41% of cardiovascular events (7) and 44% of all deaths amongindividuals with diabetes (7). Additionally, hypertension is alsoa major causal factor of end stage kidney failure, blindness andnontraumatic amputation in people with diabetes, where attrib-utable risks are 50%, 35% and 35%, respectively (6). Observationaldata from the United Kingdom Prospective Diabetes Study (UKPDS)has shown that the risks of macrovascular and microvascularcomplications in type 2 diabetes are strongly associated with meansystolic blood pressure, with each 10 mm Hg reduction in bloodpressure reducing the risk of a fatal or nonfatal stroke by 19%, fataland nonfatal myocardial infarction by 12% and microvasculardisease by 13% (8).

Randomized controlled trials of blood pressure lowering treat-ments in people with diabetes have demonstrated major reduc-tions in death, stroke, cardiovascular disease and eye and kidneydisease (9e18). For example, the blood pressure lowering arm ofthe Action in Diabetes and Vascular Disease: Preterax andDiamicron-MR Controlled Evaluation (ADVANCE) trial is one of thelargest individual studies to date that illustrates the benefits ofblood pressure lowering in patients with diabetes (12). It showedthat in comparison to a placebo, fixed dose combination therapywith perindopril/indapamide, in addition to usual therapy, reducedthe relative risk of a major macrovascular or microvascular event, ata median of 5 years, by 9%, the relative risks of cardiovascular deathby 18% and total mortality by 14%. The reduction in blood pressurein this trial was 5.6/2.2mmHg vs. placebo. Lowering blood pressureis likely the single most effective way to prevent death anddisability in those with diabetes (19).

Most recent data from the CHMS indicates that 89% of adultswith diabetes were aware of having hypertension and 88% weretreated with antihypertensive medication, but only 56% weretreated and controlled to the current Canadian HypertensionEducation Program (CHEP)- and Canadian Diabetes Association(CDA)-endorsed blood pressure target of

Table 1Hypertension 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, confirmed 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 office. Home readings can be used to: confirm the diagnosis of hypertension, improve BP control, reduce the need for medications in thosewithwhite coat effect, identifythose 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 first day and calculate theaverage of the last 6 days.

The target home reading is

M. Makowsky et al. / Can J Diabetes 36 (2012) 345e353348to high-risk patients, combination therapy with an ACE inhibitorand dihydropyridine CCB (22).

Although small studies such as Candesartan and LisinoprilMicroalbuminuria (CALM) suggest that combination ACE inhibitorand angiotensin receptor blocker (ARB) therapy may have benefitson surrogate outcomes (e.g. urinary albumin-to-creatinine ratio) inpatients with diabetes and nephropathy, combination therapy withACE inhibitor and ARB is not recommended in this population as nostudies have demonstrated benefits in long-term renal function orreductions in major cardiovascular events (32e34). Additionally,the findings of the Ongoing Telmisartan Alone and in Combinationwith Ramipril Global Endpoint Trial (ONTARGET), which showedincreased risk of hypotensive symptoms, syncope and renaldysfunction when combinations of an ACE inhibitor and ARB wereused to prevent vascular events in high-risk patients who hadcardiovascular disease or diabetes but did not have heart failure, ledto this combination being specifically not recommended in patientswith hypertension without other compelling indications (35). Anexception is advanced heart failure, where combination therapymay be considered in selected and closely monitored patientsbased on the findings of the Candesartan in Heart Failure: Assess-ment 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 anddiabetes?

Although many clinicians are uncomfortable prescribingdiuretics to people with diabetes, possibly because diuretics causea small increase in blood glucose, diuretics have been shown to beequally effective as ACE inhibitors in preventing cardiovascularcomplications (29,37). CHEP considers thiazide (e.g. hydrochloro-thiazide) or thiazide-like diuretics (e.g. chlorthalidone and inda-pamide) suitable treatment alternatives in patients withhypertension and diabetes (22). Although there are no trialsspecifically comparing hydrochlorothiazide to other thiazide orthiazide-like diuretics on clinical outcomes, some clinicians havequestioned the choice of hydrochlorothiazide as the diuretictherapy of choice (38). More robust evidence exists for chlorthali-done, which has been shown to reduce cardiovascular outcomes inmajor clinical trials including patients with diabetes (37). Chlor-thalidone isw1.5 to 2 times as potent as hydrochlorothiazide, offersa longer half-life (45e60 hours vs. 8e15 hours, respectively) anda prolonged duration of actionwith long-term dosing (48e72 hoursvs. 16e24 hours, respectively) (39). The starting dose of chlortha-lidone is 12.5 to 25 mg daily. This can be difficult to achieve giventhat it is currently only available in Canada in 50 mg and 100 mgtablets, although the tablets are scored and can be cut. An alternatedosing regimen given its long half-life is 25 mg of chlorthalidonedosed every other day but historical data suggests this regimenmay not be maximally effective (40). Comparatively, hydrochloro-thiazide offers more flexibility in dosing due to a wider availabilityof dosages and is available in many single pill combinations.

Patients with diabetes have a higher incidence of chronic kidneydisease and increased monitoring of potassium is warranted.Maintaining a normal serum potassium level is important tominimize the effect of diuretics on blood glucose and maximizecardiovascular event reductions. Although evidence regarding theimportance of kidney function in the hypotensive effects of thia-zides is contradictory, CHEP recommends substitution of a loopdiuretic if creatinine clearance is

M. Makowsky et al. / Can J Diabetes 36 (2012) 345e353 349to 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 overallresults were consistent in the diabetes subgroup as well as thosewith chronic kidney disease (50,51). In addition to the ADAs strongrecommendation, Portaluppi and Smolensky (52) have called forurgent reconsideration of a number of commonly acceptedconcepts currently applied in practice such as the normotensivenondipper, aiming for constant blood pressure lowering over the24-hour dosing interval, and reliance on occasional blood pressureassessments without regard for blood pressure levels at other timesof the day and night. On the flip side, others have expressed a desirefor more confirmatory research before full-scale implementation ofthis studysfindings into practice. This desire is driven by the studyslimitations including poorly described randomization, single center,open label design, lack of a robust validated algorithm for antihy-pertensivemedication titration, and the large relative risk reductionformajor cardiovascular events (71%) that seems out of linewith, forexample, the Heart Outcome Prevention Evaluation (HOPE) trialthat also found a reduction in bedtime blood pressure but showeda 22% relative risk reduction in cardiovascular events (53).Table 3Lifestyle recommendations and impact on blood pressure (60)

Intervention Targeted change Expected blood pressurechange (mm Hg)

Sodium reduction

M. Makowsky et al. / Can J Diabetes 36 (2012) 345e353350a week for women (62). Alcohol restriction from 3 to 6 drinks perday to 1 to 2 drinks per day is associated with expected bloodpressure reductions in the magnitude of 3.9/2.4 mm Hg in hyper-tensive patients (60).

Stress management

CHEP recommends that for hypertensive people in whom stressmay be a contributing factor to blood pressure elevation, stressmanagement should be considered as an intervention (22).

Smoking cessation

Living and working in a tobacco free environment is recom-mended by CHEP and the CDA. It has been shown that the excessrisk of coronary heart disease caused by smoking is reduced byw50% 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 ofantiplatelet agents may reduce vascular risk. The current evidencefor the use of ASA in patients with hypertension and diabetes inprimary prevention is unclear. In the 2008 guidelines, the CDArecommended consideration of low dose ASA therapy in peoplewith established coronary artery disease and recommended thatthe decision to prescribe antiplatelet therapy for primary preven-tion of cardiovascular events should be based on individual clinicaljudgment (67). Two recent studies and a systematic review by theAntithrombotic Trialists collaborators have shown no benefit fromASA in the primary prevention of cardiovascular events in patientswith diabetes (68e71). Additionally, the 2011 Canadian Cardio-vascular Society (CCS) antiplatelet guidelines state that there is noevidence to recommend routine use of ASA at any dose for theprimary prevention of ischemic vascular events in patients withdiabetes (Class III, Level A) (72). For patients over 40 years of agewith diabetes who are at low risk of major bleeding, low dose ASAmay be considered for primary prevention and in patients withother cardiovascular risk factors for which its benefits are estab-lished (Class IIb, Level B). Even if antiplatelet therapy is helpful, itappears that the benefits in reduction of cardiovascular outcomesin patients at low risk of events are modest (71,73).

How can adherence to medications and lifestyle therapies beoptimized?

There are several strategies to improve adherence to medicationand lifestyle interventions in patients with diabetes andhypertension:

Fixed dose single pill combination therapies: the use of fixeddose single pill combination therapies is a strategy to improveadherence to drug therapy in patients requiring multiplemedications (22).

Vascular age: CHEP recommends considering informingpatients of their global risk to improve the effectiveness of riskfactor modification (22). Clinicians may consider using analo-gies 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 isone strategy to increase adherence to lifestyle interventionsand medications. Ways to promote self-managementeducation in patients with hypertension and diabetes includeself-monitoring blood pressure, interdisciplinary team careand behavioural interventions.

Multidisciplinary team-based healthcare: advocated for themanagement of chronic diseases and has been advocated asroutine clinical care of hypertension in Canada (22). Forexample, care from a community pharmacist and nurse teamwas associated with clinically important improvements inblood pressure in patients with hypertension and diabetes (74).CHEP recommends that healthcare teams incorporate a phar-macist to improve monitoring of adherence with pharmaco-logic and lifestyle modification (22).What is the optimal regimen for home blood pressure monitoring?

People with hypertension and diabetes should be encouraged tobe involved in all aspects of their care plan including home bloodpressure monitoring (22). Patients should be advised to purchaseand use approved blood pressure monitoring devices and health-care professionals should ensure that patients have adequatetraining to take measurements appropriately. Blood pressuretargets should be discussed with the patient and a follow-up planshould be in place so that the patient knows how to respond ifblood pressure levels are outside the target range.

In most instances, a manual office blood pressure reading of140/90mmHg is equated to a mean home blood pressure of 135/85mm Hg (75). This would suggest that for patients who are moni-toring their blood pressure at home, a home target below thecurrently recommended

M. Makowsky et al. / Can J Diabetes 36 (2012) 345e353 351ethnocultural background can influence medication effectiveness.The only instance of ethnocultural adaptation of therapy in thecurrent CHEP guidelines is in the area of uncomplicated hyper-tension, where CHEP recommends that ACE inhibitors are notrecommended for monotherapy in blacks (22). Type 2 diabetes hasreached epidemic proportions among Aboriginal peoples inCanada, where national age adjusted prevalence is 3 to 5 timeshigher than that of the general population (76). In Ontario, theprevalence of hypertension was found to be 3-fold higher in SouthAsians compared with the general population (20). Individualsfrom high-risk ethnic populations also develop diabetes compli-cations, particularly cardiovascular disease and renal failure, muchearlier than other populations (77). Given the high cardiovascularmortality in South Asians, aggressive management of risk factors,including hypertension and dyslipidemia, has been recommendedby the CDA to reduce morbidity and mortality. Ethnoculturalminority groups frequently have poorly controlled hypertensionand diabetes and ethnocultural-specific disease managementprograms may play a role in better management (76e78).Case Resolution

This is a case of hypertension in diabetes that is complicated bymicroalbuminuria and additional cardiovascular risk factors (i.e.smoking, sedentary lifestyle). Mr. Js office based blood pressure of144/93 mm Hg is above the guideline recommended target of

M. Makowsky et al. / Can J Diabetes 36 (2012) 345e353352a comprehensive approach is required to address other vascularrisk factors. Home monitoring of blood pressure with approveddevices should be encouraged to promote adherence. Althoughsustained adherence to medication and lifestyle interventionsrepresents a challenge, the collaboration of an integrated multi-disciplinary team with consistent education and support maypromote the best health outcome for the patient.

Author Disclosures

APHP is a consultant for Eli Lilly and Novo Nordisk and receivesspeakers honorarium from AstraZeneca, Bristol-Myers Squibb,Sanofi and Eli Lilly. Preparation of this material was supported bya grant from the Public Health Agency of Canada.

Author Contributions

All authors contributed to conception of the study. MMpreparedthe first draft of the manuscript. APHP, CJ, MG and AM criticallyreviewed the manuscript for intellectual content. All authors gavefinal approval of the version to be published.

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Management of Hypertension in People with Diabetes Mellitus: Translating the 2012 Canadian Hypertension Education Program R ...IntroductionCaseTranslating the CHEP 2012 Recommendations into PracticeWhat is the target blood pressure for people with diabetes?What is the optimal combination therapy for hypertension treatment in the context of diabetes?Is diuretic therapy suitable in patients with hypertension and diabetes?What is the role of aldosterone antagonists in hypertension and diabetesWhat is the role of aliskiren in patients with hypertension and diabetes?Is bedtime dosing of antihypertensive agents beneficial in patients with diabetes?What are the benefits of sodium reduction on blood pressure control in diabetes?What are the benefits of other lifestyle interventions on blood pressure and glucose control?Healthy eatingBody weight and abdominal obesityPhysical activityLow risk alcohol consumptionStress managementSmoking cessationVascular risk reduction with antiplatelet therapy?How can adherence to medications and lifestyle therapies be optimized?What is the optimal regimen for home blood pressure monitoring?Are there differences in treatment for special populations as defined by ethnocultural background (e.g. Canadian Aboriginal ...

Case ResolutionPharmacotherapy interventionsLifestyle interventionsVascular risk reduction with antiplatelet therapyStrategies to optimize adherence

ConclusionsAuthor DisclosuresAuthor ContributionsReferences