Management of Hypertension in People with Diabetes Mellitus: Translating the 2012 Canadian Hypertension Education Program Recommendations into Practice

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, benefits 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 modification concurrently, 5) assess and manage all other vascular risk factors, and 6) enable sustained lifestyle and medication adherence. Ó 2012 Canadian Diabetes Association

Keywords: diabetes hypertension

r é s u m é Mots clés: diabète hypertension

L’hypertension est un problème fréquent chez les personnes ayant le diabète, et de nombreuses modifications sont apparues aux recommandations conjointes sur l’hypertension du Programme éducatif canadien sur l’hypertension et de l’Association canadienne du diabète au cours des 5 dernières années. Cet article utilise une approche par cas pour passer en revue les problèmes contemporains de la prise en charge de l’hypertension dans le contexte du diabète, incluant les objectifs de traitement, le traitement combiné optimal, le choix d’un traitement diurétique, le rôle des antagonistes de l’aldostérone, le rôle de l’aliskirène, la posologie des agents antihypertenseurs au coucher, les bénéfices de la réduction du sodium, les effets des interventions sur le mode de vie, la réduction du risque vasculaire par un traitement antiplaquettaire, les stratégies d’observance, le rôle de la surveillance de la pression artérielle à domicile et les plans de traitement fondés sur le milieu ethnoculturel. Une importance particulière est accordée au fait de lier les recommandations à la pratique. Jusqu’à 80 % des personnes ayant le diabète et de l’hypertension mourront d’une maladie cardiovasculaire, particulièrement d’un accident vasculaire cérébral. Les messages clés sur l’application des connaissances du Programme éducatif canadien sur l’hypertension au sujet de l’hypertension au cours du diabète sont que les cliniciens doivent : 1) faire en sorte que les personnes ayant le diabète soient soumises à un dépistage de l’hypertension; 2) évaluer la pression artérielle lors de toutes visites appropriées en soins de santé; 3) encourager la surveillance à domicile à l’aide d’appareils approuvés; 4) amorcer simultanément la pharmacothérapie et la modification du mode de vie; 5) évaluer et prendre en charge tous les autres facteurs de risque vasculaires; 6) permettre un mode de vie viable et l’observance médicamenteuse. Ó 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: [email protected] (A.P.H. Prebtani). 1499-2671/$ e see front matter Ó 2012 Canadian Diabetes Association http://dx.doi.org/10.1016/j.jcjd.2012.09.002

346

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 specific 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 benefits of blood pressure lowering in patients with diabetes (12). It showed that in comparison to a placebo, fixed 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 specifically 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 office, 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 first diagnosed with diabetes 4 years ago and his blood glucose has been well controlled (glycated hemoglobin ¼ 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 filtration 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 significant benefits 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 prespecified secondary outcomes. Significant 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, 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 professional’s office.  Home readings can be used to: confirm 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 first day and calculate the average of the last 6 days.  The target home reading is <130/80 mm Hg. 4. Pharmacotherapy and lifestyle modification 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 individual’s vascular risk by more than half. 6. Enable sustained lifestyle modification 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 benefit 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% confidence 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 first-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 influence 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 findings, 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 findings 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 first-line drugs or similarly

348

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 benefits 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 benefits in long-term renal function or reductions in major cardiovascular events (32e34). Additionally, the findings 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 specifically 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 findings 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 specifically 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 difficult 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 flexibility 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 efficacy (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 firm 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 defined 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 identified, 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 beneficial 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 first 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 significantly 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 ADA’s 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 flip side, others have expressed a desire for more confirmatory research before full-scale implementation of this study’s findings into practice. This desire is driven by the study’s 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 benefits 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 sufficient to sustain health even under conditions in which significant 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 significant 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 benefits 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 modifications 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 specifically with hypertension and diabetes, several studies in patients with diabetes have established benefits of lifestyle modification 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 Canada’s 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 fibre, 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 difficult 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 benefit 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 benefits are established (Class IIb, Level B). Even if antiplatelet therapy is helpful, it appears that the benefits 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 fixed 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 modification (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 modification (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 office 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 office and home blood pressure measures may be reduced by the use of automated office blood pressure measurement devices such as the BpTRU automatic blood pressure monitor, BPM-100 electronic oscillometric office 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 first 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 Canada’s YouTube channel. Are there differences in treatment for special populations as defined 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 defined 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 influence 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-specific 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. J’s office 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 patient’s blood pressure readings and current therapy, consideration should be given to:  Increasing the dose of ramipril. However, considering the relatively flat dose response curve, increasing the dose beyond 10 mg daily may have limited benefit on blood pressure reduction (79,80).  Increasing the dose of hydrochlorothiazide to 25 mg daily given Mr. J’s normal renal function.  Adding a dihydropyridine CCB (e.g. amlodipine) as a third antihypertensive agent.  Minimizing use of the as-needed nonsteroidal anti-inflammatory 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 fit the inclusion criteria of the MAPEC study as he is neither untreated nor defined 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 patient’s 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 benefits of ASA for primary prevention of cardiovascular events should take place with the patient to uncover the patient’s 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 patient’s 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 benefits 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. J’s 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 benefit 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 speaker’s honorarium from AstraZeneca, Bristol-Myers Squibb, Sanofi 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 first draft of the manuscript. APHP, CJ, MG and AM critically reviewed the manuscript for intellectual content. All authors gave final approval of the version to be published. References 1. Public Health Agency of Canada. Diabetes in Canada: facts and figures 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 fixed 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, intensified 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, fiction, 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 scientific 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. Influence 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. Influence 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 ¼ 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 modifications 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 Benefits of Smoking Cessation. Surgeon General’s 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, Office 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 office: 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 efficacy 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.