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Diabetes Care Volume 40, September 2017 1273

Diabetes and : Ian H. de Boer,1 Sripal Bangalore,2 Athanase Benetos,3 Andrew M. Davis,4 A Position Statement by the Erin D. Michos,5 Paul Muntner,6 Peter Rossing,7 Sophia Zoungas,8 and American Diabetes Association George Bakris4

Diabetes Care 2017;40:1273–1284 | https://doi.org/10.2337/dci17-0026

Hypertension is common among patients with diabetes, with the prevalence depend- ing on type and duration of diabetes, age, sex, race/ethnicity, BMI, history of glycemic control, and the presence of , among other factors (1–3). Furthermore, hypertension is a strong for atherosclerotic (ASCVD), failure, and microvascular complications. ASCVDddefined as , myocardial (MI), , coronary or other arterial revasculariza- STATEMENT POSITION tion, , transient ischemic attack, or peripheral arterial disease presumed to be of atherosclerotic origindis the leading of morbidity and mortality for individuals with diabetes and is the largest contributor to the direct and indirect costs of diabetes. Numerous studies have shown that antihypertensive therapy reduces ASCVD events, , and microvascular complications in people with diabetes (4–8). Large benefits are seen when multiple risk factors are addressed simultaneously (9). There is evidence that ASCVD morbidity and mortality have decreased for people with diabetes since 1990 (10,11) likely due in large part to improvements in pressure control (12–14). This Position Statement is intended to update the assessment and treatment of hypertension among people with diabetes, including advances in care since the American 1 Diabetes Association (ADA) last published a Position Statement on this topic in 2003 (3). University of Washington, Seattle, WA 2New York University, New York, NY 3 DEFINITIONS, SCREENING, AND DIAGNOSIS Universite´ de Lorraine, Nancy, France 4The University of Chicago , Chicago, IL 5 Recommendations The Johns Hopkins University School of Medi- c cine, Baltimore, MD should be measured at every routine clinical care visit. Patients 6 $ School of , University of Alabama found to have an elevated blood pressure ( 140/90 mmHg) should have blood at Birmingham, Birmingham, AL pressure confirmed using multiple readings, including measurements on a sep- 7Steno Diabetes Center Copenhagen, University arate day, to diagnose hypertension. B of Copenhagen, Copenhagen, 8 c All hypertensive patients with diabetes should have home blood pressure mon- School of Public Health and Preventive Medi- itored to identify white-coat hypertension. B cine, Monash University, Melbourne, Australia c Orthostatic measurement of blood pressure should be performed during initial Corresponding author: George Bakris, gbakris@ evaluation of hypertension and periodically at follow-up, or when symptoms of medicine.bsd.uchicago.edu. are present, and regularly if orthostatic hypotension has This position statement was reviewed and ap- proved by the American Diabetes Association been diagnosed. E Professional Practice Committee in June 2017 and ratified by the American Diabetes Associa- Blood pressure should be measured at every routine clinical care visit (15). At the ini- tion Board of Directors in July 2017. tial visit, blood pressure should be measured in both arms to detect and account for For further information on the ADA evidence abnormalities that may lead to spurious blood pressures, such as arterial . grading system and the levels of evidence, please Patients with elevated blood pressure ($140/90 mmHg) who are not known to have see Table 1 in the American Diabetes Associa- ’ hypertension should have elevated blood pressure confirmed on a separate day, within tion s Introduction section of the Standards of Medical Care in Diabetesd2017. Diabetes Care 1 month, to confirm the diagnosis of hypertension. 2017;40(Suppl. 1):S2, https://doi.org/10.2337/ Office-based semiautomated oscillometric blood pressure (conventional or office dc17-S001. blood pressure) is the conventional method used to diagnose hypertension and mon- This article is featured in a podcast available at itor treatment response. Blood pressure should be measured by a trained individual http://www.diabetesjournals.org/content/ (15) in the seated position, with feet on the floor and arm supported at heart level. Cuff diabetes-core-update-podcasts. size should be appropriate for the upper-arm circumference (Table 1). To reduce within- © 2017 by the American Diabetes Association. patient variability, blood pressure should be measured after 5 min of rest, 2–3 readings Readers may use this article as long as the work – is properly cited, the use is educational and not should be taken 1 2 min apart, and blood pressure measurements should be averaged for profit, and the work is not altered. More infor- (16). It is particularly important to make and average repeated measurements of blood mation is available at http://www.diabetesjournals pressure for the diagnosis of hypertension and titration of antihypertensive treatment. .org/content/license. 1274 Position Statement Diabetes Care Volume 40, September 2017

Table 1—Recommended blood pressure on outcome studies (31) demonstrating from support stockings or other approaches measurement cuff size for a given arm that lower home blood pressures corre- (38). circumference spond to higher office-based measure- BLOOD PRESSURE TARGETS Arm circumference (cm) Usual cuff size ments. White-coat hypertension is elevated fi $ 22–26 Small adult of ce blood pressure ( 140/90 mmHg) Recommendations and normal (untreated) home blood pres- 27–34 Adult c Most patients with diabetes and hy- sure (,135/85 mmHg) (32). Identifying 35–44 Large adult pertension should be treated to a these conditions with home blood pres- , 45–52 Adult thigh systolic blood pressure goal of 140 sure can help prevent over- mmHg and a diastolic blood pres- treatment of people with white-coat sure goal of ,90 mmHg. A hypertension who are not at elevated c Lower systolic and diastolic blood Automated office blood pressure (AOBP) risk of ASCVD and, in the case of masked pressure targets, such as ,130/80 is an alternate method to measure blood hypertension, allow proper use of med- mmHg, may be appropriate for in- pressure in which a fully automated device ications to reduce side effects during pe- dividuals at high risk of cardiovascu- is used to make and average multiple read- riods of normal pressure (33,34). lar disease if they can be achieved ings (usually 3–5) taken over a few min- Home blood pressure measurements without undue treatment burden. B utes, ideally while a patient rests quietly include daytime blood pressure mea- alone (17). AOBP was used in two large, sured with ambulatory blood pressure important clinical trials, Action to Control monitoring as well as measurements Epidemiologic analyses show that blood Cardiovascular Risk in Diabetes (ACCORD) taken with home blood pressure moni- pressure $115/75 mmHg is associated (18) and Systolic Blood Pressure Interven- tors. The cuff size is very important, as with increased rates of ASCVD (27), heart tion Trial (SPRINT) (19). If the patient is too small a cuff will give higher than ac- failure, , , and alone when the readings are taken, the tual blood pressure values and too large a mortality in a graded fashion, contribut- approach is also useful for diagnosing cuff will give values that are lower than ing to the evidence that blood pressure white-coat hypertension (20). AOBP gener- actual blood pressure. The correct cuff control is important in the clinical outcomes ates values 5–10 mmHg lower than con- size, such that the bladder encircles 80% of diabetes (1,2,24,26,39). However, ob- ventional office readings, on average. of the arm (Table 1), should be used. The servational studies of blood pressure tar- Thus, results of trials using this technique cuff should be placed such that the mid- gets are subject to confounding factors cannot be directly applied to practices dle is on the patient’supperarmatthe and do not directly assess the effects of that measure conventional office blood level of the right atrium (the midpoint of blood pressure lowering. Clinical trials and pressure (17,21–23). With the exception the sternum), and it should never be meta-analysesofclinicaltrialsprovidethe of ACCORD (18), most of the evidence of placed over clothes. strongest evidence addressing blood pres- benefits of hypertension treatment in sure and offer substantial guidance for people with diabetes is based on conven- Orthostatic Hypotension treatment targets, particularly for patients tional office measurements. Diabetic or vol- with . Hypertension is defined as a sustained ume depletion can cause orthostatic hy- Treatment of hypertension to blood blood pressure $140/90 mmHg. This potension (35), which may be further pressure ,140/90 mmHg is supported by definition is based on unambiguous data exacerbated by antihypertensive medica- unequivocal evidence that pharmacologic that levels above this threshold are tions. The definition of orthostatic hypo- treatment of blood pressure $140/90 strongly associated with ASCVD, , tension is a decrease in systolic blood mmHg reduces cardiovascular events as , and microvascular complications pressure of 20 mmHg or a decrease in well as some microvascular complica- (1,2,24–27) and that antihypertensive diastolic blood pressure of 10 mmHg tions. In type 2 diabetes, the UK Prospec- treatment in populations with baseline within 3 min of standing when compared tive Diabetes Study (UKPDS) showed that blood pressure above this range reduces with blood pressure from the sitting or targeting blood pressure ,150/85 mmHg the risk of ASCVD events (4–6,28,29). The supine position (36). Orthostatic hypo- versus ,180/105 mmHg reduced com- “sustained” aspect of the hypertension tensioniscommoninpeoplewithtype2 posite microvascular and macrovascular definition is important, as blood pressure diabetes and hypertension and is associ- diabetes complications by 24% (28). has considerable normal variation. The cri- ated with an increased risk of mortality Moreover, meta-analyses of clinical trials teria for diagnosing hypertension should and heart failure (37). demonstrate that antihypertensive treat- be differentiated from blood pressure It is important to assess for symptoms ment of populations with diabetes and treatment targets. of orthostatic hypotension to individual- baseline blood pressure $140/90 mmHg Hypertension diagnosis and manage- ize blood pressure goals, select the most reduces the risks of ASCVD, heart failure, ment can be complicated by two com- appropriate antihypertensive agents, and retinopathy, and (4–8,40). mon conditions: masked hypertension minimize adverse effects of antihyper- Therefore, most patients with type 1 or and white-coat hypertension. Masked hy- tensive therapy. Additionally, antihyper- type 2 diabetes who have hypertension pertension is defined as a normal blood tensive type or timing (switch should, at a minimum, be treated to blood pressure in the clinic or office (,140/90 to nocturnal dosing) may require adjust- pressure targets of ,140/90 mmHg. mmHg) but an elevated home blood pres- ment. In particular, a-blockers and di- Intensification of antihypertensive sure of $135/85 mmHg (30); the lower uretics may need to be stopped. People therapy to target blood pressures lower home blood pressure threshold is based with orthostatic hypotension may benefit than ,140/90 mmHg (e.g., ,130/80 care.diabetesjournals.org de Boer and Associates 1275

or ,120/80 mmHg) may be beneficial for control, though the relevance of their re- resulted in no significant difference in selected patients with diabetes. Such in- sults to people with diabetes is less clear. the primary composite outcome of MI, tensive blood pressure control has been The Action in Diabetes and Vascular stroke, or cardiovascular death (hazard evaluated in landmark clinical trials and Disease: Preterax and Diamicron MR ratio 0.88, 95% CI 0.73 to 1.06). Stroke meta-analyses of clinical trials. Controlled Evaluation–Blood Pressure was reduced by 41% (hazard ratio 0.59, (ADVANCE BP) trial, which tested the 95% CI 0.39 to 0.89), but serious adverse fi Randomized Clinical Trials of Intensive effects of a xed-dose combination of events attributed to antihypertensive Blood Pressure Control antihypertensive interventions versus therapyoccurredin3.3%vs.1.3%of The ACCORD blood pressure (ACCORD placebo among people with type 2 diabe- participants, with significantly increased BP) trial examined the effects of intensive tes, also informs blood pressure targets incidence of hypotension, electrolyte ab- blood pressure control (goal systolic (41). Study details are given in Table 2. normalities, and elevated serum creati- blood pressure ,120 mmHg) versus stan- In ACCORD BP, intensive blood pres- nine. Therefore, the ACCORD BP results dard blood pressure control (target sys- sure control did not reduce total major suggest that blood pressure targets more tolic blood pressure ,140 mmHg) among atherosclerotic cardiovascular events intensive than ,140/90 mmHg may be people with type 2 diabetes. Additional but did reduce the risk of stroke, at the reasonable in selected patients who have studies, such as Hypertension Optimal expense of increased adverse events (18). been educated about added treatment Treatment (HOT) trial and SPRINT, also Specifically, compared with a target sys- burden, side effects, and costs (18,42). examined the potential benefits of in- tolic blood pressure ,140 mmHg, a tar- The achieved blood pressure in ADVANCE tensive versus standard blood pressure get systolic blood pressure ,120 mmHg in the intervention group (136/73) was

Table 2—Randomized controlled trials of intensive vs. standard hypertension treatment strategies Clinical trial Population Intensive Standard Outcomes ACCORD BP (18) 4,733 participants with T2D Systolic blood pressure Systolic blood pressure c No benefit in primary end point: aged 40–79 years with target: ,120 mmHg target: 130–140 mmHg composite of nonfatal MI, prior evidence of CVD or Achieved (mean) systolic/ Achieved (mean) systolic/ nonfatal stroke, and CVD death multiple cardiovascular diastolic: 119.3/64.4 diastolic: 133.5/70.5 c Stroke risk reduced 41% with risk factors mmHg mmHg intensive control, not sustained through follow-up beyond the period of active treatment c Adverse events more common in intensive group, particularly elevated serum creatinine and electrolyte abnormalities ADVANCE BP (43) 11,140 participants with Intervention: a single-pill, Control: placebo c Intervention reduced risk of T2D aged 55 years and fixed-dose combination Achieved (mean) systolic/ primary composite end point of older with prior evidence of perindopril and diastolic: 141.6/75.2 major macrovascular and of CVD or multiple indapamide mmHg microvascular events (9%), death cardiovascular risk Achieved (mean) systolic/ from any cause (14%), and death factors diastolic: 136/73 mmHg from CVD (18%) c 6-year observational follow-up found reduction in risk of death in intervention group attenuated but still significant (134) HOT (135) 18,790 participants, Diastolic blood pressure Diastolic blood pressure c In the overall trial, there was no including 1,501 with target: #80 mmHg target: #90 mmHg cardiovascular benefit with more diabetes intensive targets c In the subpopulation with diabetes, an intensive diastolic target was associated with a significantly reduced risk (51%) of CVD events SPRINT (19) 9,361 participants without Systolic blood pressure Systolic blood pressure c Intensive systolic blood pressure diabetes target: ,120 mmHg target: ,140 mmHg target lowered risk of the primary Achieved (mean): 121.4 Achieved (mean): 136.2 composite outcome 25% (MI, mmHg mmHg acute coronary syndrome, stroke, heart failure, and death due to CVD) c Intensive target reduced risk of death 27% c Intensive therapy increased risks of electrolyte abnormalities and acute kidney injury CVD, cardiovascular disease; T2D, type 2 diabetes. 1276 Position Statement Diabetes Care Volume 40, September 2017

higher than that achieved in ACCORD Individualization of Treatment Targets TREATMENT intensive arm (119/64 mmHg) and Patients and clinicians should engage in a Lifestyle Management would be consistent with a target shared decision-making process to deter- blood pressure of ,140/90 mmHg, though mine individual blood pressure targets, Recommendation ADVANCE did not explicitly test blood with the acknowledgment that the bene- c For patients with systolic blood . pressure targets (43). Of note, ACCORD fits and risks of intensive blood pressure pressure 120 mmHg or diastolic . BPandSPRINTmeasuredbloodpres- targets are uncertain and may vary across blood pressure 80 mmHg, life- style intervention consists of weight sure using AOBP, which yields values patients. Following the ADA approach loss if or obese; a Dietary that are generally lower than typical of- to the management of , Approaches to Stop Hypertension fice blood pressure by approximately factors that influence treatment targets (DASH)-style dietary pattern includ- 5–10 mmHg (17), suggesting that imple- may include risks of treatment (e.g., hy- ing reduced sodium and increased menting the ACCORD BP or SPRINT pro- potension, drug adverse effects), life potassium intake; increased fruit tocols in a typical clinic might require a expectancy, including and vegetable consumption; moder- systolic blood pressure target higher vascular complications, patient atti- ation of alcohol intake; and increased than ,120 mmHg. tude and expected treatment efforts, physical activity. B and resources and support system Meta-analyses of Trials (44). Specific factors to consider are the Meta-analyses of placebo-controlled Lifestyle management is an important absolute risk of cardiovascular events clinical trials using multiple classes of an- component of hypertension treatment (40,45), risk of progressive kidney disease tihypertensive clearly dem- because it lowers blood pressure, en- as reflected by albuminuria, adverse ef- onstrate that antihypertensive treatment hances the effectiveness of some antihy- in general reduces the risks of ASCVD, fects, age, and overall treatment burden. pertensive medications, promotes other heart failure, retinopathy, albuminuria, Patients who have higher risk of cardio- aspects of metabolic and vascular health, and mortality among people with diabe- vascular events (particularly stroke) or al- and generally leads to few adverse ef- tes (4–8,40). Overall, compared with peo- buminuria and who can attain intensive fects. In addition, patients with diabetes ple without diabetes, the relative benefits blood pressure control relatively easily and systolic blood pressure .120 mmHg of antihypertensive treatment are similar, and without substantial adverse effects or diastolic blood pressure .80 mmHg and absolute benefits may be greater may be best suited to intensive blood are at risk for developing hypertension (5,8,40). To clarify optimal blood pressure pressure control. In contrast, patients and its complications (48,49), and lifestyle targets in the setting of diabetes, meta- with conditions more common in older management may help prevent or delay a analyses have stratified clinical trials by adults, such as functional limitations, pol- diagnosis of hypertension with need for mean baseline blood pressure or mean ypharmacy, and multimorbidity, may be pharmacologic therapy. To facilitate long- blood pressure attained in the interven- best suited to less intensive blood pres- term maintenance of behavioral change, tion or intensive treatment arm. Based sure control. lifestyle therapy should be adapted to suit on these analyses, antihypertensive treat- Notably, there is an absence of high- the needs of the patient and discussed as ment appears to be beneficial when mean quality data available to guide blood part of . baseline blood pressure is $140/90 mmHg pressure targets in . Asso- Although there are no well-controlled or mean attained intensive blood pres- ciations of blood pressure with macrovas- studies of and in the treat- sure is $130/80 mmHg (4,6–8). Among cular and microvascular outcomes in ment of elevated blood pressure or hy- trials with lower baseline or achieved type 1 diabetes are generally similar to pertension in individuals with diabetes, blood pressure, antihypertensive treat- those in type 2 diabetes and the general the Dietary Approaches to Stop Hyperten- ment reduced the risk of stroke, retinop- population (1). Given an absence of ran- sion (DASH) study evaluated the impact athy, and albuminuria, but effects on domized trials with clinical outcomes in of healthy dietary patterns in individuals other ASCVD and heart failure were not type 1 diabetes, effects of antihyperten- without diabetes and has shown antihy- evident. A critical point is that these are pertensive effects similar to those of sive therapy can only be extrapolated all trial-level meta-analyses that are sub- pharmacologic monotherapy (50). A re- from trials in other populations, poten- ject to confounding and imprecise in their cent meta-analysis found that lifestyle in- tially drawing from both ACCORD BP stratification, as opposed to individual- tervention can help lower blood pressure and SPRINT. Of note, diastolic blood level meta-analyses, which are needed in patients with type 2 diabetes (51). to best address the issue (8). In addition, pressure, as opposed to systolic blood Medium- or high-intensity combined life- meta-analyses have focused largely on pressure, is a key variable predicting car- style counseling has shown benefitinpa- treatment benefits, and additional data diovascular outcomes in people under tients selected for cardiovascular risk weighing potential harms are needed. age 50 years without diabetes and may factors, including diabetes, for the inter- Taken together, these meta-analyses be prioritized in younger adults (46,47). mediate outcomes of blood pressure, lip- consistently show that treating patients Though convincing data are lacking, youn- ids, fasting blood , and weight, with baseline blood pressure $140 ger adults with type 1 diabetes might especially over 12 to 24 months (52). mmHg to targets ,140 mmHg is benefi- more easily achieve intensive blood pres- Lifestyle therapy consists of reducing cial, while more intensive targets may of- sure levels and may derive substantial excess body weight through caloric restric- fer additional though probably less robust long-term benefit from tight blood pres- tion, restricting sodium intake (,2,300 benefits. sure control. mg/day), increasing consumption of fruits care.diabetesjournals.org de Boer and Associates 1277

and vegetables (8–10 servings per day) blood pressure levels, so these must be may begin with a single drug. For patients and low- dairy products (2–3 servings used with care. with blood pressure $160/100 mmHg, per day), avoiding excessive alcohol con- initial pharmacologic treatment with sumption (no more than 2 servings per Treatment of two antihypertensive medications is rec- day in men and no more than 1 serving has been shown to reduce blood pres- ommended. The Study of Hypertension fi per day in women) (53), cessa- sure in randomized studies of people and the Ef cacy of Lotrel in Diabetes fi tion, reducing sedentary time (54), and with diabetes (61). (SHIELD) trial was one of the rst trials increasing physical activity levels (55). to evaluate whether a higher percentage These lifestyle strategies may also posi- Pharmacologic Antihypertensive of people with diabetes would achieve tively affect glycemic and lipid control Treatment the blood pressure goal when a single- and should be encouraged in those with pill combination was given rather than Recommendations even mildly elevated blood pressure. In c Patients with confirmed office- monotherapy at average blood pressures addition, clinicians are encouraged to based blood pressure $140/90 above 160/100 mmHg. The 214 patients routinely review patient medication lists mmHg should, in addition to life- received initial therapy with an ACE inhib- for agents that may raise blood pres- style therapy, have timely titration itor plus dihydropyridine calcium channel sure, including over-the-counter and of pharmacologic therapy to achieve blocker (CCB) compared with the ACE herbal ones. As an example, one meta- blood pressure goals. A inhibitor alone, which resulted in an in- analysis suggested that nonsteroidal c Patients with confirmed office- creased proportion of participants achiev- fl anti-in ammatory drugs increase systolic based blood pressure $160/100 ing the target blood pressure at 3 months 5 blood pressure on average by 5 mmHg mmHg should, in addition to life- (63% vs. 37%; P 0.002) (62). The Sim- fi (56). style therapy, have prompt initia- pli ed Treatment Intervention to Control Hypertension (STITCH) trial randomized Sodium tion and timely titration of two Sodium reduction has not been tested in drugs or a single-pill combination over 2,000 patients with and without di- controlled clinical trials in people with of drugs demonstrated to reduce abetes whose mean blood pressure was ; diabetes. However, results from trials in cardiovascular events in patients 160/95 mmHg to an ACE inhibitor alone primary hypertension have shown a reduc- with diabetes. A or ACE inhibitor plus -like tion in systolic blood pressure of ;5 c Treatment for hypertension should and found that the proportion of patients , mmHg and diastolic blood pressure of include drug classes demonstrated achieving a blood pressure 140/90 2–3 mmHg with moderate sodium reduc- to reduce cardiovascular events in mmHg at 6 months was higher in the com- tion (from a daily intake of 200 mmol patients with diabetes: ACE inhibi- bination intervention group (65% vs. 53%; 5 [4,600 mg] to 100 mmol [2,300 mg] of tors, angiotensin blockers P 0.026) (63). Single-pill combinations sodium per day) (57). A dose-response ef- (ARBs), thiazide-like , or may improve medication (64). fecthasbeenobservedwithsodiumreduc- dihydropyridine calcium channel Classes of Antihypertensive Medications tion. Even when pharmacologic agents are blockers. Multiple-drug therapy is Initial treatment for hypertension should used, there may be a better response when generally required to achieve blood include drug classes demonstrated to re- there is concomitant salt restriction due to pressure targets (but not a combina- duce cardiovascular events in patients the volume component of hypertension. tion of ACE inhibitors and ARBs). A with diabetes: ACE inhibitors (65,66), an- c Physical Activity An ACE inhibitor or ARB, at the max- giotensin receptor blockers (ARBs) (65,66), Moderately intense physical activity, such imum tolerated dose indicated for thiazide-like diuretics (67), or dihydropyr- as 30–45 min of brisk most days blood pressure treatment, is the idine CCBs (68). For patients with albu- fi of the week, has been shown to lower blood recommended rst-line treatment minuria ( albumin-to-creatinine pressure (58). Regular exercise may lower for hypertension in patients with ratio [UACR] $30 mg/g creatinine), initial blood pressure, necessitating dose adjust- diabetes and urine albumin-to- treatment should include an ACE inhibitor $ ment of antihypertension medications creatinine ratio 300 mg/g creati- or ARB in order to reduce the risk of pro- – (59). b-Blockers may reduce maximal nine (A)or30 299 mg/g creatinine gressive kidney disease, detailed below. In exercise capacity, while diuretics may in- (B). If one class is not tolerated, the the absence of albuminuria, risk of progres- crease risk of . Physical activ- other should be substituted. B sive kidney disease is low, and ACE inhibitors ities should be promoted in all patients c For patients treated with an ACE and ARBs have not been found to afford including older adults with physical limi- inhibitor, ARB, or diuretic, serum superior cardioprotection when compared tations. The type and intensity of physical creatinine/estimated glomerular with other antihypertensive agents (69). fi activities should be adapted to the prefer- ltration rate and serum potassium b-Blockers may be used for the treatment ences and functional status of the patient. levels should be monitored. B of coronary disease or heart failure but have not been shown to reduce mortality as blood pressure–lowering agents in the Weight reduction should be considered Initial Number of Antihypertensive absence of these conditions (5,70). in the management of blood pressure. Medications The loss of 1 kg in body weight has been Initial treatment for people with diabetes Multiple-Drug Therapy associated with a decrease in blood pres- depends on the severity of hypertension Multiple-drug therapy is often required to sure of ;1 mmHg (60). Some weight-loss (Fig. 1). Those with blood pressure be- achieve blood pressure targets, particularly medications may induce increases in tween 140/90 mmHg and 159/99 mmHg in the setting of diabetic kidney disease. 1278 Position Statement Diabetes Care Volume 40, September 2017

Figure 1—Recommendations for the treatment of confirmed hypertension in people with diabetes. *An ACE inhibitor (ACEi) or ARB is suggested to treat hypertension for patients with UACR 30–299 mg/g creatinine and strongly recommended for patients with UACR $300 mg/g creatinine. **Thiazide- like diuretic; long-acting agents shown to reduce cardiovascular events, such as chlorthalidone and indapamide, are preferred. ***Dihydropyridine. BP, blood pressure.

However, the use of both ACE inhibitors pressure medications should be made Avoiding Cardiovascular Events Through and ARBs in combination is not recom- in a timely fashion to overcome clinical in- Combination Therapy in Patients Living mended given the lack of added ASCVD ertia in achieving blood pressure targets. With Systolic Hypertension (ACCOMPLISH) benefit and increased rate of adverse There is only one large trial including trial enrolled participants at high risk of car- eventsdnamely, hyperkalemia, syncope, people with diabetes that randomized diovascular events (60% with diabetes) and and acute kidney injury (71–73). Titration two single-pill combinations and assessed demonstrated a decrease in morbidity and of and/or addition of further blood cardiovascular and renal outcomes. The mortality with the ACE inhibitor benazepril care.diabetesjournals.org de Boer and Associates 1279

plus the dihydropyridine CCB amlodipine of 30 mL/min/1.73 m2 (86,87). Below an Sodium–glucose cotransport 2 inhibi- versus benazepril and the thiazide-like di- eGFR of 30 mL/min/1.73 m2, a long-acting tors are associated with a mild diuretic uretic hydrochlorothiazide (68,74). Other loop diuretic, such as torsemide, should effect and a reduction in blood pressure such trials are needed to confirm these be prescribed instead. of 3–6 mmHg systolic blood pressure and outcomes and assess other antihyperten- To prevent inadvertent declines in 1–2 mmHg diastolic blood pressure sive medication combinations. eGFR, patients treated with an ACE inhib- (102,103). -like peptide 1 recep- Diabetic Kidney Disease itor or ARB should be aware of volume tor agonists are also associated with a Patients with diabetes and albuminuria status and avoid volume depletion to re- reduction in systolic/diastolic blood pres- – – (UACR $30 mg/g creatinine and parti- duce the risk for acute kidney injury. Also, sure of 2 3/0 1 mmHg (104). cularly $300 mg/g creatinine) are at in- in volume depleted states, risk for hyper- creased risk of progressive kidney disease kalemia increases (71,72,88). RESISTANT HYPERTENSION (24). In this setting, ACE inhibitors and Bedtime Dosing Recommendations ARBs have unique renoprotective advan- Evidence suggests an association between c Patients with resistant hypertension tages in the treatment of hypertension. absence of nocturnal blood pressure dip- who are not meeting blood pressure Outcometrialsofpeoplewithtype1 ping and ASCVD events. A meta-analysis targets on conventional drug ther- fi and type 2 diabetes and established di- of clinical trials found a small bene tof apy with three agents, including a abetic kidney disease (including urinary evening versus morning dosing of anti- diuretic, should be referred to a cer- $ albumin excretion 300 mg/g creatinine) hypertensive medications with regard to tified hypertension specialist. E have demonstrated that an ACE inhibitor blood pressure control but no data on c Patients with resistant hypertension or ARB, at a maximal antihypertensive clinical effects (89). In two subgroup anal- who are not meeting blood pressure dose, slows the progression of kidney dis- yses of a single subsequent randomized targets on conventional drug ther- – ease compared with placebo (75 77). clinical trial, moving at least one antihy- apy with three agents should be Therefore, patients with urinary albumin pertensive medication to bedtime signif- considered for mineralocorticoid re- $ excretion 300 mg/g creatinine should icantly reduced cardiovascular events, ceptor antagonist therapy. B have an ACE inhibitor or an ARB included but results were based on small numbers as part of their blood pressure–lowering of events (90,91). fi regimen. Clinicians should also consider Resistant hypertension is de ned as $ an ACE inhibitor or ARB in patients with Monitoring blood pressure 140/90 mmHg despite a therapeutic strategy that includes ap- hypertension at any level of albuminuria Recommendation propriate lifestyle management plus a di- (urinary albumin excretion $30 mg/g c In patients receiving pharmacologic uretic and two other antihypertensive creatinine) (66). antihypertensive treatment, home drugs belonging to different classes at In the absence of albuminuria, the su- blood pressure should be measured adequate doses. Prior to diagnosing resis- periority of ACE inhibitors or ARBs over to promote patient engagement in tant hypertension, several other condi- other antihypertensive agents for preven- treatment and adherence. B tion of cardiovascular outcomes has not tions should be excluded (Table 3). been consistently shown (66,69,78,79), Since multiple agents are often neces- Self-management is a key component of although smaller trials suggest reduction sary to achieve blood pressure targets, diabetes care and extends to antihyper- in composite cardiovascular events and medication adherence issues may pre- tensive treatment. Home blood pressures reduced progression to advanced stages sent as resistant hypertension. Potential may improve patient medication adher- of kidney disease (80–82). In general, ACE barriers to medication adherence (such as ence (92–94) and reduce cardiovascular inhibitors and ARBs are considered to cost, number of medications, and side risk factors (95). Furthermore, evidence have similar benefits and risks, and if one effects) should routinely be assessed. If suggests home blood pressure monitor- is not tolerated, the other can often blood pressure remains uncontrolled de- ingisasaccurateas24-hambulatory fi be used (65,83). spite con rmed adherence, clinicians blood pressure monitoring (96,97) and should consider an evaluation for second- Hyperkalemia and Acute Kidney Injury may better correlate with ASCVD risk ary causes of hypertension. In people with diabetic kidney disease, than office measurements (98,99). Mineralocorticoid receptor antagonists hyperkalemia risk dramatically increases (MRAs) are effective for management of when the estimated glomerular filtration Interactions with Diabetes Medications resistant hypertension in patients with rate (eGFR) is below 45 mL/min/1.73 m2 and exogenous type 2 diabetes when added to existing or serum potassium is .4.5 mEq/L while may theoretically lead to hypertension treatment with a renin-angiotensin system the patient is already receiving a diuretic through vasoconstriction and sodium (RAS) inhibitor, diuretic, and CCB (105), in (84). Moreover, the combination of reduced and fluid retention (100). However, insu- part because they reduce sympathetic eGFR and elevated potassium in a given pa- lin can also promote vasodilation, and basal activity (106). MRAs also reduce tient can raise the risk eightfold for hyper- insulin compared with standard care was albuminuria and have additional cardio- kalemia development if and not associated with a change in blood pres- vascular benefits (107–110). However, an ACE inhibitor or ARB are added (85). sure in the Outcome Reduction With an adding an MRA to an ACE inhibitor or Thiazide-like diuretics are only effec- Initial Glargine Intervention (ORIGIN) trial ARB may increase the risk for hyper- tive in maintaining volume and reducing of people with type 2 diabetes or prediabe- kalemic episodes. Hyperkalemia can the risk of hyperkalemia down to an eGFR tes (101). be managed with dietary potassium 1280 Position Statement Diabetes Care Volume 40, September 2017

restriction, potassium-wasting diuretics, For women requiring antihypertensive iatrogenic complications, including hypo- or potassium binders (111), but long- therapy, blood pressure should be main- glycemia, orthostatic hypotension, and term outcome studies are needed to eval- tained between 120 and 160 mmHg sys- volume depletion. uate the role of MRAs (with or without tolic and 80 and 105 mmHg diastolic, as In older adults with diabetes and hy- adjunct potassium management) in blood lower blood pressure levels may be asso- pertension, functional status, comorbid- pressure management. ciated with impaired fetal growth. Preg- ities, and are important nantwomenwithhypertensionand considerations when establishing ther- evidence of end-organ damage including apeutic strategies and blood pressure cardiovascular and renal may be goals (125). Systolic blood pressure Recommendations considered for lower blood pressure tar- should be the main target of treatment. c Pregnant women with diabetes and gets (i.e., ,140/90 mmHg) to avoid the In fitter patients, a therapeutic strategy preexisting hypertension or mild ges- progression of these diseases during similartothatusedinyoungerindividuals tational hypertension with systolic pregnancy. may be used. In the subgroup with loss of blood pressure ,160 mmHg, dia- During pregnancy, treatment with ACE autonomy and major functional limita- , stolic blood pressure 105 mmHg, inhibitors, ARBs, or spironolactone is con- tions (e.g., those needing daily assistance and no evidence of end-organ dam- traindicated, as they may cause fetal for their basic activities), higher systolic age do not need to be treated with damage. Antihypertensive drugs known blood pressure goals should be consid- pharmacologic antihypertensive to be effective and safe in pregnancy in- ered (e.g., 145–160 mmHg) and treat- therapy. E clude methyldopa, labetalol, hydralazine, ment should be reduced in the presence c In pregnant patients with diabetes and long-acting nifedipine. Diuretics may of low supine systolic blood pressure and preexisting hypertension who be used during late-stage pregnancy (,130 mmHg) or presence of orthostatic are treated with antihypertensive if needed for volume control (115). hypotension (125,126). therapy, systolic or diastolic blood Postpartum patients with gestational hy- In older people with impaired vascular – – pressure targets of 120 160/80 pertension, preeclampsia, and superim- compliance, as indicated by a difference 105 mmHg are suggested in the posed preeclampsia should have their of .60 mmHg between systolic and di- interest of optimizing long-term blood pressures observed for 72 h in the astolic pressures (i.e., pulse pressure), at- – ’ maternal health and fetal growth. E hospital and for 7 10 days postpartum tempts to reach a target systolic pressure (112). Long-term follow-up is recom- must be balanced against the risk of low- The American College of Obstetricians mended for these women, as they have ering diastolic pressure below 65–70 and Gynecologists (ACOG) does not increased lifetime cardiovascular risk. mmHg. Lowering diastolic pressures be- recommend that women with mild gesta- low this range in older adults may increase tional hypertension (systolic blood pres- OLDER ADULTS (AGED ‡65 YEARS) the risk for coronary heart disease, mor- sure ,160 mmHg or diastolic blood tality, and other adverse cardiovascular may develop during the pressure ,110 mmHg) be treated with outcomes (127–130). aging process and contribute to an in- antihypertensive medications, as there When considering pharmacologic anti- crease in systolic and decrease in diastolic is no benefit identified that clearly out- hypertensive treatment in older adults blood pressure in older adults (116,117). weighs potential risks of therapy (112). with diabetes, note that b-blockers may Diabetes is itself associated with an in- A Cochrane systematic review did not mask signs of , antihyper- crease in arterial stiffness (118), leading find conclusive evidence for or against tensive drugs can worsen orthostatic hy- to a greater age-related increase in sys- blood pressure treatment for mild to potension, and diuretics can exacerbate moderate preexisting hypertension to tolic blood pressure compared with peo- volume depletion. Cognitive dysfunction – reduce the risk of preeclampsia, preterm ple without diabetes (119 121). Older may affect medication-taking behaviors, birth, small-for-gestational-age infants, or adults with diabetes and hypertension particularly in the context of poor overall fetal death (113). For pregnant women at (mainly systolic) typically present with health status, multiple comorbidities, high risk of preeclampsia, low-dose aspi- high risk for cardiovascular events and acute illness, polypharmacy, and poor nu- rin is recommended starting at 12 weeks other age-related diseases (122–124), dif- trition. Tolerance of the antihypertensive of gestation to reduce the risk of ficulties achieving blood pressure targets treatment should be regularly assessed, preeclampsia (114). due to arterial stiffness, and high risk of especially orthostatic hypotension.

Table 3—Conditions to exclude before making the diagnosis of resistant hypertension Conditions Definition Secondary hypertension (136)* Hypertension elicited or exacerbated by other drugs or diseases Pseudoresistance (136,137) Apparent hypertension due to lack of medication adherence, poor blood pressure measurement technique Masked hypertension (137) Clinic blood pressure ,140/90 mmHg; daytime blood pressure $135 or $85 mmHg White-coat hypertension (137) Clinic blood pressure $140 or $90 mmHg; daytime blood pressure ,135/85 mmHg *Secondary causes of hypertension include endocrine issues, renal arterial disease, excessive edema in advanced kidney disease, and , suchas testosterone. Drugs that increase blood pressure include NSAIDs, decongestants, and some illicit substances. care.diabetesjournals.org de Boer and Associates 1281

ANTIHYPERTENSIVE TREATMENT risk of adverse events. This conversation disease: a scientific statement from the American IN THE ABSENCE OF should be part of a shared decision- Heart Association and American Diabetes Associ- – HYPERTENSION making process between the clinician ation. Circulation 2014;130:1110 1130 2. Fox CS, Golden SH, Anderson C, et al.; Ameri- For people with diabetes and untreated and the individual patient. can Heart Association Diabetes Committee of the blood pressure ,140/90 mmHg, there is Council on Lifestyle and Cardiometabolic Health; FUTURE UPDATES little evidence that antihypertensive Council on Clinical , Council on Cardio- treatment improves health outcomes. As more evidence becomes available to vascular and Stroke Nursing, Council on Cardio- guide the assessment and treatment of vascular Surgery and Anesthesia, Council on Some have suggested treatment with an Quality of Care and Outcomes Research; Ameri- ACE inhibitor or ARB to prevent or delay hypertension among people with diabe- fi can Diabetes Association. Update on prevention diabetic kidney disease, but the data do tes, updated, re ned, and additional rec- of cardiovascular disease in adults with type 2 not support such an approach. In a trial of ommendations will be published in the diabetes mellitus in light of recent evidence: a “ fi people with type 2 diabetes and normal annual ADA Standards of Medical Care scienti c statement from the American Heart As- in Diabetes,” available from https:// sociation and the American Diabetes Association. urine albumin excretion with and without – professional.diabetes.org/content/clinical- Diabetes Care 2015;38:1777 1803 hypertension, an ARB reduced or sup- 3. Arauz-Pacheco C, Parrott MA, Raskin P; Amer- pressed the development of albuminuria practice-recommendations. ican Diabetes Association. Treatment of hyperten- but increased the rate of cardiovascular sion in adults with diabetes. Diabetes Care 2003; 26(Suppl. 1):S80–S82 events (131). In two trials of patients Acknowledgments.We wouldvery muchliketo 4. Emdin CA, Rahimi K, Neal B, Callender T, express our gratitude and thanks to Erika Gebel without albuminuria or hypertension, Perkovic V, Patel A. Blood pressure lowering in one including people with type 1 diabetes Berg of the ADA for her help in writing the manuscript drafts and coalescing information type 2 diabetes: a systematic review and meta- – (132) and the other type 2 diabetes (133), from all the authors. analysis. JAMA 2015;313:603 615 5. Ettehad D, Emdin CA, Kiran A, et al. Blood pres- RAS inhibitors did not prevent the de- Funding and Duality of Interest. I.H.d.B. has velopment of diabetic glomerulopathy been a consultant for Boehringer Ingelheim and sure lowering for prevention of cardiovascular Ironwood Pharmaceuticals, and his institution has disease and death: a systematic review and meta- assessed by kidney biopsy. Therefore, RAS analysis. Lancet 2016;387:957–967 inhibitors are not recommended for pa- received research equipment and supplies from Medtronic and Abbott. S.B. has received research 6. Brunstrom¨ M, Carlberg B. Effect of antihyper- tients without hypertension to prevent the grants from the National Heart, Lung, and Blood tensive treatment at different blood pressure lev- development of diabetic kidney disease. Institute and Abbott Vascular; has been on advi- els in patients with diabetes mellitus: systematic sory boards for Pfizer, AstraZeneca, and The Med- review and meta-analyses. BMJ 2016;352:i717 CONCLUSIONS icines Company; and has received speaker fees 7. Bangalore S, Kumar S, Lobach I, Messerli FH. fi Blood pressure targets in subjects with type 2 Hypertension is a strong, modifiable risk from Merck, Abbott, P zer, and Abbott Vascular. A.B. has received honoraria from Fukuda-Denshi. diabetes mellitus/: obser- factor for the macrovascular and micro- E.D.M. has received an honorarium from Siemens vations from traditional and Bayesian random- vascular complications of diabetes. Ro- Healthcare Diagnostics for being a blinded events effects meta-analyses of randomized trials. – bust literature demonstrates the clinical adjudicator in a clinical trial unrelated to the sub- Circulation 2011;123:2799 2810 fi ject of this article (i.e., it was not related to either 8. Thomopoulos C, Parati G, Zanchetti A. Effects ef cacy of lowering blood pressure, with of blood-pressure-lowering treatment on out- cardiovascular and microvascular benefits hypertension or diabetes). P.M. has received re- search support and honorarium from Amgen. P.R. come incidence in hypertension: 10 - Should demonstrated for multiple classes of anti- has been a steering committee member for A blood pressure management differ in hyperten- hypertensive medications. Strong evidence Study to Evaluate the Effect of Dapagliflozin on sive patients with and without diabetes mellitus? from clinical trials and meta-analyses sup- Renal Outcomes and Cardiovascular Mortality in Overview and meta-analyses of randomized trials. J Hypertens 2017;35:922–944 ports targeting blood pressure reduction to Patients With (DAPA-CKD) fi 9. Gæde P, Oellgaard J, Carstensen B, et al. Years at least ,140/90 mmHg in most adults (AstraZeneca) and Ef cacy and Safety of Finere- none in Subjects With Type 2 Diabetes Mellitus of life gained by multifactorial intervention in pa- with diabetes. Lower blood pressure tar- and the Clinical Diagnosis of Diabetic Kidney Dis- tients with type 2 diabetes mellitus and microal- gets may be beneficial for selected pa- ease (FIGARO)/Efficacy and Safety of Finerenone buminuria: 21 years follow-up on the Steno-2 tients with high cardiovascular disease in Subjects With Type 2 Diabetes Mellitus and Di- randomised trial. Diabetologia 2016;59:2298– 2307 risk if they can be achieved without un- abetic Kidney Disease (FIDELIO) () and has received consultancy and/or speaking fees (all hon- 10. Gregg EW, Li Y, Wang J, et al. Changes in due burden, and such lower targets may oraria to his institution) from AbbVie, Astellas, As- diabetes-related complications in the United States, be considered on an individual basis. In traZeneca, Bayer, Boehringer Ingelheim, Eli Lilly, 1990-2010. N Engl J Med 2014;370:1514–1523 addition to lifestyle modifications, multi- and . S.Z. has been a consultant for 11. Rawshani A, Rawshani A, Franzen´ S, et al. ple medication classes are often needed AstraZeneca/Bristol-Myers Squibb Australia, Mortality and cardiovascular disease in type 1 and type 2 diabetes. N Engl J Med 2017;376:1407– to attain blood pressure goals. ACE inhib- Janssen-Cilag, Merck Sharp & Dohme, Novo Nor- disk, Sanofi Australia, and Servier International. 1418 itors, ARBs, dihydropyridine CCBs, and G.B. has been a principal investigator on FIDELIO 12. Ali MK, Bullard KM, Saaddine JB, Cowie CC, thiazide-like diuretics have been demon- (Bayer), a steering committee member for Evalu- Imperatore G, Gregg EW. Achievement of goals in strated to improve clinical outcomes and ation of the Effects of Canagliflozin on Renal and U.S. diabetes care, 1999-2010. N Engl J Med 2013; are preferred for blood pressure control. Cardiovascular Outcomes in Participants With Di- 368:1613–1624 13. Afkarian M, Zelnick LR, Hall YN, et al. Clinical For patients with albuminuria, an ACE in- abetic Nephropathy (CREDENCE) (Janssen) and Study Of With Atrasentan manifestations of kidney disease among US adults hibitor or ARB should be part of the anti- (SONAR) (AbbVie), and a consultant for Merck, Re- with diabetes, 1988-2014. JAMA 2016;316:602– hypertensive regimen. Treatment should lypsa, Vascular Dynamics, GlaxoSmithKline, Bayer, 610 be individualized to the specific patient Janssen, and AbbVie. No other potential conflicts of 14. Ford ES, Ajani UA, Croft JB, et al. Explaining based on their comorbidities; their antic- interest relevant to this article were reported. the decrease in U.S. from coronary disease, – fi 1980-2000. N Engl J Med 2007;356:2388 2398 ipated bene t for reduction in ASCVD, References 15. Pickering TG, Hall JE, Appel LJ, et al.; Subcom- heart failure, progressive diabetic kidney 1. de Ferranti SD, de Boer IH, Fonseca V, et al. mittee of Professional and Public Education of the disease, and retinopathy events; and their Type 1 diabetes mellitus and cardiovascular American Heart Association Council on High Blood 1282 Position Statement Diabetes Care Volume 40, September 2017

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