Article:Blood pressure control in type 2 diabetic patients. (5217560)

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This page is the ScienceSource HTML version of the scholarly article described at Its title is Blood pressure control in type 2 diabetic patients. and the publication date was 2017-01-06. The initial author is Alon Grossman.

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Journal Information

Title: Cardiovascular Diabetology

Blood pressure control in type 2 diabetic patients

  • Alon Grossman
  • Ehud Grossman

Publication date (epub): 1/2017

Publication date (pmc-release): 1/2017

Publication date (collection): /2017


Diabetes mellitus (DM) and essential hypertension are common conditions that are frequently present together. Both are considered risk factors for cardiovascular disease and microvascular complications and therefore treatment of both conditions is essential. Many papers were published on blood pressure (BP) targets in diabetic patients, including several works published in the last 2 years. As a result, guidelines differ in their recommendations on BP targets in diabetic patients. The method by which to control hypertension, whether pharmacological or non-pharmacological, is also a matter of debate and has been extensively studied in the literature. In recent years, new medications were introduced for the treatment of DM, some of which also affect BP and the clinician treating hypertensive and diabetic patients should be familiar with these medications and their effect on BP. In this manuscript, we discuss the evidence supporting different BP targets in diabetics and review the various guidelines on this topic. In addition, we discuss the various options available for the treatment of hypertension in diabetics and the recommendations for a specific treatment over the other. Finally we briefly discuss the new diabetic drug classes and their influence on BP.



Essential hypertension and diabetes mellitus (DM) are both extremely common conditions and therefore it is not surprising that their co-existence is extremely prevalent. Since both are considered risk factors for coronary artery disease, cerebrovascular disease, renal failure and congestive heart failure, treatment of both conditions is essential. Whether blood pressure (BP) should be lowered to a different target in diabetic patients has been a debate for many years. Current guidelines are inconsistent regarding BP target in diabetic patients. Whereas several guidelines recommend a BP goal of <140/90 mmHg [[1], [2]], some recommend a lower target for diastolic BP [[3], [4]] and some recommend lower systolic BP thresholds in certain diabetic population [[5][7]]. The class of drug treatment most appropriate for the treatment of hypertensive diabetics is also unclear and different guidelines emphasize use of different drug classes for the treatment of hypertension in diabetic patients. Recently introduced drug classes for the treatment of DM have also been found to lower BP, thus making the interaction between BP and DM even more complex. In this review, we discuss the epidemiology of diabetes and hypertension, the benefit of lowering BP in diabetic patients, the target BP and the recommended treatment to achieve the target in these patients. This review deals mainly with BP control in type 2 DM, but some of the data derived from studies that included also non diabetic patients.


Hypertension is twice more common in diabetics than in non-diabetics [[8]], but the definition of hypertension in diabetics is generally similar to the general populations and the threshold for treatment is persistent BP values ≥140/90 mmHg. As both hypertension and DM are highly associated with obesity, it is not surprising that their co-existence is particularly common in obese individuals [[9]]. Both hypertension and DM increase significantly with increasing age and their co-existence is highest in older individuals [[10]]. Patients with DM more commonly present with isolated systolic hypertension and are more resistant to treatment. In the EUROASPIRE IV survey only 54% of the diabetic patients achieved BP levels of less than 140/90 mmHg [[11]]. In addition, the presence of autonomic neuropathy in diabetic patients is associated with a less nocturnal BP decrease, a higher baseline heart rate and a higher BP variability than in non-diabetics [[12][18]].

The co-existence of DM and hypertension significantly increase the risk for coronary heart disease [[19]], left ventricular hypertrophy [[20]], congestive heart failure [[21]] and stroke [[22]] compared with either condition alone. In addition, both hypertension and DM are present in all prediction models for the occurrence of stroke in patients with atrial fibrillation [[23][25]]. Microvascular complications are also more common in patients with co-existent hypertension and DM and both retinopathy and nephropathy are more prevalent in patients with DM and hypertension [[26], [27]]. Lowering BP is particularly beneficial in diabetic patients [[28], [29]], however how low should BP be is controversial.

What should be the blood pressure target in diabetes mellitus?

The BP targets in diabetic hypertensive individuals are controversial. For many years it was common practice to aim for BP targets lower than 130/80 mmHg in non-proteinuric diabetic patients. This was based on evidence from several large studies, including The Hypertension Optimal Treatment (HOT) study, the United Kingdom Prospective Diabetes Study (UKPDS) 38 and the Action in Diabetes and Vascular disease Controlled Evaluation (ADVANCE) trial [[29][31]]. However, in most studies the achieved BP was higher than 135/85 mmHg and therefore the recommendation to lower BP to less than 130/80 mmHg was not solid [[32], [33]]. Moreover, several studies reported no benefit and even harm when lower BP targets were achieved. In the Ongoing Telmisartan Alone and in Combination with Ramipril Global End point Trial (ONTARGET) study, which included 9612 diabetic patients, the composite primary outcome of death from cardiovascular (CV) causes, myocardial infarction, stroke, or hospitalization for heart failure did not differ between groups despite achievement of lower BP values in the telmisartan-ramipril arm [[34]]. In the Prevention Regimen for Effectively Avoiding Second Strokes (PROFESS) trial, which included 5743 diabetics, recurrence of stroke was not less in patients receiving telmisartan despite a significant decrease in BP [[35]]. The PROFESS results were different from those of the Perindopril Protection Against Recurrent Stroke Study Collaborative Group (PROGRESS) trial [[36]], in which treatment with the ACE inhibitor perindopril was associated with a 38% risk reduction in the occurrence of stroke, but the PROGRESS trial included only 762 diabetic patients and they were recruited much longer following the initial stroke than in the PROFESS trial. The Telmisartan Randomised Assessment Study in ACE Intolerant Subjects with CV Disease (TRANSCEND) study [[37]] was another study which 35.7% of the patients were diabetics and in which more significant BP reduction with telmisartan was not associated with CV benefit.

In the International Verapamil SR/Trandolapril (INVEST DM) study there was no difference in short term outcome in diabetic patients with coronary artery disease despite achievement of significantly lower BP (<130 mmHg vs. <140 mmHg) and in fact, there was an increased in the long term all-cause mortality in the more tightly controlled group [[38]]. In the Action to Control Cardiovascular Risk in Diabetes Blood Pressure (ACCORD-BP) trial, BP reduction to <120 mmHg did not reduce mortality or overall CV outcomes, but did reduce significantly only the occurrence of stroke a pre specified secondary outcome [[39]]. Moreover, intensive BP lowering was associated with an increased rate of syncope and hyperkalemia, both directly related to the intensive treatment. The results of this large prospective study, in addition to data from other studies, led most of the societies to recommend less stringent BP target in diabetic patients.

However, the results of the recent systolic blood pressure intervention trial (SPRINT) raised again the discussion what should be the target BP in diabetic patients. The SPRINT randomized 9361 persons with systolic BP > 130 mmHg and increased CV risk, but without type 2 DM, to a systolic BP target <120 mmHg (intensive treatment) or a target of <140 mmHg (standard treatment). At 1 year, the mean systolic BP was 121.4 mmHg in the intensive treatment group and 136.2 mmHg in the standard-treatment group. The study was stopped early after a median follow-up of 3.26 years owing to 25% lower rate of the primary composite outcome in the intensive-treatment group than in the standard-treatment group (P < 0.001). All-cause mortality was also lower by 27% in the intensive treatment group (P = 0.003) [[40]]. The main benefit was observed in elderly subjects (>75 years) who constituted 28% of the study population [[41]]. Rates of serious adverse events of hypotension, syncope, electrolyte abnormalities, and acute kidney injury or failure, but not of injurious falls, were higher in the intensive-treatment group than in the standard-treatment group [[40]]. This recent study supports intensive BP lowering in non-diabetic patients with increased CV risk. The most important question came from the SPRINT is related to diabetic patients who were excluded from this study. In light of the discrepancy between the ACCORD and the SPRINT can we assume that the better results in SPRINT with intensive BP lowering does not apply to diabetic patients?

One approach is to explain why the results of the SPRINT should not be applied to diabetic patients and, unlike our previous thoughts BP targets in diabetic patients should be higher than in non-diabetics. DM has a negative influence on arteriolar function and blood flow autoregulation that shifts the pressure/flow relationship. Therefore diabetic patients are more vulnerable to compromised blood flow to vital organs when BP reaches a critical low point.

The opposite approach is that the results of the SPRINT should be applied to diabetic patients, since in most previous trials the benefits of BP reduction in diabetic patients were at least as good if not better than in non-diabetic individuals [[29], [42]]. To justify this approach one should look at the effect of intensive BP lowering in diabetic patients on stroke, the long-term follow up results of the ACCORD study and the differences between the ACCORD and the SPRINT.

In the ACCORD study, despite the failure to show a decrease in primary endpoints in the intensive treatment arm the rate of stroke was significantly lower in the intensive than in the usual treatment arm [[39]]. It is possible that the ACCORD trial was underpowered, with a much lower event rate than anticipated and therefore the benefit of intensive BP lowering was not observed. Recently, new results from a long-term follow-up of the ACCORD patients, dubbed the ACCORDION trial, were presented at the 2015 AHA meeting [[43]]. In this extended study 3957 patients were followed for an additional 54–60 months. During this time, patients who had been in the intensive BP arm in the main trial were no longer aiming for the lower BP goals, so the difference in BP between the two groups narrowed from 14.5 mmHg at the end of the main trial to 4.2 mmHg at the end of the follow-up period. Results from the follow-up period showed a 9% non-significant reduction in the primary end point of major CV events over a median follow-up of 8.8 years from randomization. During the long-term follow-up, an interaction between BP and glycemia interventions became significant (P for interaction 0.037), with evidence of benefit for intensive BP lowering in participants randomized to standard glycemia therapy (HR = 0.79, 95% CI 0.65–0.96). These long-term results of the ACCORD trial do take on enhanced importance when viewed alongside the SPRINT results.

Several differences in the design of the studies may also explain the different results. ACCORD had lower event rates than initially predicted because of a lower CV risk profile in participants. The exclusion of participants aged >80 years led to a younger group of patients in ACCORD than in SPRINT. The mean age for ACCORD was 62 years and for SPRINT was 68 years.

Participants in the BP arm of the ACCORD were also at lower risk because patients with dyslipidemia were assigned to the lipid arm and were excluded from the BP arm.

Another significant difference in the design of the SPRINT and ACCORD studies was the use of diuretics. The treatment regimen for hypertension in the ACCORD study often used hydrochlorthiazide, and the SPRINT study primarily used chlorthalidone.

In addition, the complexity of the factorial study design in ACCORD may have made it less likely that a statistically significant difference could be demonstrated. This may suggest that if diabetic patients were included in the SPRINT they would also benefit from intensive BP lowering.

When we try to explain the reason for the difference between the SPRINT and the ACCORD it should be emphasized that the results of the SPRINT are provocative. In the recent Heart Outcomes Prevention Evaluation (HOPE)–3 trial 12,705 participants at intermediate risk who did not have CV disease were randomized to receive either candesartan at a dose of 16 mg per day plus hydrochlorothiazide at a dose of 12.5 mg per day or placebo and were followed for 5.6 years. The first co-primary outcome was the composite of death from CV causes, nonfatal myocardial infarction, or nonfatal stroke; the second co-primary outcome additionally included resuscitated cardiac arrest, heart failure, and revascularization. Therapy with candesartan plus hydrochlorothiazide was not associated with a lower rate of major CV events than placebo despite a BP decrease of 6.0/3.0 mmHg in the active treatment group. The only subgroup who benefited from BP lowering was the subgroup of participants with initial systolic BP > 143.5 mmHg [[44]]. A recent study that used the extended follow-up data from the US cohort of the International Verapamil [SR]/Trandolapril Study (INVEST) showed that in hypertensive patients with coronary artery disease, achieving a systolic BP of 130–140 mmHg seems to be associated with lower all-cause mortality after approximately 11.6 years of follow-up [[45]]. Similarly, the Secondary Prevention of Small Subcortical Strokes (SPS3) trial) evaluated BP goals in patients with a previous lacunar stroke testing a systolic goal of 130–149 mmHg versus <130 mmHg [[46]]. This trial also did not demonstrate significant reductions in ischemic stroke or intracranial hemorrhage in the more intensive treated group. Why the results of the SPRINT showed a clear benefit of lowering systolic BP to <120 mmHg whereas other studies failed to show it?

One explanation is the technique of BP measurements. In the SPRINT, BP was measures with an automated oscillometric office BP method that eliminated the need for a human to participate in the actual measurement and therefore reduces the white coat effect. Compared with a reasonably well-done standard office-based BP, the use of an automated oscillometric office BP method will yield a systolic BP that is 7–10 mmHg lower in the same patient, measured on the same day. If this is true the systolic BP of 120 mmHg in the SPRINT is equivalent to almost 130 mmHg in clinical practice. Thus, it is reasonable to suggest in high risk patients a target systolic BP of <130 rather than <120 mmHg.

To solve the discrepancy between the various studies and to find out what should be the target systolic BP several meta- analysis were recently published (Table 1).Table 1

Meta-analyses of anti-hypertensive treatment in diabetic patients

Topic Year Journal Number of studies included Number of patients included Number of diabetics Mean follow-up (years) Main conclusions
Effect of antihypertensive treatment at different BP levels in patients with diabetes mellitus [[47]] 2016 British Medical Journal 49 73,738 Only diabetic, most type 2 3.7 If BP was greater than 150 mmHg, treatment reduced all-cause mortality, CV mortality, myocardial infarction, stroke and end stage renal disease. If baseline systolic BP was less than 140 mmHg, further treatment increased the risk of CV mortality with a tendency towards an increased risk of all-cause mortality
BP lowering for prevention of CV disease and death [[49]] 2016 The Lancet 123 613,815 NA NA Every 10 mmHg reduction in systolic BP significantly reduced the risk of major CV disease events, coronary heart disease, stroke and heart failure which, in the populations studied, led to a significant 13% reduction in all-cause mortality. The effect on renal failure was not significant. Proportional risk reductions (per 10 mmHg lower systolic BP) were noted in trials with higher mean baseline systolic BP and trials with lower mean baseline systolic BP. There was no clear evidence that proportional risk reductions in major CV disease differed by baseline disease history, except for diabetes and chronic kidney disease, for which smaller, but significant, risk reductions were detected
BP targets for hypertension in people with diabetes mellitus [[48]] 2013 Cochrane Database systematic reviews 5 7314 7134 4.5 Reduction in incidence of stroke in intensive BP reduction compared with standard reduction, no effect on mortality, significant increase in other serious adverse events
BP Targets in Subjects With Type 2 Diabetes Mellitus/Impaired Fasting Glucose [[50]] 2011 Circulation 13 37,736 All 4.8 ± 1.3 A systolic BP treatment goal of 130 to 135 mmHg is acceptable. However, with more aggressive goals (<130 mmHg), the risk of stroke continues to fall, but there is no benefit regarding the risk of other macrovascular or microvascular events, and the risk of serious adverse events even increased
Effects of intensive BP reduction on myocardial infarction and stroke in diabetes [[51]] 2011 Journal of Hypertension 31 73,913 159 NA Tighter BP control reduced the risk of stroke by 31% compared with less tight control, whereas the reduction in the risk of MI was not significant

CV, cardiovascular; BP, blood pressure, NA, not available; MI, myocardial infarction

A meta-analysis of 49 trials including 73,738 patients (most of them diabetic) showed that at BP values greater than 140 mmHg, BP reduction was associated with a decrease in mortality and CV morbidity. On the other hand, BP reduction in patients with initial BP values <140 mmHg resulted in increased CV mortality and a tendency towards increased overall mortality [[47]]. Another meta-analysis evaluated randomized controlled trails performed only in diabetic individuals and concluded that the present evidence does not support BP targets lower than the standard targets in people with elevated BP and diabetes [[48]]. A recently published meta-analysis evaluated BP lowering for prevention of CV disease and death and reported that the proportional reduction in major CV disease events by BP reduction seemed to be larger in trials done in people without diabetes or chronic kidney disease [[49]]. This was attributed to different methodological characteristics in studies in diabetic patients. Another meta-analysis of 13 randomized control studies including over 37,000 diabetic hypertensive patients has shown that intensive systolic BP control to less than 130 mmHg was associated with a 10% reduction in all-cause mortality, yet no effects on microvascular or macrovascular events were noted. Regarding stroke, such an intensive BP reduction has led to a 17% risk reduction, accompanied by an additional risk reduction with further lowering systolic BP to <120 mmHg, without an increased risk for adverse effects [[50]]. Another meta-analysis included 31 randomized control studies with over 73,000 diabetic hypertensive patients reported a 31% reduction in relative risk of stroke, with a 13% reduction for every 5 mmHg systolic BP or 2 mmHg diastolic BP reductions. The risk of myocardial infarction was not significantly reduced with a more intensive BP control [[51]].

Thus it seems that a target of systolic BP < 130 mmHg is reasonable in most diabetic patients. In elderly diabetic patients (>80 years) but otherwise healthy, a BP target of <140–150/90 mmHg is reasonable. Lower BP levels may be adequate if tolerated by the patients. BP levels should be monitored closely in the sitting and the standing position and the treatment should be tailored to prevent excessive fall in BP [[52]].

Treatment goals according to current guidelines

Although previous guidelines recommended strict BP control in diabetic patients [[53], [54]], this has been challenged in recent guidelines (Table 2). The British National Institute for Health and Clinical Excellence (NICE) guidelines published in 2011 [[55]] recommended commencing treatment in diabetic patients with stage 1 hypertension (Clinic BP > 140/90 mmHg and ambulatory BP monitoring (ABPM) daytime average or home BP monitoring (HBPM) average BP of >135/85 mmHg). The recently published 2016 American Diabetes Association (ADA) guidelines recommended that hypertensive diabetic patients be treated if they have a diastolic BP of >80 mmHg or a systolic BP > 140 mmHg, with a target BP value of <140/90 mmHg [[6]]. These guidelines state that individuals in whom stroke risk is a concern may, as part of shared decision making, have lower systolic targets such as 130 mmHg. This is especially true if lower BP can be achieved with few drugs and without side effects of therapy. The American Heart association (AHA)/American College of Cardiology (ACC) guidelines from 2014 recommend a target BP of <140/90 mmHg, but point out that lower targets may be considered [[56]]. The American Society of Hypertension (ASH)/International Society of Hypertension (ISH) guidelines from 2014 suggest a BP goal of <140/90 mmHg in diabetic patients [[2]]. These values are lower than those recommended by the majority of the JNC 8 panel for non-diabetic patients aged 60–79, which was <150/90 mmHg, yet similar to those recommended for non-diabetics aged 18–60 years, and similar to the values of all non-diabetic patients by the minority view of the JNC8 [[1]]. The 2013 European Society of Hypertension (ESH) and European Society of Cardiology (ESC) guidelines recommend lowering systolic BP below 140 mmHg, and diastolic BP below 85 mmHg [[3]]. The Canadian Hypertension Education Program (CHEP) suggests a target BP of <130/80 mmHg [[7]]. The International Diabetes Federation (IDF) suggests age-adjusted BP targets (BP target values of <130/80 mmHg for diabetic patients younger than 70 years, target values of <140/90 mmHg for patients 70–80 years old, and target values of <150/90 mmHg for patients over 80 years old) [[5]].Table 2

BP goals in diabetics according to major guidelines

Guidelines NICE [[54]] ESH/ESC [[3], [4]] ASH/ISH [[2]] JNC 8 [[1]] ADA [[6]] CHEP [[7]] IDF [[5]]
Year published 2011 2013 2014 2014 2016 2016 2012
Blood pressure (mmHg) Not addressed <140/85 <140/90 <140/90 <140/90 <130/80 <130/80
Special considerations Begin treatment if BP > 140/90 mmHg Systolic BP < 130 mmHg and diastolic BP < 80 may be appropriate for certain individuals with diabetes, such as younger patients, those with albuminuria, and/or those with hypertension and one or more additional atherosclerotic CV disease risk factors, if they can be achieved without undue treatment burden. <140/90 mmHg in patients 70-80 years old <150/90 mmHg in patients over 80 years old
Recommended initial treatment ACE inhibitor plus either a diuretic or a CCB All classes of antihypertensive agents are recommended. RAAS blockers may be preferred, especially in the presence of proteinuria or microalbuminua ARB or ACE inhibitor. In black patients, it is acceptable to start with a CCB or a thiazide. Thiazide-type diuretic, CCB, ACE inhibitor or ARB ACE inhibitor, ARB ACE inhibitor, ARB in patients with CV or kidney disease, including microalbuminuria, or with CV risk factors In patients without albuminuria, Thiazide-type diuretic, CCB, ACE inhibitor or ARB

NICE, National Institute for Health and Clinical Excellence; ESH/ESC, European Society of Hypertension/European Society of Cardiology; JNC, Joint National Committee; ASH+, American Society of Hypertension; ISH, International Society of Hypertension; ADA, American Diabetes Association; CHEP, Canadian Hypertension Education Program; BP, blood pressure; ACE, angiotensin converting enzyme; CCB, calcium channel blocker; RAS, renin angiotensin system; ARB, angiotensin receptor blocker; BB, beta blocker

How to reach goal blood pressure in diabetics

Non-pharmacological treatment

Non-pharmacological anti-hypertensive therapy includes weight loss, increased potassium-based diet (DASH- dietary Approach to Stop Hypertension- style diet), low sodium consumption (below 2400 mg/day), moderation of alcohol intake and regular physical activity and exercise. Although the CV benefits of lifestyle interventions were not evaluated in diabetic patients, their implementation seems reasonable in diabetics since they may positively affect glycemia and lipid profile. Therefore their adoption for all diabetic patients with BP values >120/80 mmHg was recommended by recent ADA standards of care [[6]].

Pharmacological treatment

Renin-angiotensin-aldosterone blockers

Angiotensin converting enzyme inhibitors (ACEI), and angiotensin receptor blockers (ARBs) have long been considered the cornerstone of anti-hypertensive treatment in diabetic patients. Previous studies have demonstrated that both renin-angiotensin-aldosterone system (RAAS) blockers, ACEI and ARB, are associated with prevention of new onset DM in hypertensive patients [[57]] and are particularly favorable among patients with albuminuria [[57]]. Although ACEIs were reported to reduce overall CV risk, overt nephropathy, renal failure and retinopathy among non-hypertensive diabetics, other studies failed to show the superiority of ACEI over beta blockers in lowering BP and preventing nephropathy or retinopathy in diabetic patients [[58], [59]]. Despite the fact that ACEIs were found to be superior to ARBS in preventing all-cause mortality and CV morbidity and mortality in two meta-analysis [[60], [61]], in the ONTARGET study, outcome was similar between the two drug classes [[34]] and in a recent real-world study ARBS were found to be more effective than ACEI in the prevention of stroke [[62]]. Therefore it seems that ACEIs and ARBs are probably equally efficacious for the prevention of CV outcomes in hypertensive diabetics. ARBs and ACEIs are equally effective in preventing progression of kidney disease in diabetic patients with early nephropathy with ARBS having comparable BP lowering capacity with fewer side effects compared with ACEIs [[63]]. In a recent study that compared the BP lowering effect of ARBs in diabetic patients, azilsartan medoxomil was more effective than olmesartan and valsartan [[64]]. A recent meta-analysis of 19 randomized controlled trials with over 25,000 participants found that ACEIs or ARBs were associated with a similar risk of death (relative risk 0.99, 95% CI 0.93–1.05), CV death (1.02, 0.83–1.24), myocardial infarction (0.87, 0.64–1.18), angina pectoris (0.80, 0.58–1.11), stroke (1.04, 0.92–1.17), heart failure (0.90, 0.76–1.07), revascularization (0.97, 0.77–1.22) and end stage renal disease (0.99, 0.78–1.28) as compared with other anti-hypertensive agents [[65]]. Combining two RAAS blockers is discouraged based on the discouraging results of the Aliskiren Trial in Type 2 Diabetes Using Cardiorenal Endpoints (ALTITUDE) and the ONTARGET trials [[34], [66]]. In summary, it seems that use of ACEIs or ARBs is not superior to use of other anti-hypertensive agents in diabetics without evidence of nephropathy, but these classes are legitimate first-line treatment options in the absence of contraindications.

Beta blockers

The use of beta blockers has been discouraged in diabetic patients due to its potential adverse metabolic effects, including an increase in triglyceride levels, a decrease in HDL cholesterol levels, weight gain, masking hypoglycemia and impairing insulin sensitivity [[67]]. In addition, it has been suggested that use of beta blockers in non-diabetic individuals, particularly those who are overweight or obese, might increase the risk for development of diabetes compared with an alternative agent [[68]]. As beta blockers are being used infrequently as first-line agents for the treatment of hypertension, their use in diabetes is also infrequent, but beta blockers may still be used as add-on treatment in those who require multiple agents and in patients in whom another indication for the use of beta blockers is present, such as those with tachycardia, heart failure or ischemic heart disease [[1], [3]].

Calcium channel blockers (CCBs)

CCBs are considered a potential first-line treatment for hypertensive diabetics, particularly in the elderly with isolated systolic hypertension [[69]]. CCBs have been shown to be particularly effective in the prevention of stroke, but are less effective than RAAS blockers in prevention of heart failure [[70]]. Although non-dihydropyridines decrease urinary protein excretion and serve as an alternative in RAAS inhibitor-intolerant patients [[71]], most research in recent years has focused on the efficacy and safety of dihydropyridines. The Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT BPLA) compared use of atenolol with amlodipine and found that amlodipine was more effective than atenolol in reducing stroke, CV events and all-cause mortality [[67]]. This advantage of amlodipine was evident in the large group of 5137 diabetics included in the study [[72]]. Notably, an ACEI was added to the amlodipine arm when BP was not controlled, whereas in the atenolol arm, a thiazide was added. A systematic review from 2015 evaluated the efficacy of amlodipine in the treatment of patients with hypertension with concomitant DM and/or renal dysfunction compared with other classes of antihypertensive medication and found that amlodipine was at least as effective as other anti-hypertensive agents in the treatment of hypertension, was associated with a decrease in stroke risk and an increase in heart failure risk [[73]]. CCBs are ineffective for the prevention of diabetes in non-diabetic individuals [[74]]. In summary, CCBs may be used as first-line agents for the treatment of hypertension in diabetic individuals, particularly in the elderly with isolated systolic hypertension.


Although there has been concern that diuretics might increase the risk for the development of diabetes mellitus [[75]] due to their potential to negatively influence insulin resistance [[76]], diuretics are important agents used for the treatment of hypertension in diabetics. In a sub-analysis of the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), chlortalidone was found to be as good as amlodipine or lisinopril in preventing fatal and non-fatal coronary artery disease and was more effective in the prevention of heart failure in diabetic patients [[77]]. The benefits of diuretics were also observed in the SHEP trial [[78], [79]]. In all studies in which diuretics were found to be effective in hypertensive diabetics, chlorthalidone or indapamide were used. To summarize, diuretics may be used for the treatment of hypertension in diabetics either as first line agents or as add-on treatment, but glucose and electrolytes should be monitored when initiating therapy.

Alpha blockers

There are no specific studies which evaluated the efficacy of alpha blockers in diabetic patients. Alpha blockers do not adversely affect glucose metabolism or lipid profile, but they have been reported to be less effective than chlorthalidone for prevention of stroke and heart failure [[80], [81]] and therefore are used almost exclusively in patients with hypertension and prostate hyperplasia or as third or fourth-line agents.

Aldosterone antagonists

Low dose spironolactone was found to be effective in controlling BP in patients with hypertension and diabetes [[82]]. The addition of spironolactone is particularly effective in those with serum potassium of <4.5 mmol/L [[83]]. To prevent hyperkalemia thiazide or thiazide like diuretics should be continued when aldosterone antagonists are added [[84]]. The addition of spironolactone to conventional antihypertensive treatment in diabetic patients was shown to reduce albuminuria [[85]] and in diabetic patients with albuminuria, addition of an aldosterone antagonist to an ACEI has been shown to have renoprotective effects superior to those shown with the addition of an ARB, even when BP reduction rates were similar [[86]]. Finerenone is a new non-steroidal anti mineralocorticoid which has less relative affinity than spironolactone and eplerenone to other steroid hormone receptors, and therefore has less adverse effects like gynaecomastia, impotence, low sex drive and hyperkalemia. A recent study showed that in patients with diabetic nephropathy the addition of finerenone to an angiotensin-converting enzyme inhibitor or an angiotensin receptor blocker improved urinary albumin-creatinine ratio better than placebo [[87]]. It seems that aldosterone antagonists have a renoprotective effect that is independent of systemic hemodynamic alterations [[88]]. Diabetic individuals tend to develop type 4 renal tubular acidosis and therefore hyperkalemia may be a concern in those treated with aldosterone antagonists, particularly when combined with ACEIs or ARBs, although the long-term risk is low [[89]].

Combination therapy

More than two-thirds of hypertensive individuals are inadequately controlled on mono therapy [[90]]. Most diabetic individuals are treated with RAAS inhibitors and most guidelines recommend adding a calcium antagonist or diuretic as add-on therapy [[1], [5], [6]]. In a sub-analysis of 6946 diabetic patients, in the Avoiding cardiovascular Events through combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) trial, a combination of benazepril plus amlodipine was significantly more effective in reducing the composite of CV death, nonfatal myocardial infarction, nonfatal stroke, hospitalization for angina, resuscitation after sudden cardiac arrest, and coronary revascularization, compared to therapy with benazepril plus hydrochlorothiazide [[42]]. The superiority of amlodipine over hydrochlorothiazide as an addition to benazepril disappeared in obese individuals [[91]]. Combining a RAAS blocker with a CCB provides better renoprotection and leads to less ankle edema compared with a CCB alone [[92]]. In addition, combining an ARB with a CCB was associated with improved insulin sensitivity compared with an ARB and a diuretic [[93]]. Based on these studies, it seems that CCBs are appropriate as second-line agents in diabetic patients already treated with RAAS blockers. In obese individuals or when volume overload is present, diuretics may be used as well. In a large group of patients with stage I hypertension a combination of chlorthalidone and amiloride yielded a greater reduction in BP than the ARB losartan [[94]]. In patients requiring triple therapy, RAAS blockers should be combined with diuretics and CCBs, unless there is compelling indication for the use for a different anti-hypertensive class (heart failure or ischemic heart disease for beta blockers or benign prostate hyperplasia for alpha blockers). Patients with resistant hypertension, particularly in the presence of low potassium levels, may benefit from aldosterone antagonists. These should be used cautiously, particularly in patients already on RAAS blockers. Once BP goal has been achieved antihypertensive treatment should be continued. In the ADVANCE trial discontinuation of antihypertensive medications was associated with increased risk of combined macro and microvascular events [[95]].

Diabetic treatment effective for the control of hypertension

In the last decade there is a surge of new anti-diabetic medications working on different pathways in insulin production and glucose disposal. Some of these agents have beneficial effects on BP and may prove as important agents for the control of hypertension in diabetic individuals. In this paragraph we will discuss these classes of agents and the evidence for their effect on elevated BP in both normotensive and hypertensive individuals.

Glucagon-like-polypeptide 1 analogues

Glucagon-like-polypeptide 1 analogues (GLP1a) lead to a clinically significant weight loss in both diabetics and non-diabetics [[96], [97]] and thus may aid in a better BP control. On the other hand, they have been reported to increase heart rate through sympathetic nervous system activation [[98]] and this may result in BP elevation. In the recently published Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial [[99]], patients treated with liraglutide had a mild decrease in systolic BP (1.5 mmHg) and a mild increase in diastolic BP (0.6 mmHg). In the trial to evaluate CV and other long-term outcomes with Semaglutide in Subjects with Type 2 Diabetes (SUSTAIN-6) in which the CV safety of semaglutide was evaluated [[100]], the mean systolic BP in the semaglutide group, as compared with the placebo group, was 1.3 mmHg lower in the group receiving 0.5 mg (P = 0.10) and 2.6 mmHg lower in the group receiving 1.0 mg (P < 0.05). Thus it seems the GLP1a have a neutral effect on BP and may even result in a mild decrease in BP, but probably cannot serve as an alternative to anti-hypertensive treatment in hypertensive diabetics.

Dipeptidyl peptidase-4 (DPP4) inhibitors

DPP4 inhibitors elevate endogenous GLP1 through inhibition of the endogenous substance responsible for its degradation. Several studies reported that these agents produce a modest decrease in BP [[101][103]], others reported that they increase BP [[104]] and yet others reported that they negate the hypotensive effects of ACEI [[105]]. Overall it seems that DPP4 inhibitors are neutral in term of BP control and their initiation probably does not significantly affect BP control.

Sodium-glucose- transporter 2 (SGLT2) inhibitors

Three representatives of this new class of anti-diabetics are currently in the market-canagliflozin, dapagliflozin and empagliflozin. Some others are under development. Although agents differ in their affinity for the sodium-glucose transporter, their clinical efficacy is quite similar. All three have similar efficacy in terms of glucose control and all are associated with significant weight loss [[106]]. All three have been reported to significantly decrease systolic and diastolic BP by 3–5/2–3 mmHg [[107]]. A meta-analysis published in 2014 reported that SGLT2 inhibitors decrease systolic and diastolic BP by 4 and 1.6 mmHg compared with placebo [[108]]. A pooled analysis of studies of canagliflozin and dapagliflozin concluded that orthostatic hypotension was not increased during treatment with these SGLT2 inhibitors compared with placebo. Three independent studies published after this meta-analysis specifically evaluated the effect of SGLT2 inhibitors on BP in diabetic individuals. The dapagliflozin BP study [[109]] reported a 4.28 mmHg statistically significant decrease in seated systolic BP during a 12-week period compared with placebo and a non-statistically significant decrease in diastolic BP compared with placebo. Orthostatic hypotension was not increased in the treatment arm compared with placebo. In another study Weber MA et al. showed a 3.1 mmHg fall in seated systolic BP and 2.9 mmHg fall in systolic BP recorded by 24H ambulatory blood pressure monitoring after 12 weeks of treatment with dapagliflozin[[110]]. The Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG) BP study [[111]] reported that mean systolic BP as evaluated by ambulatory BP monitoring was significantly lower in patients treated with both 10 and 25 mg empagliflozin compared with placebo. Patients who entered the study with uncontrolled hypertension had a more significant response to empagliflozin compared with those in which BP was well controlled prior to study initiation. Orthostatic hypotension was more prevalent in the empagliflozin group, but none of the patients who had orthostatic hypotension experienced clinical events related to this finding, making its clinical significance questionable. The canagliflozin BP study was the smallest of the three studies [[112]] and reported findings consistent with the previously mentioned studies with a decrease in systolic BP as assessed by ambulatory BP monitoring of approximately 2 mmHg for both 100 and 300 mg. Orthostatic hypertension as assessed by ambulatory BP monitoring or through clinical symptoms occurred only in the canagliflozin group. It is important to note that patients enrolled to all three studies of SGLT2 inhibitors in hypertensive diabetics were Caucasian and data evaluating the influence of SGLT inhibitors on BP in diabetics of non-Caucasian origin is much less extensive.

In addition, these drugs were reported to have a positive effect on the circadian rhythm in rats who developed hypertension [[113]]. The mechanism underlying the BP decrease by SGLT2 inhibitors is unclear and potential mechanisms include diuresis, nephron remodeling, decrease in arterial stiffness, and weight loss [[114]]. This class of agents is certainly promising as it can be used to control glucose, weight and BP. In fact, the EMPA-REG trial indeed showed that empagliflozin is associated with decreased CV morbidity, CV mortality and overall mortality [[115]]. Several potential non-glycemic mechanisms such as BP decrease and weight reduction have been suggested to explain the CV benefit of SGLT2 (Fig.  1). Whether SGLT2 inhibitors can be used for BP control in non-diabetic individuals is unclear. The results of the Canagliflozin Cardiovascular Assessment Study (CANVAS) [[116]] and DECLARE-TIMI 55 (for dapagliflozin) [[117]] studies which are expected to be complete on 2017 and 2019 respectively will clarify whether the CV benefits reported for empagliflozin are a class-effect.Fig. 1

Beneficial effects of SGLT2 inhibitors, SNS, sympathetic nervous system; LDL-c, low density lipoprotein cholesterol; HDL, high density lipoprotein cholesterol


Current evidence does not support a more stringent BP control strategy for all diabetic patients and the evidence to support stringent control in certain diabetic patients is also inconclusive. In elderly diabetic patients (>80 years) BP levels should be less than 140–150/90 mmHg and should be monitored closely in the sitting and the standing position and the treatment should be tailored to prevent excessive fall/decrease in BP. This is reflected in recommendations in most current BP treatment guidelines. The choice of anti-hypertensive agent is supported by minimal evidence although RAAS blockers are usually used as first-line agents. When requiring more than one agent for the control of hypertension in diabetics, calcium antagonists or diuretics are probably appropriate as second line agents. New agents used for the treatment of diabetes may aid in the control of hypertension and a diagnosis of hypertension in a diabetic person may influence the clinician’s choice to use a certain anti-diabetic treatment.

In addition to lowering BP it is very important to control all other risk factors in diabetic patients. This heterogeneous treatment model, relates directly to general trends in modern medicine, reflecting an aspiration for individually tailored medicine, adapted specifically for the particular demographic and biologic characteristics of each patient.


Authors’ contributions

AG reviewed the literature and wrote the first draft. EG reviewed the literature and finalized the manuscript. Both authors read and approved the final manuscript.


Not applicable.

Competing interests

The authors declare that they have no competing interests.

The authors give their consent for publication.


  1. PA JamesS OparilBL CarterWC CushmanC Dennison-HimmelfarbJ HandlerDT LacklandML LeFevreTD MacKenzieO Ogedegbe2014 evidence-based guideline for the management of high blood pressure in adults: report from the panel members appointed to the Eighth Joint National Committee (JNC 8)JAMA2014311550752010.1001/jama.2013.28442724352797
  2. MA WeberEL SchiffrinWB WhiteS MannLH LindholmJG KenersonJM FlackBL CarterBJ MatersonCV RamClinical practice guidelines for the management of hypertension in the community: a statement by the American Society of Hypertension and the International Society of HypertensionJ Clin Hypertens (Greenwich)2014161142610.1111/jch.1223724341872
  3. 2013 Practice guidelines for the management of arterial hypertension of the European Society of Hypertension (ESH) and the European Society of Cardiology (ESC): ESH/ESC Task Force for the Management of Arterial Hypertension. J Hypertens. 2013; 31(10):1925–38.
  4. L RydenPJ GrantSD AnkerC BerneF CosentinoN DanchinC DeatonJ EscanedHP HammesH HuikuriESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD: the Task Force on diabetes, pre-diabetes, and cardiovascular diseases of the European Society of Cardiology (ESC) and developed in collaboration with the European Association for the Study of Diabetes (EASD)Eur Heart J201334393035308710.1093/eurheartj/eht10823996285
  5. International Diabetes Federation Clinical Guidelines Task Force. Global Guideline for Type 2 Diabetes. info@idforg. 2012.
  6. Cardiovascular DiseaseRisk ManagementDiabetes Care201639Suppl 1S60S7126696684
  7. AA LeungK NerenbergSS DaskalopoulouK McBrienKB ZarnkeK DasguptaL CloutierM GelferM Lamarre-ClicheA MilotHypertension Canada’s 2016 Canadian Hypertension Education Program Guidelines for blood pressure measurement, diagnosis, assessment of risk, prevention, and treatment of hypertensionCan J Cardiol201632556958810.1016/j.cjca.2016.02.06627118291
  8. JR SowersRecommendations for special populations: diabetes mellitus and the metabolic syndromeAm J Hypertens20031611 Pt 241S45S10.1016/j.amjhyper.2003.07.00914625160
  9. AG CrawfordC CoteJ CoutoM DaskiranC GunnarssonK HaasS HaasSC NigamR SchuettePrevalence of obesity, type II diabetes mellitus, hyperlipidemia, and hypertension in the United States: findings from the GE Centricity Electronic Medical Record databasePopul Health Manag201013315116110.1089/pop.2009.003920521902
  10. DC SuhCM KimIS ChoiCA PlauschinatJA BaroneTrends in blood pressure control and treatment among type 2 diabetes with comorbid hypertension in the United States: 1988–2004J Hypertens20092791908191610.1097/HJH.0b013e32832d4aee19491704
  11. V GybergD De BacquerG De BackerC JenningsK KotsevaL MellbinO SchnellJ TuomilehtoD WoodL RydenPatients with coronary artery disease and diabetes need improved management: a report from the EUROASPIRE IV survey: a registry from the EuroObservational Research Programme of the European Society of CardiologyCardiovasc Diabetol20151413310.1186/s12933-015-0296-y26427624
  12. MJ BrownA CastaignePW de LeeuwG ManciaCR PalmerT RosenthalLM RuilopeInfluence of diabetes and type of hypertension on response to antihypertensive treatmentHypertension20003551038104210.1161/01.HYP.35.5.103810818061
  13. R FogariA ZoppiGD MalamaniP LazzariM DestroL CorradiAmbulatory blood pressure monitoring in normotensive and hypertensive type 2 diabetes. Prevalence of impaired diurnal blood pressure patternsAm J Hypertens199361178427656
  14. E GrossmanJ ShemeshM MotroHypertensive patients with diabetes mellitus have higher heart rate and pulse pressureJ Hypertens200220Suppl 4S60
  15. M OzawaK TamuraK IwatsuboK MatsushitaM SakaiY Tsurumi-IkeyaK AzumaA ShigenagaY OkanoS MasudaAmbulatory blood pressure variability is increased in diabetic hypertensivesClin Exp Hypertens200830321322410.1080/1064196080206847718425701
  16. R Pop-BusuiCardiac autonomic neuropathy in diabetes: a clinical perspectiveDiabetes Care201033243444110.2337/dc09-129420103559
  17. SL StevensS WoodC KoshiarisK LawP GlasziouRJ StevensRJ McManusBlood pressure variability and cardiovascular disease: systematic review and meta-analysisBMJ2016354i409810.1136/bmj.i409827511067
  18. D WeitzmanG ChodickV ShalevC GrossmanE GrossmanPrevalence and factors associated with resistant hypertension in a large health maintenance organization in IsraelHypertension201464350150710.1161/HYPERTENSIONAHA.114.0371824958503
  19. G AssmannH SchulteThe Prospective Cardiovascular Munster (PROCAM) study: prevalence of hyperlipidemia in persons with hypertension and/or diabetes mellitus and the relationship to coronary heart diseaseAm Heart J19881166 Pt 21713172410.1016/0002-8703(88)90220-73202078
  20. JB SomaratneGA WhalleyKK PoppeMM ter BalsG WadamsA PearlW BaggRN DoughtyScreening for left ventricular hypertrophy in patients with type 2 diabetes mellitus in the communityCardiovasc Diabetol2011102910.1186/1475-2840-10-2921492425
  21. S GovindS SahaLA BrodinSS RameshSR ArvindM QuintanaImpaired myocardial functional reserve in hypertension and diabetes mellitus without coronary artery disease: searching for the possible link with congestive heart failure in the myocardial Doppler in diabetes (MYDID) study IIAm J Hypertens200619885185710.1016/j.amjhyper.2006.01.00516876686
  22. E GrossmanFH MesserliU GoldbourtHigh blood pressure and diabetes mellitus: are all antihypertensive drugs created equal?Arch Intern Med2000160162447245210.1001/archinte.160.16.244710979055
  23. TF ChaoGY LipCJ LiuTC TuanSJ ChenKL WangYJ LinSL ChangLW LoYF HuValidation of a modified CHA2DS2-VASc score for stroke risk stratification in Asian patients with atrial fibrillation: a Nationwide Cohort StudyStroke201647102462246910.1161/STROKEAHA.116.01388027625386
  24. S RietbrockE HeeleyJ PlumbT van StaaChronic atrial fibrillation: incidence, prevalence, and prediction of stroke using the congestive heart failure, hypertension, age >75, diabetes mellitus, and prior stroke or transient ischemic attack (CHADS2) risk stratification schemeAm Heart J20081561576410.1016/j.ahj.2008.03.01018585497
  25. YW YangYH ChenCC HsuCC LeeYH KuoHY ChuangTF HsiehCHADS2 scores as a predictor of ischemic stroke in patients with peripheral artery diseaseMayo Clin Proc2016911455010.1016/j.mayocp.2015.09.02126678007
  26. JP LeaSB NicholasDiabetes mellitus and hypertension: key risk factors for kidney diseaseJ Natl Med Assoc2002948 Suppl7S15S12152917
  27. WC KnowlerPH BennettEJ BallintineIncreased incidence of retinopathy in diabetics with elevated blood pressure. A 6-year follow-up study in Pima IndiansN Engl J Med19803021264565010.1056/NEJM1980032030212016986550
  28. E GrossmanU GoldbourtHypertension optimal treatment (HOT) trialLancet1998352912757457510.1016/S0140-6736(05)79278-39716085
  29. L HanssonA ZanchettiSG CarruthersB DahlofD ElmfeldtS JuliusJ MenardKH RahnH WedelS WesterlingEffects 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 GroupLancet199835191181755176210.1016/S0140-6736(98)04311-69635947
  30. UK Prospective Diabetes Study GroupTight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38BMJ1998317716070371310.1136/bmj.317.7160.7039732337
  31. A PatelS MacMahonJ ChalmersB NealM WoodwardL BillotS HarrapN PoulterM MarreM CooperEffects 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 trialLancet2007370959082984010.1016/S0140-6736(07)61303-817765963
  32. E GrossmanFH MesserliManagement of blood pressure in patients with diabetesAm J Hypertens201124886387510.1038/ajh.2011.7721525967
  33. Y GrossmanG ShlomaiE GrossmanTreating hypertension in type 2 diabetesExpert Opin Pharmacother201415152131214010.1517/14656566.2014.94726725084118
  34. S YusufKK TeoJ PogueL DyalI CoplandH SchumacherG DagenaisP SleightC AndersonTelmisartan, ramipril, or both in patients at high risk for vascular eventsN Engl J Med2008358151547155910.1056/NEJMoa080131718378520
  35. S YusufHC DienerRL SaccoD CottonS OunpuuWA LawtonY PaleschRH MartinGW AlbersP BathTelmisartan to prevent recurrent stroke and cardiovascular eventsN Engl J Med2008359121225123710.1056/NEJMoa080459318753639
  36. Randomised trial of a perindopril-based blood-pressure-lowering regimen among 6105 individuals with previous stroke or transient ischaemic attack. Lancet. 2001; 358(9287):1033–1041.
  37. S YusufK TeoC AndersonJ PogueL DyalI CoplandH SchumacherG DagenaisP SleightEffects of the angiotensin-receptor blocker telmisartan on cardiovascular events in high-risk patients intolerant to angiotensin-converting enzyme inhibitors: a randomised controlled trialLancet200837296441174118310.1016/S0140-6736(08)61242-818757085
  38. RM Cooper-DeHoffY GongEM HandbergAA BavrySJ DenardoGL BakrisCJ PepineTight blood pressure control and cardiovascular outcomes among hypertensive patients with diabetes and coronary artery diseaseJAMA20103041616810.1001/jama.2010.88420606150
  39. WC CushmanGW EvansRP ByingtonDC Goff JrRH Grimm JrJA CutlerDG Simons-MortonJN BasileMA CorsonJL ProbstfieldEffects of intensive blood-pressure control in type 2 diabetes mellitusN Engl J Med2010362171575158510.1056/NEJMoa100128620228401
  40. JT Wright JrJD WilliamsonPK WheltonJK SnyderKM SinkMV RoccoDM ReboussinM RahmanS OparilCE LewisA randomized trial of intensive versus standard blood-pressure controlN Engl J Med2015373222103211610.1056/NEJMoa151193926551272
  41. JD WilliamsonMA SupianoWB ApplegateDR BerlowitzRC CampbellGM ChertowLJ FineWE HaleyAT HawfieldJH IxIntensive vs standard blood pressure control and cardiovascular disease outcomes in adults aged ≥75 years: a randomized clinical trialJAMA2016315242673268210.1001/jama.2016.705027195814
  42. MA WeberGL BakrisK JamersonM WeirSE KjeldsenRB DevereuxEJ VelazquezB DahlofRY KellyTA HuaCardiovascular events during differing hypertension therapies in patients with diabetesJ Am Coll Cardiol2010561778510.1016/j.jacc.2010.02.04620620720
  43. ACCORDION: long-term follow-up of ACCORD patients. American Heart Association (AHA) 2015 Scientific Sessions, November 7–11, 2015; Orlando, Florida.
  44. EM LonnJ BoschP Lopez-JaramilloJ ZhuL LiuP PaisR DiazD XavierK SliwaA DansBlood-pressure lowering in intermediate-risk persons without cardiovascular diseaseN Engl J Med2016374212009202010.1056/NEJMoa160017527041480
  45. IY ElgendyAA BavryY GongEM HandbergRM Cooper-DeHoffCJ PepineLong-term mortality in hypertensive patients with coronary artery disease: results from the US cohort of the International Verapamil (SR)/Trandolapril StudyHypertension20166851110111410.1161/HYPERTENSIONAHA.116.0785427620390
  46. OR BenaventeCS CoffeyR ConwitRG HartLA McClureLA PearcePE PergolaJM SzychowskiBlood-pressure targets in patients with recent lacunar stroke: the SPS3 randomised trialLancet2013382989150751510.1016/S0140-6736(13)60852-123726159
  47. M BrunstromB CarlbergEffect of antihypertensive treatment at different blood pressure levels in patients with diabetes mellitus: systematic review and meta-analysesBMJ2016352i71710.1136/bmj.i71726920333
  48. JA ArguedasV LeivaJM WrightBlood pressure targets for hypertension in people with diabetes mellitusCochrane Database Syst Rev201310008277
  49. D EttehadCA EmdinA KiranSG AndersonT CallenderJ EmbersonJ ChalmersA RodgersK RahimiBlood pressure lowering for prevention of cardiovascular disease and death: a systematic review and meta-analysisLancet20163871002295796710.1016/S0140-6736(15)01225-826724178
  50. S BangaloreS KumarI LobachFH MesserliBlood pressure targets in subjects with type 2 diabetes mellitus/impaired fasting glucose: observations from traditional and bayesian random-effects meta-analyses of randomized trialsCirculation2011123242799281010.1161/CIRCULATIONAHA.110.01633721632497
  51. G ReboldiG GentileF AngeliG AmbrosioG ManciaP VerdecchiaEffects of intensive blood pressure reduction on myocardial infarction and stroke in diabetes: a meta-analysis in 73,913 patientsJ Hypertens20112971253126910.1097/HJH.0b013e328346997621505352
  52. A SoliniE GrossmanWhat should be the target blood pressure in elderly patients with diabetes?Diabetes Care201639Suppl 2S234S24310.2337/dcS15-302727440838
  53. AV ChobanianGL BakrisHR BlackWC CushmanLA GreenJL Izzo JrDW JonesBJ MatersonS OparilJT Wright JrThe seventh report of the joint national committee on prevention, detection, evaluation, and treatment of high blood pressure: the JNC 7 reportJAMA2003289192560257210.1001/jama.289.19.256012748199
  54. Standards of medical care in diabetes—2010. Diabetes Care 2010; 33(Suppl 1):S11–S61.
  55. T KrauseK LovibondM CaulfieldT McCormackB WilliamsManagement of hypertension: summary of NICE guidanceBMJ2011343d489110.1136/bmj.d489121868454
  56. AS GoMA BaumanSM Coleman KingGC FonarowW LawrenceKA WilliamsE SanchezAn effective approach to high blood pressure control: a science advisory from the American Heart Association, the American College of Cardiology, and the Centers for Disease Control and PreventionJ Am Coll Cardiol201463121230123810.1016/j.jacc.2013.11.00724246165
  57. AJ ScheenRenin-angiotensin system inhibition prevents type 2 diabetes mellitus. Part 2. Overview of physiological and biochemical mechanismsDiabetes Metab200430649850510.1016/S1262-3636(07)70147-715671919
  58. UK Prospective Diabetes Study GroupEfficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39BMJ1998317716071372010.1136/bmj.317.7160.7139732338
  59. Heart Outcomes Prevention Evaluation Study InvestigatorsEffects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudyLancet2000355920025325910.1016/S0140-6736(99)12323-710675071
  60. J ChengW ZhangX ZhangF HanX LiX HeQ LiJ ChenEffect of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers on all-cause mortality, cardiovascular deaths, and cardiovascular events in patients with diabetes mellitus: a meta-analysisJAMA Intern Med2014174577378510.1001/jamainternmed.2014.34824687000
  61. LC van VarkM BertrandKM AkkerhuisJJ BrugtsK FoxJJ MouradE BoersmaAngiotensin-converting enzyme inhibitors reduce mortality in hypertension: a meta-analysis of randomized clinical trials of renin-angiotensin-aldosterone system inhibitors involving 158,998 patientsEur Heart J201233162088209710.1093/eurheartj/ehs07522511654
  62. PY PaiCH MuoFC SungHC HoYT LeeAngiotensin receptor blockers (ARB) outperform angiotensin-converting enzyme (ACE) inhibitors on ischemic stroke prevention in patients with hypertension and diabetes—a real-world population study in TaiwanInt J Cardiol201621511411910.1016/j.ijcard.2016.04.09627111172
  63. AH BarnettSC BainP BouterB KarlbergS MadsbadJ JervellJ MustonenAngiotensin-receptor blockade versus converting-enzyme inhibition in type 2 diabetes and nephropathyN Engl J Med2004351191952196110.1056/NEJMoa04227415516696
  64. WB WhiteRH CuadraE LloydGL BakrisS KupferEffects of azilsartan medoxomil compared with olmesartan and valsartan on ambulatory and clinic blood pressure in patients with type 2 diabetes and prediabetesJ Hypertens201634478879710.1097/HJH.000000000000083926766564
  65. S BangaloreR FakheriB TokluFH MesserliDiabetes mellitus as a compelling indication for use of renin angiotensin system blockers: systematic review and meta-analysis of randomized trialsBMJ2016352i43810.1136/bmj.i43826868137
  66. HH ParvingBM BrennerJJ McMurrayD de ZeeuwSM HaffnerSD SolomonN ChaturvediF PerssonAS DesaiM NicolaidesCardiorenal end points in a trial of aliskiren for type 2 diabetesN Engl J Med2012367232204221310.1056/NEJMoa120879923121378
  67. B DahlofPS SeverNR PoulterH WedelDG BeeversM CaulfieldR CollinsSE KjeldsenA KristinssonGT McInnesPrevention of cardiovascular events with an antihypertensive regimen of amlodipine adding perindopril as required versus atenolol adding bendroflumethiazide as required, in the Anglo-Scandinavian Cardiac Outcomes Trial-Blood Pressure Lowering Arm (ASCOT-BPLA): a multicentre randomised controlled trialLancet2005366948989590610.1016/S0140-6736(05)67185-116154016
  68. S BangaloreS ParkarE GrossmanFH MesserliA meta-analysis of 94,492 patients with hypertension treated with beta blockers to determine the risk of new-onset diabetes mellitusAm J Cardiol200710081254126210.1016/j.amjcard.2007.05.05717920367
  69. Tuomilehto J, Rastenyte D, Birkenhager WH, Thijs L, Antikainen R, Bulpitt CJ, Fletcher AE, Forette F, Goldhaber A, Palatini P, et al. Systolic Hypertension in Europe Trial Investigators. Effects of calcium-channel blockade in older patients with diabetes and systolic hypertension. N Engl J Med 1999; 340(9):677–684.
  70. E GrossmanFH MesserliAre calcium antagonists beneficial in diabetic patients with hypertension?Am J Med20041161444910.1016/j.amjmed.2003.07.01514706665
  71. BK DemarieGL BakrisEffects of different calcium antagonists on proteinuria associated with diabetes mellitusAnn Intern Med19901131298798810.7326/0003-4819-113-12-9872240922
  72. J OstergrenNR PoulterPS SeverB DahlofH WedelG BeeversM CaulfieldR CollinsSE KjeldsenA KristinssonThe Anglo-Scandinavian Cardiac Outcomes Trial: blood pressure-lowering limb: effects in patients with type II diabetesJ Hypertens200826112103211110.1097/HJH.0b013e328310e0d918854748
  73. BW JeffersJ RobbinsR BhambriD WajsbrotA systematic review on the efficacy of amlodipine in the treatment of patients with hypertension with concomitant diabetes mellitus and/or renal dysfunction, when compared with other classes of antihypertensive medicationAm J Ther201522532234110.1097/MJT.000000000000020225738570
  74. H NotoA GotoT TsujimotoM NodaEffect of calcium channel blockers on incidence of diabetes: a meta-analysisDiabetes Metab Syndr Obes2013625726110.2147/DMSO.S4976723935375
  75. AK GuptaB DahlofJ DobsonPS SeverH WedelNR PoulterDeterminants of new-onset diabetes among 19,257 hypertensive patients randomized in the Anglo-Scandinavian Cardiac Outcomes trial-blood pressure lowering arm and the relative influence of antihypertensive medicationDiabetes Care200831598298810.2337/dc07-176818235048
  76. JJ LinHC ChangCT KuHY ChenHydrochlorothiazide hypertension treatment induced metabolic effects in type 2 diabetes: a meta-analysis of parallel-design RCTsEur Rev Med Pharmacol Sci201620132926294627424996
  77. PK WheltonJ BarzilayWC CushmanBR DavisE IiamathiJB KostisFH LeenenGT LouisKL MargolisDE MathisClinical 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 Med2005165121401140910.1001/archinte.165.12.140115983290
  78. Cooperative Research GroupPrevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension Final results of the Systolic Hypertension in the Elderly Program (SHEP)Jama1991265243255326410.1001/jama.1991.034602400510272046107
  79. JB KostisAC WilsonRS FreudenbergerNM CosgroveSL PresselBR DavisLong-term effect of diuretic-based therapy on fatal outcomes in subjects with isolated systolic hypertension with and without diabetesAm J Cardiol2005951293510.1016/j.amjcard.2004.08.05915619390
  80. ALLHAT Collaborative Research GroupMajor cardiovascular events in hypertensive patients randomized to doxazosin vs chlorthalidone: the antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT)Jama2000283151967197510.1001/jama.283.15.196710789664
  81. JI BarzilayBR DavisJ BettencourtKL MargolisDC Goff JrH BlackG HabibA EllsworthRW ForceT WiegmannCardiovascular outcomes using doxazosin vs. chlorthalidone for the treatment of hypertension in older adults with and without glucose disorders: a report from the ALLHAT studyJ Clin Hypertens (Greenwich)20046311612510.1111/j.1524-6175.2004.03216.x15010644
  82. CS OxlundJE HenriksenL TarnowK SchousboeJ GramIA JacobsenLow dose spironolactone reduces blood pressure in patients with resistant hypertension and type 2 diabetes mellitus: a double blind randomized clinical trialJ Hypertens201331102094210210.1097/HJH.0b013e3283638b1a24107738
  83. G ShlomaiT SellaY SharabiA LeibowitzE GrossmanSerum potassium levels predict blood pressure response to aldosterone antagonists in resistant hypertensionHypertens Res201437121037104110.1038/hr.2014.7724671013
  84. Y SharabiE AdlerA ShamisN NussinovitchA MarkovitzE GrossmanEfficacy of add-on aldosterone receptor blocker in uncontrolled hypertensionAm J Hypertens200619775075510.1016/j.amjhyper.2005.11.01616814132
  85. M EpsteinAdding spironolactone to conventional antihypertensives reduces albuminuria in patients with diabetic nephropathyNat Clin Pract20062631031110.1038/ncpneph0192
  86. UF MehdiB Adams-HuetP RaskinGL VegaRD TotoAddition of angiotensin receptor blockade or mineralocorticoid antagonism to maximal angiotensin-converting enzyme inhibition in diabetic nephropathyJ Am Soc Nephrol200920122641265010.1681/ASN.200907073719926893
  87. GL BakrisR AgarwalJC ChanME CooperRT GansevoortH HallerG RemuzziP RossingRE SchmiederC NowackEffect of finerenone on albuminuria in patients with diabetic nephropathy: a randomized clinical trialJAMA2015314988489410.1001/jama.2015.1008126325557
  88. S KatoS MaruyamaH MakinoJ WadaD OgawaT UzuH ArakiD KoyaK KanasakiY OisoAnti-albuminuric effects of spironolactone in patients with type 2 diabetic nephropathy: a multicenter, randomized clinical trialClin Exp Nephrol20151961098110610.1007/s10157-015-1106-225795029
  89. S GwooYN KimHS ShinYS JungH RimPredictors of hyperkalemia risk after hypertension control with aldosterone blockade according to the presence or absence of chronic kidney diseaseNephron Clin Pract20141283–438138610.1159/00036913825572273
  90. G ShlomaiE KopelI GoldenbergE GrossmanTemporal trends in management of hypertension among Israeli adults, 2002–2010: lesson from the Acute Coronary Syndromes Israeli Survey (ACSIS)J Am Soc Hypertens2014829410210.1016/j.jash.2013.08.00424269166
  91. MA WeberK JamersonGL BakrisMR WeirD ZappeY ZhangB DahlofEJ VelazquezB PittEffects of body size and hypertension treatments on cardiovascular event rates: subanalysis of the ACCOMPLISH randomised controlled trialLancet2013381986653754510.1016/S0140-6736(12)61343-923219284
  92. G ReboldiG GentileF AngeliP VerdecchiaChoice of ACE inhibitor combinations in hypertensive patients with type 2 diabetes: update after recent clinical trialsVasc Health Risk Manag20095141142710.2147/VHRM.S423519475778
  93. G DerosaF QuerciI FranzettiP Dario RagonesiA D’AngeloP MaffioliComparison of the effects of barnidipine + losartan compared with telmisartan + hydrochlorothiazide on several parameters of insulin sensitivity in patients with hypertension and type 2 diabetes mellitusHypertens Res2015381069069410.1038/hr.2015.5725994603
  94. FD FuchsLC ScalaJF Vilela-MartinRB de MelloF MoselePK WheltonCE Poli-de-FigueiredoPR de AlencastroM GusEffectiveness of chlorthalidone/amiloride versus losartan in patients with stage I hypertension: results from the PREVER-treatment randomized trialJ Hypertens201634479880610.1097/HJH.000000000000083726938814
  95. Y HirakawaH ArimaR WebsterS ZoungasQ LiS HarrapL LishengP HametG ManciaN PoulterRisks associated with permanent discontinuation of blood pressure-lowering medications in patients with type 2 diabetesJ Hypertens201634478178710.1097/HJH.000000000000084126938813
  96. N SuY LiT XuL LiJS KwongH DuK RenQ LiJ LiX SunExenatide in obese or overweight patients without diabetes: a systematic review and meta-analyses of randomized controlled trialsInt J Cardiol201621929330010.1016/j.ijcard.2016.06.02827343423
  97. L BlondeR PencekL MacConellAssociation among weight change, glycemic control, and markers of cardiovascular risk with exenatide once weekly: a pooled analysis of patients with type 2 diabetesCardiovasc Diabetol2015141210.1186/s12933-014-0171-225645567
  98. MM SmitsMH MuskietL TonneijckT HoekstraMH KramerM DiamantDH van RaalteExenatide acutely increases heart rate in parallel with augmented sympathetic nervous system activation in healthy overweight malesBr J Clin Pharmacol201681461362010.1111/bcp.1284326609792
  99. SP MarsoGH DanielsK Brown-FrandsenP KristensenJF MannMA NauckSE NissenS PocockNR PoulterLS RavnLiraglutide and cardiovascular Outcomes in type 2 diabetesN Engl J Med2016375431132210.1056/NEJMoa160382727295427
  100. SP MarsoSC BainA ConsoliFG EliaschewitzE JodarLA LeiterI LingvayJ RosenstockJ SeufertML WarrenSemaglutide and cardiovascular outcomes in patients with type 2 diabetesN Engl J Med20163751834184410.1056/NEJMoa160714127633186
  101. GC MistryAL MaesKC LasseterMJ DaviesKM GottesdienerJA WagnerGA HermanEffect of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on blood pressure in nondiabetic patients with mild to moderate hypertensionJ Clin Pharmacol200848559259810.1177/009127000831688518353996
  102. RP MasonRF JacobR KubantA CiszewskiJJ CorbalanT MalinskiDipeptidyl peptidase-4 inhibition with saxagliptin enhanced nitric oxide release and reduced blood pressure and sICAM-1 levels in hypertensive ratsJ Cardiovasc Pharmacol201260546747310.1097/FJC.0b013e31826be20422932707
  103. L LiuJ LiuWT WongXY TianCW LauYX WangG XuY PuZ ZhuA XuDipeptidyl peptidase 4 inhibitor sitagliptin protects endothelial function in hypertension through a glucagon-like peptide 1-dependent mechanismHypertension201260383384110.1161/HYPERTENSIONAHA.112.19511522868389
  104. EK JacksonJH DubinionZ MiEffects of dipeptidyl peptidase iv inhibition on arterial blood pressureClin Exp Pharmacol Physiol2008351293410.1111/j.1440-1681.2007.04737.x18047624
  105. A MarneyS KunchakarraL ByrneNJ BrownInteractive hemodynamic effects of dipeptidyl peptidase-IV inhibition and angiotensin-converting enzyme inhibition in humansHypertension201056472873310.1161/HYPERTENSIONAHA.110.15655420679179
  106. Tang H, Cui W, Li D, Wang T, Zhang J, Zhai S, Song Y. Sodium-glucose co-transporter 2 inhibitors in addition to insulin therapy for management of type 2 diabetes mellitus: a meta-analysis of randomized controlled trials. Diabetes Obes Metab 2016.
  107. I TikkanenR ChiltonOE JohansenPotential role of sodium glucose cotransporter 2 inhibitors in the treatment of hypertensionCurr Opin Nephrol Hypertens2016252818610.1097/MNH.000000000000019926808705
  108. WL BakerLR SmythDM RicheEM BourretKW ChamberlinWB WhiteEffects of sodium-glucose co-transporter 2 inhibitors on blood pressure: a systematic review and meta-analysisJ Am Soc Hypertens20148426227510.1016/j.jash.2014.01.00724602971
  109. MA WeberTA MansfieldVA CainN IqbalS ParikhA PtaszynskaBlood pressure and glycaemic effects of dapagliflozin versus placebo in patients with type 2 diabetes on combination antihypertensive therapy: a randomised, double-blind, placebo-controlled, phase 3 studyLancet Diabetes Endocrinol20164321122010.1016/S2213-8587(15)00417-926620248
  110. MA WeberTA MansfieldF AlessiN IqbalS ParikhA PtaszynskaEffects of dapagliflozin on blood pressure in hypertensive diabetic patients on renin-angiotensin system blockadeBlood Press20162529310310.3109/08037051.2015.111625826623980
  111. I TikkanenK NarkoC ZellerA GreenA SalsaliUC BroedlHJ WoerleEmpagliflozin reduces blood pressure in patients with type 2 diabetes and hypertensionDiabetes Care201538342042810.2337/dc14-109625271206
  112. RR TownsendI MachinJ RenA TrujilloM KawaguchiU VijapurkarCV DamarajuM PfeiferReductions in mean 24-h ambulatory blood pressure after 6-week treatment with canagliflozin in patients with type 2 diabetes mellitus and hypertensionJ Clin Hypertens (Greenwich)2016181435210.1111/jch.1274726663712
  113. A RahmanY TakeshigeY FujisawaH HitomiD NakanoA NishiyamaOs 32-05 Effects of Sglt2 inhibitors on circadian rhythm of blood pressure in ratsJ Hypertens201634Suppl 1e39110.1097/01.hjh.0000501000.77551.8d27754220
  114. G MalihaRR TownsendSGLT2 inhibitors: their potential reduction in blood pressureJ Am Soc Hypertens201591485310.1016/j.jash.2014.11.00125537461
  115. B ZinmanC WannerJM LachinD FitchettE BluhmkiS HantelM MattheusT DevinsOE JohansenHJ WoerleEmpagliflozin, cardiovascular outcomes, and mortality in type 2 diabetesN Engl J Med2015373222117212810.1056/NEJMoa150472026378978
  116. B NealV PerkovicD ZeeuwKW MahaffeyG FulcherP SteinM DesaiW ShawJ JiangF VercruysseRationale, design, and baseline characteristics of the canagliflozin cardiovascular assessment study (CANVAS)—a randomized placebo-controlled trialAm Heart J2013166221722310.1016/j.ahj.2013.05.00723895803
  117. RK GhoshD BandyopadhyayA HajraM BiswasA GuptaCardiovascular outcomes of sodium-glucose cotransporter 2 inhibitors: a comprehensive review of clinical and preclinical studiesInt J Cardiol2016212293610.1016/j.ijcard.2016.02.13427017118
The underlying source XML for this text is taken from The license for the article is Creative Commons Attribution 4.0 International. The main subject has been identified as maturity-onset diabetes of the young.