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Blood pressure control in type 2 diabetic patients
Cardiovascular Diabetologyvolume 16, Article number: 3 (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 , 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 . Both hypertension and DM increase significantly with increasing age and their co-existence is highest in older individuals . 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 . 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 , left ventricular hypertrophy , congestive heart failure  and stroke  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 . 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 . The PROFESS results were different from those of the Perindopril Protection Against Recurrent Stroke Study Collaborative Group (PROGRESS) trial , 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  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 . 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 . 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) . The main benefit was observed in elderly subjects (>75 years) who constituted 28% of the study population . 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 . 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 . 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 . 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 . 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 . 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 . 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).
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 . 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 . 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 . 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 . 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 .
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 .
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  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 . 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 . 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 . 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 . 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 . The Canadian Hypertension Education Program (CHEP) suggests a target BP of <130/80 mmHg . 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) .
How to reach goal blood pressure in diabetics
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 .
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  and are particularly favorable among patients with albuminuria . 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  and in a recent real-world study ARBS were found to be more effective than ACEI in the prevention of stroke . 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 . In a recent study that compared the BP lowering effect of ARBs in diabetic patients, azilsartan medoxomil was more effective than olmesartan and valsartan . 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 . 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.
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 . 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 . 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 . 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 . Although non-dihydropyridines decrease urinary protein excretion and serve as an alternative in RAAS inhibitor-intolerant patients , 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 . This advantage of amlodipine was evident in the large group of 5137 diabetics included in the study . 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 . CCBs are ineffective for the prevention of diabetes in non-diabetic individuals . 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  due to their potential to negatively influence insulin resistance , 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 . 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.
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.
Low dose spironolactone was found to be effective in controlling BP in patients with hypertension and diabetes . The addition of spironolactone is particularly effective in those with serum potassium of <4.5 mmol/L . To prevent hyperkalemia thiazide or thiazide like diuretics should be continued when aldosterone antagonists are added . The addition of spironolactone to conventional antihypertensive treatment in diabetic patients was shown to reduce albuminuria  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 . 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 . It seems that aldosterone antagonists have a renoprotective effect that is independent of systemic hemodynamic alterations . 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 .
More than two-thirds of hypertensive individuals are inadequately controlled on mono therapy . 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 . The superiority of amlodipine over hydrochlorothiazide as an addition to benazepril disappeared in obese individuals . Combining a RAAS blocker with a CCB provides better renoprotection and leads to less ankle edema compared with a CCB alone . In addition, combining an ARB with a CCB was associated with improved insulin sensitivity compared with an ARB and a diuretic . 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 . 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 .
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  and this may result in BP elevation. In the recently published Liraglutide Effect and Action in Diabetes: Evaluation of Cardiovascular Outcome Results (LEADER) trial , 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 , 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  and yet others reported that they negate the hypotensive effects of ACEI . 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 . All three have been reported to significantly decrease systolic and diastolic BP by 3–5/2–3 mmHg . A meta-analysis published in 2014 reported that SGLT2 inhibitors decrease systolic and diastolic BP by 4 and 1.6 mmHg compared with placebo . 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  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. The Empagliflozin Cardiovascular Outcome Event Trial in Type 2 Diabetes Mellitus Patients (EMPA-REG) BP study  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  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 . 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 . 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 . 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)  and DECLARE-TIMI 55 (for dapagliflozin)  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.
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.
James PA, Oparil S, Carter BL, Cushman WC, Dennison-Himmelfarb C, Handler J, Lackland DT, LeFevre ML, MacKenzie TD, Ogedegbe O, et al. 2014 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). JAMA. 2014;311(5):507–20.
Weber MA, Schiffrin EL, White WB, Mann S, Lindholm LH, Kenerson JG, Flack JM, Carter BL, Materson BJ, Ram CV, et al. Clinical practice guidelines for the management of hypertension in the community: a statement by the American Society of Hypertension and the International Society of Hypertension. J Clin Hypertens (Greenwich). 2014;16(1):14–26.
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.
Ryden L, Grant PJ, Anker SD, Berne C, Cosentino F, Danchin N, Deaton C, Escaned J, Hammes HP, Huikuri H, et al. ESC 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 J. 2013;34(39):3035–87.
International Diabetes Federation Clinical Guidelines Task Force. Global Guideline for Type 2 Diabetes. info@idforg. 2012.
Disease Cardiovascular, Management Risk. Diabetes Care. 2016;39(Suppl 1):S60–71.
Leung AA, Nerenberg K, Daskalopoulou SS, McBrien K, Zarnke KB, Dasgupta K, Cloutier L, Gelfer M, Lamarre-Cliche M, Milot A, et al. Hypertension Canada’s 2016 Canadian Hypertension Education Program Guidelines for blood pressure measurement, diagnosis, assessment of risk, prevention, and treatment of hypertension. Can J Cardiol. 2016;32(5):569–88.
Sowers JR. Recommendations for special populations: diabetes mellitus and the metabolic syndrome. Am J Hypertens. 2003;16(11 Pt 2):41S–5S.
Crawford AG, Cote C, Couto J, Daskiran M, Gunnarsson C, Haas K, Haas S, Nigam SC, Schuette R. Prevalence of obesity, type II diabetes mellitus, hyperlipidemia, and hypertension in the United States: findings from the GE Centricity Electronic Medical Record database. Popul Health Manag. 2010;13(3):151–61.
Suh DC, Kim CM, Choi IS, Plauschinat CA, Barone JA. Trends in blood pressure control and treatment among type 2 diabetes with comorbid hypertension in the United States: 1988–2004. J Hypertens. 2009;27(9):1908–16.
Gyberg V, De Bacquer D, De Backer G, Jennings C, Kotseva K, Mellbin L, Schnell O, Tuomilehto J, Wood D, Ryden L, et al. Patients 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 Cardiology. Cardiovasc Diabetol. 2015;14:133.
Brown MJ, Castaigne A, de Leeuw PW, Mancia G, Palmer CR, Rosenthal T, Ruilope LM. Influence of diabetes and type of hypertension on response to antihypertensive treatment. Hypertension. 2000;35(5):1038–42.
Fogari R, Zoppi A, Malamani GD, Lazzari P, Destro M, Corradi L. Ambulatory blood pressure monitoring in normotensive and hypertensive type 2 diabetes. Prevalence of impaired diurnal blood pressure patterns. Am J Hypertens. 1993;6(1):1–7.
Grossman E, Shemesh J, Motro M. Hypertensive patients with diabetes mellitus have higher heart rate and pulse pressure. J Hypertens. 2002;20(Suppl 4):S60.
Ozawa M, Tamura K, Iwatsubo K, Matsushita K, Sakai M, Tsurumi-Ikeya Y, Azuma K, Shigenaga A, Okano Y, Masuda S, et al. Ambulatory blood pressure variability is increased in diabetic hypertensives. Clin Exp Hypertens. 2008;30(3):213–24.
Pop-Busui R. Cardiac autonomic neuropathy in diabetes: a clinical perspective. Diabetes Care. 2010;33(2):434–41.
Stevens SL, Wood S, Koshiaris C, Law K, Glasziou P, Stevens RJ, McManus RJ. Blood pressure variability and cardiovascular disease: systematic review and meta-analysis. BMJ. 2016;354:i4098.
Weitzman D, Chodick G, Shalev V, Grossman C, Grossman E. Prevalence and factors associated with resistant hypertension in a large health maintenance organization in Israel. Hypertension. 2014;64(3):501–7.
Assmann G, Schulte H. The Prospective Cardiovascular Munster (PROCAM) study: prevalence of hyperlipidemia in persons with hypertension and/or diabetes mellitus and the relationship to coronary heart disease. Am Heart J. 1988;116(6 Pt 2):1713–24.
Somaratne JB, Whalley GA, Poppe KK, ter Bals MM, Wadams G, Pearl A, Bagg W, Doughty RN. Screening for left ventricular hypertrophy in patients with type 2 diabetes mellitus in the community. Cardiovasc Diabetol. 2011;10:29.
Govind S, Saha S, Brodin LA, Ramesh SS, Arvind SR, Quintana M. Impaired 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 II. Am J Hypertens. 2006;19(8):851–7; discussion 858.
Grossman E, Messerli FH, Goldbourt U. High blood pressure and diabetes mellitus: are all antihypertensive drugs created equal? Arch Intern Med. 2000;160(16):2447–52.
Chao TF, Lip GY, Liu CJ, Tuan TC, Chen SJ, Wang KL, Lin YJ, Chang SL, Lo LW, Hu YF, et al. Validation of a modified CHA2DS2-VASc score for stroke risk stratification in Asian patients with atrial fibrillation: a Nationwide Cohort Study. Stroke. 2016;47(10):2462–9.
Rietbrock S, Heeley E, Plumb J, van Staa T. Chronic 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 scheme. Am Heart J. 2008;156(1):57–64.
Yang YW, Chen YH, Hsu CC, Lee CC, Kuo YH, Chuang HY, Hsieh TF. CHADS2 scores as a predictor of ischemic stroke in patients with peripheral artery disease. Mayo Clin Proc. 2016;91(1):45–50.
Lea JP, Nicholas SB. Diabetes mellitus and hypertension: key risk factors for kidney disease. J Natl Med Assoc. 2002;94(8 Suppl):7S–15S.
Knowler WC, Bennett PH, Ballintine EJ. Increased incidence of retinopathy in diabetics with elevated blood pressure. A 6-year follow-up study in Pima Indians. N Engl J Med. 1980;302(12):645–50.
Grossman E, Goldbourt U. Hypertension optimal treatment (HOT) trial. Lancet. 1998;352(9127):574–5.
Hansson L, Zanchetti A, Carruthers SG, Dahlof B, Elmfeldt D, Julius S, Menard J, Rahn KH, Wedel H, Westerling S. Effects of intensive blood-pressure lowering and low-dose aspirin in patients with hypertension: principal results of the Hypertension Optimal Treatment (HOT) randomised trial. HOT Study Group. Lancet. 1998;351(9118):1755–62.
UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. BMJ. 1998;317(7160):703–13.
Patel A, MacMahon S, Chalmers J, Neal B, Woodward M, Billot L, Harrap S, Poulter N, Marre M, Cooper M, et al. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular outcomes in patients with type 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. Lancet. 2007;370(9590):829–40.
Grossman E, Messerli FH. Management of blood pressure in patients with diabetes. Am J Hypertens. 2011;24(8):863–75.
Grossman Y, Shlomai G, Grossman E. Treating hypertension in type 2 diabetes. Expert Opin Pharmacother. 2014;15(15):2131–40.
Yusuf S, Teo KK, Pogue J, Dyal L, Copland I, Schumacher H, Dagenais G, Sleight P, Anderson C. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med. 2008;358(15):1547–59.
Yusuf S, Diener HC, Sacco RL, Cotton D, Ounpuu S, Lawton WA, Palesch Y, Martin RH, Albers GW, Bath P, et al. Telmisartan to prevent recurrent stroke and cardiovascular events. N Engl J Med. 2008;359(12):1225–37.
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.
Yusuf S, Teo K, Anderson C, Pogue J, Dyal L, Copland I, Schumacher H, Dagenais G, Sleight P. Effects of the angiotensin-receptor blocker telmisartan on cardiovascular events in high-risk patients intolerant to angiotensin-converting enzyme inhibitors: a randomised controlled trial. Lancet. 2008;372(9644):1174–83.
Cooper-DeHoff RM, Gong Y, Handberg EM, Bavry AA, Denardo SJ, Bakris GL, Pepine CJ. Tight blood pressure control and cardiovascular outcomes among hypertensive patients with diabetes and coronary artery disease. JAMA. 2010;304(1):61–8.
Cushman WC, Evans GW, Byington RP, Goff DC Jr, Grimm RH Jr, Cutler JA, Simons-Morton DG, Basile JN, Corson MA, Probstfield JL, et al. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med. 2010;362(17):1575–85.
Wright JT Jr, Williamson JD, Whelton PK, Snyder JK, Sink KM, Rocco MV, Reboussin DM, Rahman M, Oparil S, Lewis CE, et al. A randomized trial of intensive versus standard blood-pressure control. N Engl J Med. 2015;373(22):2103–16.
Williamson JD, Supiano MA, Applegate WB, Berlowitz DR, Campbell RC, Chertow GM, Fine LJ, Haley WE, Hawfield AT, Ix JH, et al. Intensive vs standard blood pressure control and cardiovascular disease outcomes in adults aged ≥75 years: a randomized clinical trial. JAMA. 2016;315(24):2673–82.
Weber MA, Bakris GL, Jamerson K, Weir M, Kjeldsen SE, Devereux RB, Velazquez EJ, Dahlof B, Kelly RY, Hua TA, et al. Cardiovascular events during differing hypertension therapies in patients with diabetes. J Am Coll Cardiol. 2010;56(1):77–85.
ACCORDION: long-term follow-up of ACCORD patients. American Heart Association (AHA) 2015 Scientific Sessions, November 7–11, 2015; Orlando, Florida.
Lonn EM, Bosch J, Lopez-Jaramillo P, Zhu J, Liu L, Pais P, Diaz R, Xavier D, Sliwa K, Dans A, et al. Blood-pressure lowering in intermediate-risk persons without cardiovascular disease. N Engl J Med. 2016;374(21):2009–20.
Elgendy IY, Bavry AA, Gong Y, Handberg EM, Cooper-DeHoff RM, Pepine CJ. Long-term mortality in hypertensive patients with coronary artery disease: results from the US cohort of the International Verapamil (SR)/Trandolapril Study. Hypertension. 2016;68(5):1110–4.
Benavente OR, Coffey CS, Conwit R, Hart RG, McClure LA, Pearce LA, Pergola PE, Szychowski JM. Blood-pressure targets in patients with recent lacunar stroke: the SPS3 randomised trial. Lancet. 2013;382(9891):507–15.
Brunstrom M, Carlberg B. Effect of antihypertensive treatment at different blood pressure levels in patients with diabetes mellitus: systematic review and meta-analyses. BMJ. 2016;352:i717.
Arguedas JA, Leiva V, Wright JM. Blood pressure targets for hypertension in people with diabetes mellitus. Cochrane Database Syst Rev. 2013;10:008277.
Ettehad D, Emdin CA, Kiran A, Anderson SG, Callender T, Emberson J, Chalmers J, Rodgers A, Rahimi K. Blood pressure lowering for prevention of cardiovascular disease and death: a systematic review and meta-analysis. Lancet. 2016;387(10022):957–67.
Bangalore S, Kumar S, Lobach I, Messerli FH. Blood pressure targets in subjects with type 2 diabetes mellitus/impaired fasting glucose: observations from traditional and bayesian random-effects meta-analyses of randomized trials. Circulation. 2011;123(24):2799–810.
Reboldi G, Gentile G, Angeli F, Ambrosio G, Mancia G, Verdecchia P. Effects of intensive blood pressure reduction on myocardial infarction and stroke in diabetes: a meta-analysis in 73,913 patients. J Hypertens. 2011;29(7):1253–69.
Solini A, Grossman E. What should be the target blood pressure in elderly patients with diabetes? Diabetes Care. 2016;39(Suppl 2):S234–43.
Chobanian AV, Bakris GL, Black HR, Cushman WC, Green LA, Izzo JL Jr, Jones DW, Materson BJ, Oparil S, Wright JT Jr, et al. The seventh report of the joint national committee on prevention, detection, evaluation, and treatment of high blood pressure: the JNC 7 report. JAMA. 2003;289(19):2560–72.
Standards of medical care in diabetes—2010. Diabetes Care 2010; 33(Suppl 1):S11–S61.
Krause T, Lovibond K, Caulfield M, McCormack T, Williams B. Management of hypertension: summary of NICE guidance. BMJ. 2011;343:d4891.
Go AS, Bauman MA, Coleman King SM, Fonarow GC, Lawrence W, Williams KA, Sanchez E. An 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 Prevention. J Am Coll Cardiol. 2014;63(12):1230–8.
Scheen AJ. Renin-angiotensin system inhibition prevents type 2 diabetes mellitus. Part 2. Overview of physiological and biochemical mechanisms. Diabetes Metab. 2004;30(6):498–505.
UK Prospective Diabetes Study Group. Efficacy of atenolol and captopril in reducing risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 39. BMJ. 1998;317(7160):713–20.
Heart Outcomes Prevention Evaluation Study Investigators. Effects of ramipril on cardiovascular and microvascular outcomes in people with diabetes mellitus: results of the HOPE study and MICRO-HOPE substudy. Lancet. 2000;355(9200):253–9.
Cheng J, Zhang W, Zhang X, Han F, Li X, He X, Li Q, Chen J. Effect 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-analysis. JAMA Intern Med. 2014;174(5):773–85.
van Vark LC, Bertrand M, Akkerhuis KM, Brugts JJ, Fox K, Mourad JJ, Boersma E. Angiotensin-converting enzyme inhibitors reduce mortality in hypertension: a meta-analysis of randomized clinical trials of renin-angiotensin-aldosterone system inhibitors involving 158,998 patients. Eur Heart J. 2012;33(16):2088–97.
Pai PY, Muo CH, Sung FC, Ho HC, Lee YT. Angiotensin 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 Taiwan. Int J Cardiol. 2016;215:114–9.
Barnett AH, Bain SC, Bouter P, Karlberg B, Madsbad S, Jervell J, Mustonen J. Angiotensin-receptor blockade versus converting-enzyme inhibition in type 2 diabetes and nephropathy. N Engl J Med. 2004;351(19):1952–61.
White WB, Cuadra RH, Lloyd E, Bakris GL, Kupfer S. Effects of azilsartan medoxomil compared with olmesartan and valsartan on ambulatory and clinic blood pressure in patients with type 2 diabetes and prediabetes. J Hypertens. 2016;34(4):788–97.
Bangalore S, Fakheri R, Toklu B, Messerli FH. Diabetes mellitus as a compelling indication for use of renin angiotensin system blockers: systematic review and meta-analysis of randomized trials. BMJ. 2016;352:i438.
Parving HH, Brenner BM, McMurray JJ, de Zeeuw D, Haffner SM, Solomon SD, Chaturvedi N, Persson F, Desai AS, Nicolaides M, et al. Cardiorenal end points in a trial of aliskiren for type 2 diabetes. N Engl J Med. 2012;367(23):2204–13.
Dahlof B, Sever PS, Poulter NR, Wedel H, Beevers DG, Caulfield M, Collins R, Kjeldsen SE, Kristinsson A, McInnes GT, et al. Prevention 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 trial. Lancet. 2005;366(9489):895–906.
Bangalore S, Parkar S, Grossman E, Messerli FH. A meta-analysis of 94,492 patients with hypertension treated with beta blockers to determine the risk of new-onset diabetes mellitus. Am J Cardiol. 2007;100(8):1254–62.
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.
Grossman E, Messerli FH. Are calcium antagonists beneficial in diabetic patients with hypertension? Am J Med. 2004;116(1):44–9.
Demarie BK, Bakris GL. Effects of different calcium antagonists on proteinuria associated with diabetes mellitus. Ann Intern Med. 1990;113(12):987–8.
Ostergren J, Poulter NR, Sever PS, Dahlof B, Wedel H, Beevers G, Caulfield M, Collins R, Kjeldsen SE, Kristinsson A, et al. The Anglo-Scandinavian Cardiac Outcomes Trial: blood pressure-lowering limb: effects in patients with type II diabetes. J Hypertens. 2008;26(11):2103–11.
Jeffers BW, Robbins J, Bhambri R, Wajsbrot D. A 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 medication. Am J Ther. 2015;22(5):322–41.
Noto H, Goto A, Tsujimoto T, Noda M. Effect of calcium channel blockers on incidence of diabetes: a meta-analysis. Diabetes Metab Syndr Obes. 2013;6:257–61.
Gupta AK, Dahlof B, Dobson J, Sever PS, Wedel H, Poulter NR. Determinants 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 medication. Diabetes Care. 2008;31(5):982–8.
Lin JJ, Chang HC, Ku CT, Chen HY. Hydrochlorothiazide hypertension treatment induced metabolic effects in type 2 diabetes: a meta-analysis of parallel-design RCTs. Eur Rev Med Pharmacol Sci. 2016;20(13):2926–46.
Whelton PK, Barzilay J, Cushman WC, Davis BR, Iiamathi E, Kostis JB, Leenen FH, Louis GT, Margolis KL, Mathis DE, et al. Clinical outcomes in antihypertensive treatment of type 2 diabetes, impaired fasting glucose concentration, and normoglycemia: antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT). Arch Intern Med. 2005;165(12):1401–9.
Cooperative Research Group. Prevention of stroke by antihypertensive drug treatment in older persons with isolated systolic hypertension Final results of the Systolic Hypertension in the Elderly Program (SHEP). Jama. 1991;265(24):3255–64.
Kostis JB, Wilson AC, Freudenberger RS, Cosgrove NM, Pressel SL, Davis BR. Long-term effect of diuretic-based therapy on fatal outcomes in subjects with isolated systolic hypertension with and without diabetes. Am J Cardiol. 2005;95(1):29–35.
ALLHAT Collaborative Research Group. Major cardiovascular events in hypertensive patients randomized to doxazosin vs chlorthalidone: the antihypertensive and lipid-lowering treatment to prevent heart attack trial (ALLHAT). Jama. 2000;283(15):1967–75.
Barzilay JI, Davis BR, Bettencourt J, Margolis KL, Goff DC Jr, Black H, Habib G, Ellsworth A, Force RW, Wiegmann T, et al. Cardiovascular outcomes using doxazosin vs. chlorthalidone for the treatment of hypertension in older adults with and without glucose disorders: a report from the ALLHAT study. J Clin Hypertens (Greenwich). 2004;6(3):116–25.
Oxlund CS, Henriksen JE, Tarnow L, Schousboe K, Gram J, Jacobsen IA. Low dose spironolactone reduces blood pressure in patients with resistant hypertension and type 2 diabetes mellitus: a double blind randomized clinical trial. J Hypertens. 2013;31(10):2094–102.
Shlomai G, Sella T, Sharabi Y, Leibowitz A, Grossman E. Serum potassium levels predict blood pressure response to aldosterone antagonists in resistant hypertension. Hypertens Res. 2014;37(12):1037–41.
Sharabi Y, Adler E, Shamis A, Nussinovitch N, Markovitz A, Grossman E. Efficacy of add-on aldosterone receptor blocker in uncontrolled hypertension. Am J Hypertens. 2006;19(7):750–5.
Epstein M. Adding spironolactone to conventional antihypertensives reduces albuminuria in patients with diabetic nephropathy. Nat Clin Pract. 2006;2(6):310–1.
Mehdi UF, Adams-Huet B, Raskin P, Vega GL, Toto RD. Addition of angiotensin receptor blockade or mineralocorticoid antagonism to maximal angiotensin-converting enzyme inhibition in diabetic nephropathy. J Am Soc Nephrol. 2009;20(12):2641–50.
Bakris GL, Agarwal R, Chan JC, Cooper ME, Gansevoort RT, Haller H, Remuzzi G, Rossing P, Schmieder RE, Nowack C, et al. Effect of finerenone on albuminuria in patients with diabetic nephropathy: a randomized clinical trial. JAMA. 2015;314(9):884–94.
Kato S, Maruyama S, Makino H, Wada J, Ogawa D, Uzu T, Araki H, Koya D, Kanasaki K, Oiso Y, et al. Anti-albuminuric effects of spironolactone in patients with type 2 diabetic nephropathy: a multicenter, randomized clinical trial. Clin Exp Nephrol. 2015;19(6):1098–106.
Gwoo S, Kim YN, Shin HS, Jung YS, Rim H. Predictors of hyperkalemia risk after hypertension control with aldosterone blockade according to the presence or absence of chronic kidney disease. Nephron Clin Pract. 2014;128(3–4):381–6.
Shlomai G, Kopel E, Goldenberg I, Grossman E. Temporal trends in management of hypertension among Israeli adults, 2002–2010: lesson from the Acute Coronary Syndromes Israeli Survey (ACSIS). J Am Soc Hypertens. 2014;8(2):94–102.
Weber MA, Jamerson K, Bakris GL, Weir MR, Zappe D, Zhang Y, Dahlof B, Velazquez EJ, Pitt B. Effects of body size and hypertension treatments on cardiovascular event rates: subanalysis of the ACCOMPLISH randomised controlled trial. Lancet. 2013;381(9866):537–45.
Reboldi G, Gentile G, Angeli F, Verdecchia P. Choice of ACE inhibitor combinations in hypertensive patients with type 2 diabetes: update after recent clinical trials. Vasc Health Risk Manag. 2009;5(1):411–27.
Derosa G, Querci F, Franzetti I, Dario Ragonesi P, D’Angelo A, Maffioli P. Comparison of the effects of barnidipine + losartan compared with telmisartan + hydrochlorothiazide on several parameters of insulin sensitivity in patients with hypertension and type 2 diabetes mellitus. Hypertens Res. 2015;38(10):690–4.
Fuchs FD, Scala LC, Vilela-Martin JF, de Mello RB, Mosele F, Whelton PK, Poli-de-Figueiredo CE, de Alencastro PR, RP ES, Gus M, et al. Effectiveness of chlorthalidone/amiloride versus losartan in patients with stage I hypertension: results from the PREVER-treatment randomized trial. J Hypertens. 2016;34(4):798–806.
Hirakawa Y, Arima H, Webster R, Zoungas S, Li Q, Harrap S, Lisheng L, Hamet P, Mancia G, Poulter N, et al. Risks associated with permanent discontinuation of blood pressure-lowering medications in patients with type 2 diabetes. J Hypertens. 2016;34(4):781–7.
Su N, Li Y, Xu T, Li L, Kwong JS, Du H, Ren K, Li Q, Li J, Sun X, et al. Exenatide in obese or overweight patients without diabetes: a systematic review and meta-analyses of randomized controlled trials. Int J Cardiol. 2016;219:293–300.
Blonde L, Pencek R, MacConell L. Association among weight change, glycemic control, and markers of cardiovascular risk with exenatide once weekly: a pooled analysis of patients with type 2 diabetes. Cardiovasc Diabetol. 2015;14:12.
Smits MM, Muskiet MH, Tonneijck L, Hoekstra T, Kramer MH, Diamant M, van Raalte DH. Exenatide acutely increases heart rate in parallel with augmented sympathetic nervous system activation in healthy overweight males. Br J Clin Pharmacol. 2016;81(4):613–20.
Marso SP, Daniels GH, Brown-Frandsen K, Kristensen P, Mann JF, Nauck MA, Nissen SE, Pocock S, Poulter NR, Ravn LS, et al. Liraglutide and cardiovascular Outcomes in type 2 diabetes. N Engl J Med. 2016;375(4):311–22.
Marso SP, Bain SC, Consoli A, Eliaschewitz FG, Jodar E, Leiter LA, Lingvay I, Rosenstock J, Seufert J, Warren ML, et al. Semaglutide and cardiovascular outcomes in patients with type 2 diabetes. N Engl J Med. 2016;375:1834–44.
Mistry GC, Maes AL, Lasseter KC, Davies MJ, Gottesdiener KM, Wagner JA, Herman GA. Effect of sitagliptin, a dipeptidyl peptidase-4 inhibitor, on blood pressure in nondiabetic patients with mild to moderate hypertension. J Clin Pharmacol. 2008;48(5):592–8.
Mason RP, Jacob RF, Kubant R, Ciszewski A, Corbalan JJ, Malinski T. Dipeptidyl peptidase-4 inhibition with saxagliptin enhanced nitric oxide release and reduced blood pressure and sICAM-1 levels in hypertensive rats. J Cardiovasc Pharmacol. 2012;60(5):467–73.
Liu L, Liu J, Wong WT, Tian XY, Lau CW, Wang YX, Xu G, Pu Y, Zhu Z, Xu A, et al. Dipeptidyl peptidase 4 inhibitor sitagliptin protects endothelial function in hypertension through a glucagon-like peptide 1-dependent mechanism. Hypertension. 2012;60(3):833–41.
Jackson EK, Dubinion JH, Mi Z. Effects of dipeptidyl peptidase iv inhibition on arterial blood pressure. Clin Exp Pharmacol Physiol. 2008;35(1):29–34.
Marney A, Kunchakarra S, Byrne L, Brown NJ. Interactive hemodynamic effects of dipeptidyl peptidase-IV inhibition and angiotensin-converting enzyme inhibition in humans. Hypertension. 2010;56(4):728–33.
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.
Tikkanen I, Chilton R, Johansen OE. Potential role of sodium glucose cotransporter 2 inhibitors in the treatment of hypertension. Curr Opin Nephrol Hypertens. 2016;25(2):81–6.
Baker WL, Smyth LR, Riche DM, Bourret EM, Chamberlin KW, White WB. Effects of sodium-glucose co-transporter 2 inhibitors on blood pressure: a systematic review and meta-analysis. J Am Soc Hypertens. 2014;8(4):262–75.
Weber MA, Mansfield TA, Cain VA, Iqbal N, Parikh S, Ptaszynska A. Blood 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 study. Lancet Diabetes Endocrinol. 2016;4(3):211–20.
Weber MA, Mansfield TA, Alessi F, Iqbal N, Parikh S, Ptaszynska A. Effects of dapagliflozin on blood pressure in hypertensive diabetic patients on renin-angiotensin system blockade. Blood Press. 2016;25(2):93–103.
Tikkanen I, Narko K, Zeller C, Green A, Salsali A, Broedl UC, Woerle HJ. Empagliflozin reduces blood pressure in patients with type 2 diabetes and hypertension. Diabetes Care. 2015;38(3):420–8.
Townsend RR, Machin I, Ren J, Trujillo A, Kawaguchi M, Vijapurkar U, Damaraju CV, Pfeifer M. Reductions in mean 24-h ambulatory blood pressure after 6-week treatment with canagliflozin in patients with type 2 diabetes mellitus and hypertension. J Clin Hypertens (Greenwich). 2016;18(1):43–52.
Rahman A, Takeshige Y, Fujisawa Y, Hitomi H, Nakano D, Nishiyama A. Os 32-05 Effects of Sglt2 inhibitors on circadian rhythm of blood pressure in rats. J Hypertens. 2016;34(Suppl 1):e391.
Maliha G, Townsend RR. SGLT2 inhibitors: their potential reduction in blood pressure. J Am Soc Hypertens. 2015;9(1):48–53.
Zinman B, Wanner C, Lachin JM, Fitchett D, Bluhmki E, Hantel S, Mattheus M, Devins T, Johansen OE, Woerle HJ, et al. Empagliflozin, cardiovascular outcomes, and mortality in type 2 diabetes. N Engl J Med. 2015;373(22):2117–28.
Neal B, Perkovic V, Zeeuw D, Mahaffey KW, Fulcher G, Stein P, Desai M, Shaw W, Jiang J, Vercruysse F, et al. Rationale, design, and baseline characteristics of the canagliflozin cardiovascular assessment study (CANVAS)—a randomized placebo-controlled trial. Am Heart J. 2013;166(2):217–23.
Ghosh RK, Bandyopadhyay D, Hajra A, Biswas M, Gupta A. Cardiovascular outcomes of sodium-glucose cotransporter 2 inhibitors: a comprehensive review of clinical and preclinical studies. Int J Cardiol. 2016;212:29–36.
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.
The authors declare that they have no competing interests.
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