hypertension and diabetes

www.medscape.com 

Blood Pressure and DiabetesVicious TwinsNeel P Chokshi, Ehud Grossman, Franz H Messerli

Heart. 2013;99(8):577-585. 

EpidemiologyHypertension (HTN) and diabetes mellitus (DM) have become increasingly prevalent globally. As of the year 2000, an estimated 972 million individuals worldwide (26%) had HTN—a number that is projected to rise to 1.56 billion (29%) by 2025.w1 DM affects an estimated 285 million individuals (6%) globally with a projection of 439 million adults (8%) being affected by 2030.w2 HTN is more common in individuals with DM than in the general population, with estimates of the prevalence of HTN in DM ranging from 40–80%.w3 Patients with DM are more likely to develop HTN with the incidence of HTN being twofold higher in those with DM relative to similar aged individuals without DMw4 (see summary in figure 1).

Figure 1.

A summary of the incidence of diabetes, hypertension, and clinical manifestations. BP, blood pressure; CHD, coronary heart disease; CHF, congestive heart failure; DM, diabetes mellitus; HTN, hypertension; LVH, left ventricular hypertrophy.

Patients with DM carry a risk of cardiovascular (CV) death similar to that of patients with a previous myocardial infarction.[1] In a recent study based on the Framingham cohort, the population attributable risk from HTN in patients with DM was 30% for all cause death and 25% for any CV event. Conversely, after adjusting for HTN, the population attributable risk from DM was 7% for all cause death and 9% for any CV event in the group. The

findings reaffirmed those of previous studies that the presence of HTN is likely the strongest driver of CV outcomes in diabetic patients.[2]

Despite increasing evidence of the contribution of blood pressure (BP) to CV risk in DM, diabetic patients are less likely to achieve target BPs relative to non-DM patients.[3]

Clinical ManifestationsBP Characteristics in DM

Patients with diabetes have more isolated systolic HTN and, because of autonomic neuropathy, experience less reduction in nocturnal BP and higher baseline heart rates than their non-diabetic counterparts.[3] w5–w8 In addition, those patients with diabetes have enhanced variability in BP; they are prone to develop orthostatic hypotension, and their HTN is more resistant to treatment.[3] w6

BP control in these patients presents a great challenge, because the target BP is quite low and the response to treatment is often poor.[3]

Coronary Heart Disease and Cardiomyopathy

Coronary heart disease (CHD) is much more common in diabetic hypertensive patients than in patients suffering from HTN or diabetes alone.w9 It has recently been shown in the Framingham cohort that the incidence of CHD and CV events was significantly higher in diabetic patients with HTN than in those without HTN[2] (figure 2).

Figure 2.

The impact of hypertension (HTN) on cardiovascular (CV) outcomes in patients with incident diabetes mellitus (DM) in the Framingham cohort. Patients with both DM and HTN were at greater risk for CV events. After correcting for other risk factors, HTN accounted for a greater portion of the CV risk than DM.6 Any CV event=myocardial infarction+stroke+congestive heart failure (CHF).

The coexistence of diabetes and HTN results in a more severe cardiomyopathy than would be expected with either disease alone.w10 Clinical studies with echocardiography have shown increased left ventricular mass in diabetic hypertensive patients.w11 w12 Grossman et al showed that the prevalence of left ventricular hypertrophy (LVH) was 72% in diabetic hypertensive patients and only 32% in non-diabetic hypertensive patients with a comparable degree of HTN.w11 As it is known that the presence of LVH predisposes to a higher number of CV events, this finding may partially account for the increased morbidity and mortality seen in patients with both DM and HTN. This increase in congestive heart failure (CHF) and CV events was also demonstrated in the Framingham study[2] (figure 2).

Cerebrovascular Disease

HTN, mainly systolic, is strongly and directly related to stroke in all age groups.w13 The presence of DM more than doubles the risk of stroke in patients with HTN.w14 Lowering BP in patients with HTN and DM reduces the risk of stroke by 44%.[4]

Peripheral Arterial Disease

DM is a well established independent risk factor for the development of peripheral arterial disease (PAD), increasing the risk by two- to fourfold. The association between HTN and PAD is less clear with conflicting results among studies. In the Framingham Heart Study, the risk of developing intermittent claudication was increased in those subjects with HTN, with the risk being proportional to the severity of BP.w15 The strong correlation with DM alone with the added suggested risk from HTN likely predisposes patients further to developing PAD.w16

Microvascular Effects

DM is one of the leading causes of end stage renal disease (ESRD). HTN is a well defined risk factor for ESRD, and accounts for 27% of all the ESRD cases in the USA, and 33.4% of cases among African Americans.w17 BP control can slow the progression of renal disease in patients with DM.w18 DM may cause diabetic retinopathy, and HTN accelerates the development of diabetic retinopathy.w19

Screening for CV DiseaseAs patients with both DM and HTN are at increased risk for CV events, the question arises over if and when it is appropriate to screen asymptomatic patients for evidence of CHD. The primary consideration of whether to perform a diagnostic study in these patients should be whether it will alter the clinical management.

Coronary artery calcification (CAC), as measured by CT, is a reliable marker of the total burden of coronary atherosclerosis.w20 In asymptomatic patients, the presence of CAC indicates subclinical coronary disease and has been correlated with future CV events.[5] While some would argue that the presence of DM is a CHD risk equivalent, CAC scanning may serve as a means to stratify patients into high and low risk for CV events. A recent study showed that patients with DM and HTN with CAC experienced higher rates of CV events over both short (3 years) and long term (15 years) follow-up.[6] Lack of CAC in these patients suggests low CV risk. Screening for CAC may therefore be justified in diabetic hypertensive patients.

Indeed the recent American College of Cardiology/American Heart Association (ACC/AHA) guideline for assessment of CV risk in asymptomatic adults states that it is reasonable to consider CAC scanning in asymptomatic diabetics above 40 years of age.w21 In patients with CAC scores above 400, it is reasonable to refer them for stress testing to assess the functional and prognostic significance of the detected coronary atherosclerosis. However, routine stress testing in asymptomatic patients with DM and HTN is not recommended.

In addition, ankle–brachial index and carotid Doppler studies are considered to be reasonable tests in asymptomatic patients. Transthoracic echocardiography can be considered if LVH is suspected, but should largely be reserved for patients in whom it would have an impact on their clinical management. summarises applicable ACC/AHA guidelines.

Table 1.  Applicable tools for risk assessment in asymptomatic patients with diabetes mellitus and hypertension based on ACC/AHA guidelines.w19

ClassLevel of evidence

Urinalysis to detect microalbuminuria IIa B

Resting ECG IIa C

Ankle–brachial index IIa B

Carotid artery intima–media thickness IIa B

Exercise ECG (for assessment of exercise capacity) IIb B

Resting echocardiography (to detect left ventricular hypertrophy) IIb B

Coronary artery calcium scan (in those >40 years of age or low-intermediate risk IIa, IIb B,B

patients)

Stress myocardial perfusion imaging (in those at high risk of CHD, such as CAC score >400)

IIb C

ACC, American College of Cardiology; AHA, American Heart Association; CAC, coronary artery calcification; CHD, coronary heart disease.

TreatmentTarget Blood Pressure

The current guidelines recommend lowering BP to <130/80 mm Hg in patients with DM, although this is not grounded on evidence.[7] This is based on the higher CV risk in these patients and data suggesting improved outcomes with aggressive lowering of BP. However, more recent studies have shown the potential for harm from BP reduction that is too aggressive.

In the Action to Control Cardiovascular Risk in Diabetes (ACCORD) BP trial, diabetics were randomised to intensive HTN treatment targeting a systolic BP < 120 mm Hg or to standard therapy targeting a systolic BP < 140 mm Hg. The intensive treatment group achieved a systolic BP of 119 mm Hg compared to 139 mm Hg in the standard group. Despite the large difference in systolic BP, the composite of non-fatal myocardial infarction, non-fatal stroke or CV death was the same in the two groups. The incidence of serious adverse events attributable to antihypertensive treatment, such as hypotension, bradycardia, hyperkalaemia, and renal deterioration occurred more frequently in the intensive treatment group than in the standard treatment group (3.3% vs 1.3%, p<0.001). Of note, intensive treatment was associated with a lower stroke rate. In an additional analysis, intensive BP control showed no reduction in the progression of diabetic retinopathy.[8 w22]

Similarly, in the International Verapamil SR-Trandolapril (INVEST) study, 6400 patients with DM were divided into three groups ('not-controlled', 'usual', and 'tight control') according to mean systolic BP achieved. [9] During the follow-up, the rate of primary outcome was 19.8% in the 'not-controlled' group and 12.6% and 12.7% in the 'usual' and 'tight control' groups, respectively (p<0.001). The rate of all cause mortality was significantly higher in the tight control group than in the usual control group (11% vs 10.2%; p=0.035). During the extended follow-up, tight BP control was associated with an increase in mortality rate as compared to usual BP control (adjusted hazard ratio 1.15, 95% CI 1.01 to 1.32; p=0.04). The authors also examined the effects of very low BP and demonstrated a systolic BP < 115 mm Hg to be associated with an increased risk of mortality. The study had some limitations in that: (1) it was an observational analysis of a randomised trial; (2) it included only patients with CHD; and (3) the division of patient groups was according to the BP achieved. Nevertheless, the results of this study suggest that aggressive BP lowering may be detrimental.

A recent meta-analysis examining BP targets in patients with DM or impaired fasting glucose has further endorsed this concept of the J shape relation between BP and CV events. After reviewing 1330 randomised antihypertensive treatment trials, 13 studies including nearly 38 000 patients were included in the final analysis. The study showed that achieving a systolic BP < 135 mm Hg was associated with a 10% reduction in all cause mortality, a 17% reduction in stroke, and a 20% increase in serious adverse affects compared with a systolic BP goal < 140 mm Hg (see figure 3 for a summary of trials and outcomes). A systolic BP <130 mm Hg was associated with even greater reduction in stroke rates but no significant benefits in other outcomes. Lowering BP to <130 mm Hg, however, was related to a 40% increase in serious adverse events. Based on these findings, it seems the benefits of intensive BP control (systolic <130 mm Hg) vary based on the target organ in question and must be weighed against adverse effects.[10]

Figure 3.

Results from a meta-analysis examining intensive versus standard blood pressure control and (A) all cause mortality and (B) cardiovascular mortality.10 SBP, systolic blood pressure.

Although the ideal target BP in patients with DM has yet to be established, the previously cited target of <130/80 mm Hg is not supported by recent evidence; we recommend a target BP of 135/85 mm Hg. Lower BP levels may be appropriate in selected patients with diabetes who also have proteinuria, but this should be documented in prospective trials.w23

Non-pharmacologic Therapy

Non-pharmacologic therapy such as weight loss, low sodium diet, and regular exercise has beneficial effects in patients with HTN, those with DM, and possibly also in those who have both these disorders.w24 However, there is no good study showing that weight loss per se will decrease BP in the long run.

An initial trial of non-pharmacologic therapy for 3–6 months may be reasonable in patients with diabetes in whom BP levels are 135–139/85–89 mm Hg. However, where the BP is ≥140/90 mm Hg, drug treatment should be initiated along with non-pharmacologic therapy.w24

Drug Treatment

Blockers of the Renin–Angiotensin–Aldosterone System. Blockers of renin–angiotensin–aldosterone system (RAAS), either angiotensin converting enzyme (ACE) inhibitors or angiotensin receptor blockers (ARBs), have become the cornerstone of the management of diabetic patients with HTN. In high risk patients with DM, ACE inhibitors reduced CV related morbidity and mortality.[11] Both these classes of drugs have beneficial effects on surrogate end points such as decreasing proteinuria and slowing the decline in renal function.[11 w25–w31] Despite the theoretical advantage of blockers of RAAS over other antihypertensive agents, there is no solid evidence that they are indeed superior to other agents in these patients.[4] Nevertheless, they are considered to be the drugs of choice for patients with DM because these patients are at a high risk for CV diseases.

Unlike ACE inhibitors and ARBs, which increase plasma renin activity, direct renin inhibitors such as aliskiren reduce plasma renin activity. While this class of medication has shown some benefit in surrogate end points such as proteinuria, there are no studies to demonstrate a reduction in CV events with this class. On the contrary, the recent Aliskiren Trial In Type 2 diabetes Using cardio-renal Disease Endpoints (ALTITUDE) was terminated early because of a higher rate of non-fatal stroke, renal complications, hyperkalaemia, and hypotension in patients receiving aliskiren in addition to ACE inhibitor or ARB.w32 Until further investigation of this drug is undertaken, its use in combination with ACE inhibitors or ARB is not recommended.

Blockers of the RAAS may cause hyperkalemia and renal deterioration mainly in patients with DM who have bilateral renal artery stenosis or renal failure, and in those with hyporeninaemic hypoaldosteronism. These side effects usually occur shortly after drug initiation and, therefore, close monitoring of kidney functions and electrolytes is required soon after drug initiation. It is important to note that a small increase in creatinine (up to 20–25%) is acceptable after initiation of treatment with a RAAS blocker, and is even deemed to be 'nephroprotective'.w18 Hyperkalaemia and deterioration in renal function can be triggered by unforeseeable factors such as dehydration and the use of concomitant drugs such as non-steroidal anti-inflammatory drugs and intravenous contrast. Importantly, as the disease and renal failure progress, a dose of an ACE inhibitor that was previously well tolerated may become inappropriate.

In most patients with HTN and DM, BP is not adequately controlled with any of the RAAS blockers as monotherapy. In the Losartan Intervention For Endpoint reduction in hypertension study (LIFE), only 9% of the patients with DM remained on monotherapy with losartan.w33 Indeed, monotherapy with any drug class rarely achieves the target BP in these patients; most often, two or more drugs need to be prescribed together.w18

Combinations of RAAS Blockers. Combination therapy with ACE inhibitors and ARBs has little additive effect on BP, but may be synergistic with regard to reducing microalbuminuria.w34 Recently, the Ongoing Telmisartan Alone and in Combination with Ramipril Global End-point Trial (ONTARGET), showed that, in high risk patients, combination therapy with telmisartan and ramipril was more effective than ramipril alone in reducing BP. Importantly, combination therapy did not reduce primary end points and was associated with an increase in

hypotension, syncope, and renal failure.[12] w35 On this basis, dual therapy with an ARB and an ACE inhibitor is not recommended in patients with DM plus HTN.

Calcium Antagonists. Calcium antagonists are efficacious antihypertensive agents, and have been shown to be at least as beneficial in patients with DM plus HTN as conventional treatment.[13] Non-dihydropyridine calcium antagonists such as verapamil and diltiazem seem to be superior to dihydropyridines because they decrease proteinuria more effectively and almost to the same extent as ACE inhibitors.w36 However, most long term clinical trials in HTN showing the benefit of calcium antagonists utilised the dihydropyridine drug amlodipine.[14 w37 w38] We showed that, compared to conventional treatment in patients with DM and HTN, calcium antagonists produce similar effects on CHD, less reduction in the risk of CHF, and a somewhat greater reduction in the risk of stroke.[13] Similarly, when compared to RAAS blockers, calcium antagonists were less effective in preventing heart failure, but the two classes of drugs had similar beneficial effects regarding the risk of stroke, CHD, and total mortality. In the Anglo-Scandinavian Cardiac Outcomes Trial (ASCOT), amlodipine based treatment reduced the incidence of total CV events and procedures by 14% as compared to the atenolol based regimen in diabetic hypertensive patients.w39 Calcium antagonists are very effective in lowering BP as well as BP variability, regardless of comorbidities, concomitant medications, salt intake, race, age, diet, and activity of RAAS. They are also metabolically neutral and well tolerated. In order to achieve target BP values, a calcium antagonist is commonly needed.

β-blockers. As a general rule, β-blockers should not be used as first line therapy in patients with DM and HTN, but may be useful as add-ons in selected patients. Enhanced sympathetic activity is commonly associated with diabetes and CHD; both these conditions are favourably influenced by a β-blocker. In a recent meta-analysis, Law et al showed that β-blockers have a special effect (over and above that relating to BP reduction) in preventing recurrent CHD events in patients with a history of CHD.w40 In the UK Prospective Diabetes Study (UKPDS), outcomes were similar when patients were randomised either to a β-blocker or to an ACE inhibitor.w41

However, in this study, the risk of CHD was not significantly reduced by either one of the two drug classes.

β-blockers are not considered ideal for use in patients with DM and HTN because of their unfavourable effect on metabolic parameters. β-blockers have been shown to increase triglycerides, lower high density lipoprotein cholesterol, worsen insulin resistance, lead to weight gain, and mask hypoglycaemia.[15 w42–w44] As a class, β-blockers have never been shown to reduce the rate of occurrence of heart attacks and strokes in uncomplicated HTN.w45 In the ASCOT study, an atenolol based regimen prevented fewer CV events than an amlodipine based regimen in the whole group as well as in a subset of patients with diabetes.w37 w39

As a general rule, the use of β-blockers in patients with diabetes should be restricted to those in whom there are indications for this drug class. These indications include symptoms of sympathetic excess or tachycardia, the presence of CHD or CHF, or the need for an add-on therapy for uncontrolled HTN.

Diuretics. Thiazide diuretics have been, are, and will be a major component of the antihypertensive drug arsenal. In the 13 100 patients with diabetes who participated in the Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT), chlorthalidone was shown to be as effective as a calcium antagonist and an ACE inhibitor in reducing CV related morbidity and mortality.[16] The trial also showed chlorthalidone to be superior to the α-blocker doxazosin in preventing stroke, and to the ACE inhibitor lisinopril in preventing stroke in black patients.w39 w46 Several placebo controlled studies have demonstrated the efficacy of diuretics in reducing CV related morbidity and mortality in the elderly.w47 w48 In the Systolic Hypertension in the Elderly Programme (SHEP), in elderly patients (age >60 years) with isolated systolic HTN, chlorthalidone reduced the rate of total stroke by 36%, the rate of major CV events by 32%, and the rate of all cause mortality by 13%.w47 The beneficial effects of chlorthalidone were the same in patients with or without diabetes.w49 In the recent Hypertension in the Very Elderly Trial (HYVET), indapamide—a thiazide-like diuretic—reduced the rate of stroke, CHD, CHF, and all cause mortality in very elderly hypertensive patients.w48 It would therefore appear that, at least in elderly patients, chlorthalidone or indapamide should remain in consideration.

Diuretics have also been shown to have negative effects on metabolic parameters relating to insulin resistance and electrolytes.w50 w51 However, a recent long term follow-up (15 years) of the SHEP study showed no diabetogenic impact of chlorthalidone on CV morbidity and mortality.w52 Loop diuretics may have fewer diabetogenic effects than thiazides, but there is little reason for their use in patients with diabetes unless renal failure dictates the decision. Thiazides may induce hyponatraemia, which appears to be particularly common in elderly women.w53 This side effect can be prevented by the use of a low-medium dose of diuretic and by instructing patients to limit their fluid intake. Hyperuricaemia and gout are also common clinical complications of thiazides. As with most drug classes used in HTN, the long term safety of diuretics remains uncertain.

Therefore, in patients with DM plus HTN, diuretics should be used in low doses and in combination with other drugs such as ACE inhibitors or ARBs.

Aldosterone Antagonists. Aldosterone antagonists such as spironolactone and eplerenone can be exceedingly helpful in selected patients.[17 w54] These drugs have been shown to reduce target organ disease and surrogate end points such as microproteinuria and LVH.w55 The addition of spironolactone to a regimen that includes maximal ACE inhibition affords greater renoprotection than the addition of the ARB losartan in diabetic nephropathy.[18] Spironolactone is particularly effective in hypertensive patients with low serum potassium concentrations (<4 mmol/l) and in those with aldosterone breakthrough.w54 w56 Eplerenone may be considered in patients when possible, as it has a more favourable side effect profile by causing less gynaecomastia.w57 Given that patients with DM plus HTN are prone to hyperkalaemia, these drugs should be dosed cautiously with frequent monitoring of serum potassium and creatinine concentrations.

α-blockers. As a class, α-blockers are not recommended for initial treatment in uncomplicated HTN. However, they may be useful agents as a third or fourth step therapy, and in patients with symptoms of prostatism.w46

Combination Therapy

In this population, achieving BP goals with monotherapy is difficult, and most will require a combination of two or three drugs to reach targets. Therefore, the main question should be: which combination is preferable? A blocker of the RAAS, either an ACE inhibitor or an ARB, represents the cornerstone of the antihypertensive arsenal for patients with DM plus HTN. As a second step, the American Diabetes Association suggests a low dose of a thiazide diuretic.w24 However, the recent Avoiding CV Events through combination Therapy in Patients Living with Systolic Hypertension (ACCOMPLISH) trial showed that combination therapy with the ACE inhibitor benazepril and hydrochlorothiazide was less effective in reducing primary end points than combination therapy with benazepril and amlodipine.[14] Moreover, treatment with benazepril plus amlodipine attenuated the progression of nephropathy.w58 In the 6946 diabetics included in ACCOMPLISH, combination therapy with benazepril plus amlodipine was more effective than benazepril plus hydrochlorothiazide in preventing events (hazard ratio 0.79, 95% CI 0.68 to 0.92, p=0.003).[19] In light of these results, we suggest that a calcium antagonist—that is, amlodipine—be prescribed in addition to a RAAS blocker unless there is a clear indication, such as CHF, for diuretics.

Many patients will require triple therapy consisting of a RAAS blocker, a calcium antagonist, and low dose chlorthalidone. A β-blocker can be used in patients with CHD, CHF, or in patients with tachycardia. Aldosterone antagonists should be considered in patients with low serum potassium concentrations (<4 mmol/l). In order to prevent hyperkalaemia, a thiazide diuretic should be continued and serum potassium should be monitored frequently, especially in patients with chronic renal failure. α-blockers and/or anti-adrenergic agents can be considered for patients requiring treatment with four drugs. Combination therapy with ACE inhibitor and ARB, or direct renin inhibitor with ACE inhibitor or ARB, is not recommended. A complete algorithm for treatment is shown in figure 4.

Figure 4.

An approach to the medical treatment of hypertension in patients with diabetes mellitus. ACEI, angiotensin converting enzyme inhibitor; ARB, angiotensin receptor blocker; BP, blood pressure; CCB, calcium channel blocker; HR, heart rate; K, potassium.

Furthermore, in order to minimise the number of medications and improve patient compliance, fixed dose combinations of drugs may be helpful.

Resistant HTN

Patients who have DM alongside HTN are more resistant to antihypertensive treatment than those with HTN alone. Also, given that the target BP in patients having both diseases simultaneously is lower than in those with HTN alone, the rate of BP control is generally lower in patients with diabetes plus HTN. In the ACCOMPLISH trial, ~75% of HTN patients achieved the BP target, whereas only ~45% of patients with concomitant diabetes achieved the BP target. When resistant HTN is suspected, 24 h ambulatory BP monitoring should be performed to exclude a white coat effect. If 24 h ambulatory BP monitoring confirms the diagnosis of resistant HTN, treatable secondary causes such as renal artery stenosis, primary hyperaldosteronism, pheochromocytoma, sleep apnoea, and drug induced HTN should be excluded. After excluding secondary causes, weight loss, sodium restriction, and regular physical exercise should be encouraged. We recommend intensification of treatment, where necessary, mainly by increasing the diuretic dose and adding an aldosterone antagonist if required.

Renal Denervation. Recent studies have shown endovascular renal sympathetic denervation to be of great promise in treating patients with resistant HTN and diabetes. Increased sympathetic activation is a common feature in the pathogenesis of both resistant HTN and insulin resistance.w59 In this procedure, the sympathetic innervation to the kidneys is non-selectively ablated via the renal arteries using a catheter based technique. In SIMPLICITY HTN-2, patients with resistant HTN were randomised to endovascular renal sympathetic ablation with medical treatment versus medical treatment alone.[20] At 6 months follow-up, the ablation group showed an average of 32/12 mm Hg reduction in systolic/diastolic pressures relative to 1/0 mm Hg in the control group. The impact of renal denervation on glucose metabolism in patients with resistant HTN has also shown benefit. In a pilot study by Mahfoud et al, at 3 months follow-up the procedure showed a significant reduction in fasting glucose values, serum insulin values, and improvement in oral glucose tolerance testing in addition to a large reduction in BP (−32 mm Hg/−12 mm Hg).w60 The procedure is available in Europe and is investigational in the USA with further trials currently underway.

Adjunctive Treatment

When event rates are scrutinised in patients with DM among the cohorts in randomised trials,w61 it becomes increasingly clear that statins are efficacious in reducing adverse events in this high risk population. The recent guidelines of the American Diabetes Association state that lipid lowering treatment should be used regardless of baseline low density lipoprotein cholesterol values, in all patients >40 years of age with type 2 diabetes and one or more CV risk factors including HTN.w24

Sidebar 1Blood Pressure and Diabetes: Key Points

Hypertension (HTN) and diabetes mellitus (DM) are frequently coexisting disease entities, with DM patients more than twice as likely to develop HTN relative to those without DM.

While both diseases independently increase the risk for development of cardiovascular (CV) disease, in the setting of concomitant disease, HTN accounts for a significant portion of the future risk of CV events.

The presence of both HTN and DM increases the incidence of coronary heart disease (CHD), cardiomyopathy, stroke, peripheral arterial disease, end stage renal disease, and microvascular complications relative to either HTN or DM alone.

In asymptomatic individuals, screening for subclinical CHD and risk stratifying patients with a coronary artery calcium scan is reasonable if the results will alter the subsequent clinical management of patients.

Clinical guidelines recommend a blood pressure (BP) < 130/80 mm Hg in diabetic hypertensive patients, but this target is not evidence based. As recent data have suggested the possibility of increased adverse effects with intensive lowering, we recommend a general BP goal <135/85 mm Hg with tailoring of targets to clinical circumstances.

The choice of medication should be tailored to the clinical scenario and is unique for each patient, but generally most will require two or more medications to achieve appropriate targets. In the diabetic hypertensive, ACE inhibitors and angiotensin receptor blockers are the cornerstone of treatment.

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References

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2. Chen G, McAlister FA, Walker RL, et al. Cardiovascular outcomes in Framingham participants with diabetes: the importance of blood pressure. Hypertension 2011;57:891–7.

This study emphasises the additional risk of HTN in diabetic patients.

3. Brown MJ, Castaigne A, de Leeuw PW, et al. Influence of diabetes and type of hypertension on response to antihypertensive treatment. Hypertension 2000;35:1038–42.

4. UK Prospective Diabetes Study Group. Tight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. UK Prospective Diabetes Study Group. BMJ 1998;317:703–13.

5. Detrano R, Guerci AD, Carr JJ, et al. Coronary calcium as a predictor of coronary events in four racial or ethnic groups. N EnglJ Med 2008;358:1336–45.

This study shows the importance of coronary calcium as a predictor of coronary events.

6. Shemesh J, Motro M, Morag-Koren N, et al. Relation of coronary artery calcium to cardiovascular risk in patients with combined diabetes mellitus and systemic hypertension. Am J Cardiol 2012;109:8446–50.

This study shows, with long term follow-up, that diabetic hypertensive patients without coronary calcium are at low cardiovascular risk.

7. Chobanian AV, Bakris GL, Black HR, 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;289:2560–72.

8. Cushman WC, Evans GW, Byington RP, et al. Effects of intensive blood-pressure control in type 2 diabetes mellitus. N Engl J Med 2010;362:1575–85.

This prospective study shows that in diabetic hypertensive patients, aggressive lowering of blood pressure does not reduce the risk of cardiovascular events and is associated with increased adverse events.

9. Cooper-DeHoff RM, Gong Y, Handberg EM, et al. Tight blood pressure control and cardiovascular outcomes among hypertensive patients with diabetes and coronary artery disease. JAMA 2010;304:61–8.

This retrospective analysis shows that in diabetic hypertensive patients with ischaemic heart disease, aggressive lowering of blood pressure is not associated with improved outcomes.

10. Bangalore S, Kumar S, Lobach I, et al. 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;123:2799–810, 9 p following 810.

This meta-analysis shows that in diabetic patients, lowering blood pressure to below 130/80 mm Hg reduces the rate of stroke but not of other cardiovascular events and is associated with adverse events. The authors demonstrate that in diabetic patients a target blood pressure of below 135/85 mm Hg may be acceptable.

11. 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. Heart Outcomes Prevention Evaluation Study Investigators. Lancet 2000;355:253–9.

12. Yusuf S, Teo KK, Pogue J, et al. Telmisartan, ramipril, or both in patients at high risk for vascular events. N Engl J Med 2008;358:1547–59.

This prospective study shows that the combination of ACE inhibitor and ARB does not reduce the primary end points more than the ACE inhibitor alone and is associated with greater adverse events.

13. Grossman E, Messerli FH. Are calcium antagonists beneficial in diabetic patients with hypertension? Am J Med 2004;116:44–9.

14. Jamerson K, Weber MA, Bakris GL, et al. Benazepril plus amlodipine or hydrochlorothiazide for hypertension in high-risk patients. N Engl J Med 2008;359:2417–28.

This prospective study shows that the combination of an ACE inhibitor with amlodipine is superior to the combination of ACE inhibitor and thiazide.

15. Bangalore S, Parkar S, Grossman E, et al. 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;100:1254–62.

16. Whelton PK, Barzilay J, Cushman WC, et al. Clinical outcomes in antihypertensive treatment of type 2 diabetes, impaired fasting glucose concentration, and normoglycemia: Antihypertensive and Lipid-Lowering Treatment to Prevent Heart Attack Trial (ALLHAT). Arch Intern Med 2005;165:1401–9.

17. Chapman N, Dobson J, Wilson S, et al. Effect of spironolactone on blood pressure in subjects with resistant hypertension. Hypertension 2007;49:839–45.

18. Mehdi UF, Adams-Huet B, Raskin P, et al. Addition of angiotensin receptor blockade or mineralocorticoid antagonism to maximal angiotensin-converting enzyme inhibition in diabetic nephropathy. J Am Soc Nephrol 2009;20:2641–50.

This study shows that the addition of spironolactone, but not losartan, to a regimen including maximal ACE inhibition affords greater renoprotection in diabetic nephropathy despite a similar effect on BP.

19. Weber MA, Bakris GL, Jamerson K, et al. Cardiovascular events during differing hypertension therapies in patients with diabetes. J Am Coll Cardiol 2010;56:77–85.

20. Esler MD, Krum H, Sobotka PA, et al. Renal sympathetic denervation in patients with treatment-resistant hypertension (the Symplicity HTN-2 trial): a randomised controlled trial. Lancet 2010;376:1903–9.

This prospective study on a small group of patients with resistant HTN shows the blood pressure lowering effect of renal nerve denervation.

Acknowledgments

This article is modified in part from the following publication: Grossman E, Messerli FH. Management of blood pressure in patients with diabetes. Am J of Hypertens 2011;24:863–75.

Provenance and peer review

Commissioned; internally peer reviewed.

Heart. 2013;99(8):577-585. © 2013  BMJ Publishing Group Ltd & British Cardiovascular Society